Vol. No. 1 Issue No. 1 OCTOBER 2020

CALICUT JOURNAL OF PEDIATRICS

Official Journal of IAP Kozhikode

Dear Senior Academicians & friends,

It is indeed exciting to be a State office bearer especially where IAP Kozhikode is a part. IAP has

given a lot to build up our profession, career as well as bonding between us. IAP Kozhikode is on

the rise at the Center because of the Community oriented programs, charity programs as well as

the excellent Academic sessions which were very useful to both PGs and practicing

pediatricians for the last couple of years.

This year again, Dr Ashraf and Dr Nihaz has brought out excellent community level activities,

Charity programs and the most sought after RAINBOW series, DOYENS series, PG Clubs and

Master classes since May 2020. I congratulate them and team Kozhikode especially

Shaji Thomas Sir, Lulu Madam, CKS Sir, Riyaz Sir, Krishnakumar Sir, Ajith Sir, Vijayakumar

Sir and all other seniors for guiding the vibrant and dynamic young leaders of Kozhikode. The

pandemic has put a hole in our fitness level and I am sure we will make it next year.

The annual journal of IAP Kozhikode with lots of papers, case discussions, research activities

and articles by the teachers and academicians will be very useful to all our members in the state

and country. Congratulations to team IAP Kozhikode especially the editors-Dr Girish S and

Dr Abdul Rauf and wish this journal will continue to enhance the knowledge of PGs and our

members in the coming years.

Dr M Narayanan

President, IAP Kerala.

Dr M Narayanan Dr Balachandar D Dr Krishna Mohan R

President Secretary Treasurer

Message

As President of IAP Kozhikode, it gives me immense pleasure that team IAP Kozhikode

is bringing out the first edition of Calicut Journal of Pediatrics. Wholeheartedly, I

appreciate the Editorial team for their immense effort in bringing out the Journal,

maintaining high standards.

Having our own scientific communication medium is no longer a mere illusion. Apart

from sharing the knowledge, the journal has a broader vision to familiarize the post

graduate students and practising pediatricians with the art of writing articles and to

provide them a platform to publish their work. I believe that the journal will serve its

purpose and will turn out to be a milestone in our unending journey towards pursuing

academic excellence.

Dr Ashraf T P

President, IAP Kozhikode

Dr Ashraf T P Dr Nihaz Naha Dr Rahul illaparambath

President Secretary Treasurer

Message

CALICUT JOURNAL OF PEDIATRICSEditorial Board

IAP KOZHIKODE

President: Dr Ashraf TP

Secretary: Dr Nihaz Naha

Treasurer: Dr Rahul Illaparambath

EDITOR

Dr Gireesh S

ASSOCIATE EDITOR

EDITORIAL BOARD

Dr Abdul Rauf KK

Dr Ashraf TP

Dr Nihaz Naha

Dr Ajay V

Dr Krishnamohan R

Dr Ranjith P

Dr Aslam

Dr Anand MR

Dr Shabeer MP

ADVISORY BOARD

Dr Shaji Thomas John

Dr Ajithkumar VT

Dr Vijayakumar M

Dr Preetha Remesh

Dr Geetha P

REVIEWER BOARD

Dr CK Sasidharan

Dr Suresh Kumar EK

Dr Jayakrishnan MP

Dr Geeta Govindraj

Dr Mohandas Nair

Dr Balraj G

EDITORIAL

Gireesh S, Abdul Rauf

REVIEW ARTICLE

1 Severe Combined Immune Deficiency – A ReviewGeeta Govindaraj, Shiny Padinjare Manakkad, Vinod Scaria

CASE REPORTS

1 Seronegative autoimmune encephalitis presenting as super refractory status

epilepticus - Experience from a tertiary care centerSmilu Mohanlal, Aleena Naushad, Satish Kumar K, Manjula Anand, Suresh Kumar EK,

Sachin Suresh Babu

2 BCGosis: an early clue to inborn errors of immunity- Report of two casesArunima Ashok, Abdul Rauf, Ajay Vijayan, CK Sasidharan, Neena Mampilly, Sudarshana J

3 C1q Nephropathy Presenting as Recurrent Gross HematuriaK. Sasidharan, Soja Vijayan, Mukesh C.V.

4 Achalasia cardia in infancy – a case reportV.K.Gopi, P.R.Babu, M.Narayanan, Shaji Thomas John, K.T. Muralikrishnan, T.P.Joseph

5 Incomplete Kawasaki Disease in Infants: A Diagnostic Challenge- Case SeriesAbdul Latheef, Sayyid Sabik , Yassar Andru, Renu P Kurup, Abdul Rauf

6 Anti NMDA receptor encephalitis in children - A Case seriesJayakrishnan MP, Krishnakumar P, Sabitha S, Rajesh TV

7 A Case of Prader-Willi Syndrome diagnosed in neonatal periodJitesh Pillai, Balraj G, Cherian NC, Anjali T

8 A Rare Case of CGD with Chromobacterium Violaceum AbscessAmrutha Visalakshi, Athulya EP, Geeta Govindaraj, Ajith Kumar VT

CLINICAL IMAGES

1 Frontal Encephalocele in a neonateShamnad M, Muralikrishnan KT

2 MERS (Mild encephalitis with reversible splenial lesion)Smilu Mohanlal, Aleena Naushad, Suresh Kumar EK, Rekha Narayanan

PG Quiz-

Vinodkumar MS

Calicut Journal of Pediatrics - 2020Volume 1

CONTENTS

1

3

11

14

18

21

25

28

33

36

39

40

41

Editorial

It gives us immense pleasure to bring out the first edition of Calicut Journal of Pediatrics with various

articles of high scientific quality. This edition includes a review article, 8 case reports (3 case series), a

couple of clinical images and a quiz section for post- graduate students

Inborn errors of immune deficiency (IEI), more commonly known as primary immune deficiency

disorders, are not as rare as they were once thought and are increasingly diagnosed in recent times

because of the improved awareness.[1] IEIs are genetic disorders with absent or abnormal functioning

immune system resulting in unusually severe, recurrent and persistent infections. Govindraj G et al has

written a comprehensive review on Severe Combined Immune Deficiency (SCID), which covers

different aspects of the disease. Ashok A et al describe a series of two patients, who presented with

disseminated infection caused by the BCG vaccine (BCGosis) and an underlying IEI was proved on

further workup. Visalakshi A et al report a case of Chromobacterium Violaceum Abscess, where an

underlying IEI in form of Chronic Granulomatous disease was detected.

Autoimmune encephalitis is a disease entity which is increasingly recognised in the pediatric age

group, commonest of which is anti-NMDAR encephalitis. Clinical suspicion is crucial for timely

diagnosis of autoimmune encephalitis and early and aggressive immunomodulation has shown to

improve outcomes.[2] Jayakrishnan MP et al describes a case series of three cases of proven anti-

NMDAR encephalitis, where early diagnosis and immunotherapy led to good neurological outcome.

Mohanlal S et al reports a case of seronegative autoimmune encephalitis where plasmapheresis was

also used as an treatment modality.

Diagnosis of Kawasaki in infants can be a diagnostic challenge as most of the times, they present with

incomplete Kawasaki disease. [3] Incomplete forms of KD in infants should not be assumed as milder

forms of KD as they do have predilection for CAA. Latheef A et al describes a series of four cases of

incomplete KD with variable presentation in whom, high index of suspicion and serial monitoring of

symptoms and investigations helped in reaching the diagnosis.

1

Tangye SG, Al-Herz W, Bousfiha A, et al.Human Inborn Errors of Immunity: 2019

Update on the Classification from theInternational Union of Immunological Societies

Expert Committee. J Clin Immunol 2020;40:24–64

Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Expert Review of

Neurotherapeutics systematic review Immune therapy in autoimmune encephalitis : a systematic

review. Expert Rev Neurother. 2015;15:1391–419.

Singh S, Agarwal S, Bhattad S, et al.Kawasaki disease in infants below 6 months: a clinical

conundrum? Int JRheum Dis. 2016;19:924-8.

Editor

Dr Gireesh SAssociate Editor

Dr Abdul Rauf KKBaby Memorial Hospital, KozhikodeGovt Medical College, Kozhikode

1.

2.

3.

Gopi VK et al describe a case of Achalasia cardia in infancy where laparoscopic Heller's cardiomyotomy

and anti-reflux procedure resulted in total relief of symptoms. Sasidharan K et al report a case of C1q

nephropathy diagnosed in a six-year-old boy, who presented with recurrent gross hematuria. Pillai J et al

describe another interesting case of Prader Willi syndrome diagnosed in a neonate with hypotonia and

feeding difficulty. Two clinical images by Shamnad M et al and Mohanlal S et al have also been included in

this edition. We extend sincere thanks and wish you all good reading.

2

Severe Combined Immune Deficiency - A Review

1 2 3Geeta Govindaraj , Shiny Padinjare Manakkad , Vinod Scaria

Review Article

Severe Combined Immune Deficiency is a pediatric emergency, which is almost

invariably fatal by the end of infancy without any intervention. Apart from the

mutation in the IL2RG gene which is X - linked, all other forms are of autosomal

recessive inheritance. Affected infants usually present with persistent thrush, recurrent

pneumonia, diarrhea and failure to thrive and may develop disseminated BCGiosis.

The classical hallmark is lymphopenia, except in leaky SCID, maternal T cell

engraftment and Omenn syndrome. CD3+ T cells are generally less than 300 / cu.mm.

Apart from the IL2RG gene, the other genetic defects involve RAG 1, RAG 2, JAK 3,

ADA and DCLRE1C genes. Hematopoietic stem cell transplant is curative, and gene

therapy has been successful in ADA - SCID and X - linked SCID. A genetic diagnosis

permits antenatal diagnosis by CVS or amniocentesis and genetic counseling.

Newborn screening programs for SCID are operational in the US and several other

countries, and are based on TREC screening, which is a measure of naive T cells. The

prognosis for SCID is best when diagnosed after newborn screening since the outcome

of HSCT is worse once infectious complications have set in.

Abstract:

Introduction:

Inborn errors of immunity, more commonly known

as primary immune deficiency disorders, are not as

rare as they were once thought and are increasingly

recognized as important causes of morbidity and

mortality in children [1]. They include defects in the

adaptive and innate arms of the immune system

and are mainly single gene defects. Infections that

are severe, frequent, recalcitrant or due to unusual

pathogens are the most common manifestations in

children. However, they also suffer due to

autoimmune, autoinflammatory and allergic

disorders and rarely, also develop malignancies [2].

By far, the most life threatening of these inborn

errors of immunity are a heterogenous group of

disorders collectively referred to as Severe

combined Immune Deficiency (SCID). The term

'combined' indicates that both cellular and humoral

immunity are impaired, and the term 'severe'

indicates the grave prognosis, with most children

succumbing to the illness before they are a year old

[3].

Professor, Department of Pediatrics, Government Medical College, Kozhikode FPID Regional Diagnostic Centre,

Government Medical College, Kozhikode Associate Professor, Department of Pathology, Government Medical College, Kozhikode Principal Scientist, CSIR Institute of Genomics & Integrative Biology (CSIR-IGIB) Delhi, India,Adjunct Professor, Academy

of Scientific and Innovative Research, New Delhi

1.

2.3.

Correspondence to: Dr Geeta Govindraj, Professor, Department of Pediatrics, Government Medical College, Kozhikode, email- geetakkumar@gmail.com

Calicut Journal of Pediatrics 2020;1:3-10

3

History

The story of David Vetter, who spent most of his life

in a plastic bubble to a bid to prevent death due to

overwhelming infection, remains etched in

memory. His short life served to create public

interest in inherited immune deficiencies, and his

death following complications of a bone marrow

transplant, galvanized global efforts to find a cure

for SCID. Due to its severity, curative therapies as

well as diagnostics of other primary immune

deficiencies have gained from experience with

SCID.

Prevalence

The prevalence of SCID varies between 1/46,000

and 1/80,000, being higher in consanguineous

populations. X- linked SCID is reported to occur

more frequently in non - consanguineous

populations, whereas autosomal recessively

inherited forms occur with increased frequency in

populations with high rates of consanguinity [4].

Pathogenesis

This syndrome is characterized by mutations in

various genes that have a role in T and B cell

development and function and often involves the

NK cells as well. Defective T cell function precludes

the development of normal humoral immunity

since antibody production by B cells is dependent

on T cell help. The NK cells, a distinct subset of

lymphocytes, may be normal in half the children

with SCID and confer a degree of protection

against bacterial and viral infections. In SCID with

normal NK cells, the affected genes are those that

encode for proteins involved in the development of

a diverse repertoire of receptors on T and B cells by

a process called V(D)J recombination [5]. This

diverse repertoire of T and B cell receptors is

necessary for recognition of a wide array of

pathogens.

The deficiency of adenosine deaminase results in

the accumulation of adenosine, deoxyadenosine

and their toxic metabolites, which inhibit DNA

s y n t h e s i s a s a r e s u l t o f d e p l e t i o n o f

deoxynucleotides and inhibition of certain other

enzymes [6]. The thymus has the highest

concentration of ADA, which explains the effects

being most severe on thymic development. In ADA

-SCID, the absolute lymphocyte counts are usually

very low due to the T-B-NK- phenotype.

Clinical Presentation

The major problem is enhanced susceptibility to a

host of pathogens including viruses, bacteria, fungi,

mycobacteria and opportunistic pathogens

including P.jiroveci. Persistent oral thrush beyond

the neonatal period is common, while the most

frequent and often lethal viral infection is

cytomegalovirus. The commonest presentations

thus include recurrent pneumonia, persistent

thrush, disseminated BCG disease, recurrent

diarrhea and failure to thrive. There is a paucity of

lymphoid tissue, including the tonsils and lymph

nodes. An erythematous scaly rash, generalized

lymphadenopathy and hepatosplenomegaly are

classic features of Omenn syndrome [7]. In SCID

due to ADA deficiency, bony anomalies including

chondrosternal dysplasia and deafness are often

observed. In NK+ SCID, presence of microcephaly

and radiation sensitivity may occur with or without

facial dysmorphism. Radiation sensitivity occurs

due to involvement of genes that are involved in

DNA repair, an example is Athabascan SCID, seen

in native Americans [8].

Laboratory diagnosis

Lymphopenia is a classical hallmark since the

numbers of T lymphocytes are usually low and

4

since they constitute about 70% of circulating

lymphocytes. The absolute lymphocyte count

(ALC) is usually < 2500 / cu.mm in typical SCID.

The numbers of B and NK cells may be normal or

low and hence, based on analysis of lymphocyte

subsets by flow cytometry, SCID may be classified

as T-B-NK-, T-B+NK+, T-B+NK- or T-B- NK+. A

lateral chest X Ray usually reveals an absent

thymus, although it is prudent to note that absence

of the thymus gland can also occur in other

conditions like severe malnutrition and fulminant

infections.

Leaky SCID

The absolute lymphocyte count may be normal in

leaky SCID, and sometimes, may be elevated due to

engraftment of maternal T cells or due to

lymphoproliferation as in Omenn syndrome.

Hence although lymphopenia is often the first

indicator of SCID, this is not invariable and normal

or elevated absolute lymphocyte counts may

confound the diagnosis. Absence of naïve T cells

(CD45 RA+) is an important pointer to the

diagnosis and this forms the basis of currently

practiced newborn screening tests.

In SCID, the CD3 count which denotes the number

of T cells is usually < 300/ cu.mm and may range

from 300-1500/cu.mm in leaky SCID. Maternally

transferred IgG levels preclude use of IgG as a

diagnostic marker in early infancy. IgA, IgM and

IgE levels are usually low, though IgE levels can be

markedly elevated in Omenn syndrome [9]

Definitive diagnosis.

Child < 2 years old with

(a) Absolute CD3 T cell count of < 300/mm3

OR

(b) Absolute CD3 T cell count of > 300/mm3 with absent naïve T cells+Any one of the following-

a. Deleterious mutations in any of the genes known to cause SCID

b. ADA activity < 2% of control / mutations in both alleles of the ADA gene.c. Maternal T cell engraftment

Probable diagnosis*

Male or female patient < 2 years of age with

(a) < 20% CD3+ T cells, an absolute lymphocyte count of less than 3000/mm3, and proliferative responses to mitogens less than 10% of control or

(b) Presence of circulating maternal lymphocytesThe absence of T cell proliferative responses to mitogen stimulation are also important in arriving at a diagnosis, but are not usually done, except in research settings [10].

Genomics for molecular diagnosis

Genomic approaches are increasingly being used

for the molecular diagnosis of PIDs. The

approaches include single gene sequencing, gene-

panel sequencing, whole exome sequencing and

whole genome sequencing [11]. Apart from these

approaches, chromosomal microarrays and array

CGH are also being employed for understanding

chromosomal deletions/duplications. The

increasing popularity of genomic approaches also

stem from the fact that molecular identification of

the genetic defect could enable the family to opt for

carrier screening as well as pre-natal counselling

and testing [12]. Additionally, genetic approaches

could confirm the diagnosis if the clinical diagnosis

and workups are inconclusive. It should be kept in

mind that each of the methodologies have its

advantages and limitations, and choosing the right

approach is always a tradeoff between the

5

availability of tests, costs involved and the

resolutions for capturing individual variants.

It is best to classify SCID based on the molecular

genetic defect since it determines the clinical

spectrum and outcome. The most common types

are the X - linked IL2RG mutation in the common

gamma chain (CD 132) and the autosomal recessive

RAG 1, RAG 2 (recombination - activating gene)

deficiencies and ADA deficiency [13, 14]. Others

include mutations in the interleukin 7 receptor

alpha chain ( IL7R gene), Janus kinase 3 (JAK 3

gene) and DNA cross-link repair protein 1C gene or

Artemis (DCLRE1C).

Differential diagnosis

It is important to rule out secondary causes of

immune deficiency like HIV infection up front [15].

Other causes of failure to thrive also need to be

excluded.Severe malnutrition and other combined

immune deficiency disorders also need to be ruled

out. Intestinal lymphangiectasia and hereditary

folate malabsorption are also diagnostic

considerations [16]. Lymphopenia is usual in

intestinal lymphangiectasia and is accompanied by

hypoalbuminemia, while severe anemia is usual in

folate malabsorption. In Omenn syndrome, the

erythematous skin rash and organomegaly make a

diagnosis of Langerhan's cell histiocytosis a close

differential and skin biopsy is often helpful. In

addition, Omenn syndrome is usually associated

with marked eosinophilia and elevated IgE levels.

DiGeorge syndrome may occur with subtle or

absent phenotypic features and is one of the

commonest causes for lymphopenia, which can

also occur in CHARGE syndrome as a result of

thymic hypoplasia [17]. Other combined immune

deficiency disorders that are included in the

differential diagnosis include the Hyper IgM

syndrome, Wiskott-Aldrich syndrome, calcium

channel deficiencies, NEMO deficiency and purine

nucleoside phosphorylase deficiency. Next

generation sequencing is often necessary to make

the diagnosis.

Management

Reverse isolation is of paramount importance for

the prevention of life - threatening infections and

the decision to keep the child in the hospital or at

home needs to be individualized depending on the

socioeconomic circumstances and compliance of

the family with advice regarding isolation.

Prevention of infections

Blood products need to be irradiated and screened

for CMV infection before being transfused in order

to prevent graft versus host disease and CMV

infection. Leukocyte - poor blood products are

preferred. Prophylaxis with cotrimoxazole,

voriconazole and acyclovir are required along with

replacement of immunoglobulins with IVIG every

four weeks.

Avoidance of live vaccines is important, inadve-

rtent administration of BCG vaccine results in

disseminated BCG disease. Oral polio vaccine and

rotavirus vaccines are also strictly contra-indicated.

This is one of the reasons why an early diagnosis

could be life – saving, children usually receive BCG

and oral polio vaccine at birth before a diagnosis is

made. Inadvertent immunization with other live

vaccines like MMR and varicella may also result in

life – threatening infection with the vaccine virus.

Household contacts should receive the killed

influenza vaccine. Revaccination is necessary after

an HSCT and is started after 6 months with the

killed influenza vaccine. After an HSCT, live viral

vaccines should be given only after a year of

stopping all immunosuppressants and after there is

no evidence of active graft versus host disease.

6

HSCT

HSCT was the first curative modality of treatment

to be tried and remains the best option when there is

a matched related or unrelated donor [19].

Outcomes mainly depend on the age at diagnosis

and the presence of infection related complications

[20], [21]. Long term complications include

neurocognitive and behavioural abnormalities. It is

being increasingly recognized that HSCT for SCID

requires genotype – specific approaches [22, 23].

Delayed diagnosis and referral, poor diagnostic

facilities, paucity of specialized centres offering

HSCT and the high cost are the main hindrances in

the developing world [24, 25].

Enzyme replacement therapy

Pegylated bovine ADA has been used as bridge

therapy to address the metabolic derangement in

ADA SCID and prevents organ damage before

definitive treatment by HSCT or gene therapy [26,

27]. Pegylation increases the biological half-life and

prevents the development of antibodies [28].

Gene therapy

Gene therapy has been widely slated as the ultimate

cure for SCID. This is largely so due to the fact that

this obviates the requirement for a donor for HSCT.

In fact gene therapy and genome editing for SCID

has been attempted in research settings, and is yet to

be approved for widespread clinical use. The

limitation of widespread application of gene

therapy has been the specificity of the gene

insertion/editing. With more understanding of the

molecular mechanism of gene editors, it is hopeful

that at least some of the approaches would be

available for limited clinical use within a decade.This modality of treatment is licensed in Europe

and available in clinical trials in the US, mainly for

ADA - SCID and X - linked SCID (common

gamma chain deficiency), especially in children

who do not have a matched sibling donor or a

matched unrelated donor. Genetically engineered

viruses in which the viral genome is replaced with

the gene to be corrected are integrated into the

chromosomal DNA of the hematopoietic stem

cells. Gene therapy has the potential to become

standard therapy for some primary immune

deficiency disorders in future [29].In ADA SCID, pegylated bovine ADA has been

used for immune reconstitution prior to gene

therapy. Although the retroviral vectors used

init ial ly were beset with the problem of

leukemogenesis probably due to activation of the

proto oncogene, currently used lentiviral vectors

have proved to be safe. A non - myeloablative pre -

conditioning regimen with busulfan prior to

infusion of the autologous genetically modified

stem cells has been found to be successful.

Prognosis

The prognosis is dismal unless curative options like

HSCT or gene therapy have been performed and

without these, survival beyond infancy is unusual,

except in leaky SCID which can present later in

childhood. Outcomes of HSCT are best under 3.5

months of age and survival rates of 90 percent have

been reported [30]. Excellent outcomes are also

reported following HSCT in the neonatal period

[31].

Newborn screening

Newborn screening for primary immunodeficiency

disorders is widely used in many developed

countries and increasingly being shown in many

developing countries to be an effective approach for

early diagnosis of primary immunodeficiency

disorders [16]. The newborn screening for PIDs rely

on the TREC/KREC assays which quantitate the

circular DNA fragments which are surrogates for

f u n c t i o n a l T - c e l l a n d B - c e l l r e c e p t o r

recombination.

Most infants with SCID are healthy at birth and

7

start developing infectious complications as

maternally transmitted IgG levels wane over the

first few months of life. A successful HSCT most

often hinges on the absence of infectious

complications and has best outcomes under 3.5

months of age.

Newborn screening is hence the only way to

identify affected individuals and start work up for

an HSCT. TRECs are circular fragments of DNA

produced in the thymus during T cell maturation

and indicate the number of naive T cells. Low

TRECs indicate either reduced production or

increased loss of lymphocytes in case of congenital

heart disease or hydrops.

Estimation of TRECs is usually performed using an

qPCR - based assay and is cost effective, apart from

working on dried blood spots collected for other

metabolic assays. TRECs may be normal if the

defect occurs after VDJ recombination as in ZAP 70

deficiency or MHC class 2 deficiency and are also

low in other syndromes associated with

lymphopenia including DiGeorge syndrome and

CHARGE syndrome.

Antenatal and prenatal diagnosis

The identification of a Pathogenic mutation in the

index member in a family would provide a unique

opportunity to enable early genetic diagnosis

during the prenatal or antenatal period. An early

diagnosis would enable the family to plan for

definitive approaches like HSCT [32].

It is possible to undertake prenatal diagnosis either

by CVS between 10 and 13 weeks or amniocentesis

by 15 weeks of gestation [33]. Pre - implantation

diagnosis is also possible with in vitro fertilization,

although it is prohibitively expensive. It is

recommended to perform testing postnatally,

although prenatal diagnosis was not suggestive. The

inherent risks including fetal loss and limb

reduction defects involved in doing CVS and

amniocentesis need to be explained prior to the

procedure. Genetic counseling by trained personnel

is essential for the family to make informed choices.

8

Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classif ication from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2020.

Bousfiha A, Jeddane L, Picard C, et al. The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 2018; 38:129.

Speckmann C, Doerken S, Aiuti A, et al. A prospective study on the natural history of p a t i e n t s w i t h p r o f o u n d c o m b i n e d immunodeficiency: An interim analysis. J Allergy Clin Immunol 2017; 139:1302.

Michos A, Tzanoudaki M, Villa A, Giliani S, Chrousos G, Kanariou M. Severe combined immunodeficiency in Greek children over a 20-year period: rarity of c-chain deficiency (X-Linked) type. J Clin Immunol. 2011; 31:778–83.

Fugmann SD, Lee AI, Shockett PE, et al. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu Rev Immunol 2000; 18:495.

Hirschhorn R. Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res 1993; 33:S35.

Ozcan E, Notarangelo LD, Geha RS. Primary immune deficiencies with aberrant IgE production. J Allergy Clin Immunol 2008; 122:1054.

Nahas SA, Gatti RA. DNA double strand break repair defects, primary immunodeficiency disorders, and 'radiosensitivity'. Curr Opin Allergy Clin Immunol 2009; 9:510.

Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for Severe Combined Immunodeficiency Disease (SCID), leaky SCID, and omenn syndrome: the primary immune deficiency treatment consortium experience. J Allergy Clin Immunol. 2014: 133:1092–8.

Picard C, Al-Herz W, Bousfiha A, et al. Primary

immunodeficiency diseases: An update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol 2015; 35:696.

Fazlollahi MR, Pourpak Z, Hamidieh AA, Movahedi M, Houshmand M, Badalzadeh M, et al. Clinical, laboratory and molecular findings of 6 3 p a t i e n t s w i t h s e v e r e c o m b i n e d immunodeficiency: a decade's experience. J Inves t A l l e rgo l C l in Immunol . 2017 ; 27:299–304.

Abolhassani H, Chou J, Bainter W, Platt CD, Tavassoli M, Momen T, et al. . Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. J Allergy Clin Immunol. 2018; 141:1450–8.

Notarangelo LD, Kim MS, Walter JE, Lee YN. Human RAG mutations: biochemistry and clinical implications. Nat Rev Immunol. 2016; 16:234–46.

Govindaraj G, Shamsudheen V, Jayarajan R et al. Whole exome sequencing identifies variation c.2308G>A p.E770K in RAG1 associated with B - T - N K + s e v e r e c o m b i n e d immunodeficiency.F1000Research. 5. 2532. 10.

Hanson IC, Shearer WT. Ruling out HIV infection when testing for severe combined immunodeficiency and other T-cell deficiencies. J Allergy Clin Immunol 2012; 129:875.

Borzutzky A, Crompton B, Bergmann AK, et al. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter. Clin Immunol 2009; 133:287.

Amatuni GS, Currier RJ, Church JA, et al. Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017. Pediatrics 2019; 143.

Kelty WJ, Beatty SA, Wu S, et al. The role of breast-feeding in cytomegalovirus transmission and hematopoietic stem cell transplant outcomes i n i n f a n t s w i t h s e v e r e c o m b i n e d immunodeficiency. J Allergy Clin Immunol

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

References

9

Pract 2019; 7:2863.

Buckley RH. Transplantation of hematopoietic s tem cel ls in human severe combined immunodeficiency: longterm outcomes. Immunol Res 2011; 49:25.

Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 2014; 371:434.

D vo r a k C C, C owa n M J, L o g a n B R , Notarangelo LD, Griffith LM, Puck JM, et al. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. J Clin Immunol.2013: 33:1156–64.

Heimall J, Logan BR, Cowan MJ, et al. Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study. Blood 2017; 130:2718.

Haddad E, Logan BR, Griffith LM, et al. SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood 2018; 132:1737.

Shah CA, Karanwal A, Desai M, Pandya M, Shah R, Shah R. Hematopoietic stem-cell transplantation in the developing world: experience from a center in Western India. J Oncol. 2015;710543.

Uppuluri R, Jayaraman D, Sivasankaran M, Patel S, Swaminathan VV, Vaidhyanathan L, et al. Hematopoetic stem cell transplantation for pr imar y immunodef ic iency d isorders : experience from a tertiary referral center in India. Indian Pediatr.2018; 55:661–4.

Kohn DB, Hershfield MS, Puck JM, et al. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol 2019; 143:852.

Polmar SH, Stern RC, Schwartz AL, et al. Enzyme replacement therapy for adenosine deaminase deficiency and severe combined immunodeficiency. N Engl J Med 1976; 295:1337.

Lainka E, Hershfield MS, Santisteban I, et al. polyethylene glycol-conjugated adenosine deaminase (ADA) therapy provides temporary immune reconstitution to a child with delayed-onset ADA deficiency. Clin Diagn Lab Immunol 2005; 12:861.

Kuo CY, Kohn DB. Gene Therapy for the Treatment of Primary Immune Deficiencies. Curr Allergy Asthma Rep 2016; 16:39.

Railey MD, Lokhnygina Y, Buckley RH. Long-term clinical outcome of patients with severe combined immunodeficiency who received related donor bone marrow transplants without pretransplant chemotherapy or post-transplant GVHD prophylaxis. J Pediatr 2009; 155:834.

Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 2002; 99:872.

Luk ADW, Lee PP, Mao H, Chan KW, Chen XY, Chen TX, et al. Family history of early infant death correlates with earlier age at diagnosis but not shorter time to diagnosis for severe c o m b i n e d i m m u n o d e f i c i e n c y. F r o n t Immunol.2017: 8:808

Tabori U, Mark Z, Amariglio N, et al. Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome. Clin Genet 2004; 65:322.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

10

Seronegative autoimmune encephalitis presenting as super refractory status epilepticus - Experience from a tertiary care center

1 2 2 2 2 1Smilu Mohanlal , Aleena Naushad , Satish Kumar K , Manjula Anand , Suresh Kumar E K , Sachin Suresh Babu

A 5-year-old boy presented with super refractory status epilepticus. Though the

infective and autoimmune panel were negative, aggressive immunomodulation

was given considering the possibility of seronegative autoimmune encephalitis.

Child showed dramatic improvement and is on regular follow up. The case report

highlights the importance of early suspicion and aggressive management of

children suspected with autoimmune encephalitis.

Keywords: Seronegative, autoimmune encephalitis, immunomodulation, super

refractory status epilepticus

Abstract:

Introduction:

Autoimmune encephalitis is a commonly

recognized etiology of acute onset neuro

psychiatric manifestations in pediatric age group.

The clinical manifestations include seizures, sleep

and behavioral disturbances, movement disorders,

mood and cognitive impairment. Both the

diagnosis and treatment of these children are

challenging especially in seronegative autoimmune

encephalitis as there are sparse data on the same.[1]

We report our experience in the management of a 5-

year-old boy with probable autoimmune

encephalitis, who presented with super refractory

status epilepticus.

Case Description:

A 5-year-old boy, developmentally normal

presented with history of fever since past 6 days,

seizures and altered sensorium since past 2 days.

seizure semiology was of a vacant stare with

impaired awareness and lip-smacking lasting for

few seconds, there were 10-15 episodes/ day. He

was admitted elsewhere and was evaluated with

MRI brain and CSF study that were normal and he

was treated with Inj. Levetiracetam, Inj.

Fosphenytoin, Inj. Phenobarbitone.As the seizures

remained refractory, he was referred to our center.

He was born to non-consanguineous parents, with

no perinatal issues and no family history of

epilepsy/ febrile seizures. On first day of admission,

he continued to have seizures, EEG showed

Periodic lateralized epileptiform discharges on the

left cerebral hemisphere and during seizures there

was ictal rhythm confined to the left hemisphere.

The differentials considered were Viral encephalitis

(Herpes simplex virus 1 and 2), Focal cortical

dysplasia, autoimmune encephalitis and CNS

Vasculitis. The child was evaluated with complete

hemogram, serum electrolytes, liver and renal

function tests that were normal. CSF study was

done which showed sugar- 55mg%, protein-

20mg%, no cells and CSF viral panel negative. In

view of presumed autoimmune etiology, he was

started on pulse dose methylprednisolone

(30mg/kg/day) for 5 days. In view of continuous

1- Department of Neurology and pediatric Neurosciences, Aster MIMS, Kozhikode

2. Department of Pediatrics, Aster MIMS, Kozhikode

Correspondence to: Dr Smilu Mohanlal, Pediatric Neurologist, Aster MIMS Hospital, Calicut

Calicut Journal of Pediatrics 2020;1:11-13

11

(MRI Brain Figure 1a &b (top row) showing diffusion restriction in the mesial temporal region, Figure 1c showing bulky hippocampal and Para hippocampal gyrus with T2 flair hyperintensities)

(Figure 2: The circled area in the PET CT Brain showing left mesial temporal hypermetabolism)

seizures on day of admission 2, child was started on

Midazolam infusion (3mcg/ kg/ min) and was

intubated. Child remained seizure free clinically

after starting midazolam but the ictal rhythms

persisted on 24 hr EEG monitoring even after

titrating midazolam up to 24mcg/kg/min on day 3

and 4 of admission, hence Ketamine was started at

10mcg/ kg/ min. CSF and serum autoimmune

panel( NMDA, AMPA ½, CASPR2, DPPX, LGI1,

GABARB1/B2) were negative . As the ictal

rhythms persisted in the EEG, 5 cycles of

plasmapheresis were done and ketamine was

titrated up to 35mcg/kg/min. Along with

levetiracetam (30mg/kg/day), fosphenytoin (8

mg/kg/day), phenobarbitone(5mg/kg/day), he

was also started on zonisamide( 5 mg/ kg/day) and

perampanel. He was also initiated on ketogenic

diet. His ESR – 10 mm/hr and Anti TPO antibodies

were negative. On day 6 of admission the ictal

rhythms reduced to 1/ day. On day 9 of admission

the electrographic seizures subsided. Repeat MRI

brain showed Left bulky hippocampus & Para

hippocampal gyrus with T2 FLAIR hyperintensity

& focal areas of diffusion restriction (Figure 1).

Gradually ketamine & midazolam infusion was

tapered & stopped & child was extubated on D11 of

a d m i s s i o n . W h o l e b o d y P E T s h o w e d

hypermetabolism in left temporal region along

with areas of hypometabolism in frontal and

parietal regions( Figure 2) .On Day 13 of admission

the EEG continued to show PLEDS and hence he

was started on Inj. Rituximab ( 3 cycles were given

one week apart with CD19 levels monitoring)and T.

mycophenolate (600mg/ m2 PO twice daily). On

day 21 of admission he was walking with one hand

support and was able to speak phrases, EEG

showed diffuse slowing. He was discharged on T.

Mycophenolate & tapering dose of oral steroids. On

follow up after 1 month, EEG was normal and child

was able to speak f luently with no other

neurological issues.

12

Discussion:

Autoimmune encephalitis are increasingly

recognised in the pediatric age group. The antibody

positivity in autoimmune encephalitis cases are

only 8.6%.[2] Consensus guidelines for pediatric

specific seronegative autoimmune encephalitis are

not available. The need to start the therapy, the role

of second line immunomodulation are challenging

in seronegative cases. Sahoo B et al has reported

super refractory status epilepticus as a presenting

feature in seronegative autoimmune encephalitis

which is s imilar to ours.[3] Init ial MRI

Brain can be normal and repeat MRI brain can

show signal changes in bilateral temporal region.

CSF may show lymphocytic pleocytosis, mildly

increased protein with oligoclonal bands. CSF

autoimmune panel are done by immunoflorescence

testing.Though our patient had antibody negativity

but he responded well to immunotherapy, similar

response was observed by Sahoo et al in all his cases

.[3] The possible explanation could be due to low

level of antibodies and presence of T cell dominant

autoimmune encephalitis.[3] Early clinical

suspicion and start of immunotherapy prevents

irreversible brain damage. Here in our case as the

CSF analysis and CSF Viral panel were negative, we

immediately started the child on pulse dose

steroids.

As the seizures continued, we started plasmap-

heresis (it is cost effective when compared to

IVIG).Even with these first line therapies, child

continued to have ictal rhythms in the EEG with

altered sensorium that necessitated us to start

Rituximab (second line immunomodulation).

Since steroids cannot be continued for longer

periods, child was started on Mycophenolate

mofetil. There are studies that report that

early and aggressive immunomodulation not only

has better outcome but also reduces the relapses.[4]

The early recovery in our patient with minimal

residual deficits is likely due to the aggressive

immunomodulation that was followed. However a

long term follow up is required to assess the further

outcome.

Conclusion:

Clinical suspicion is crucial in the diagnosis of

ch i ldren wi th seronegat ive auto immune

encephalitis. Early and aggressive immunom-

odulation has better outcome. Therapy options

should be individualized .

References:

Bruijstens AL, Bastiaansen AEM, Sonderen A Van, Schreurs MWJ, Smitt PAES, Hintzen RQ, et al. Pediatric autoimmune encephalitis. 2020;0:1–11.

Khair AM. Utility of Plasmapheresis in Autoimmune-Mediated Encephalopathy in Children : Potentials and Challenges. 2016;2016.

Sahoo B, Jain MK, Mishra R, Patnaik S. Dilemmas and Challenges in Treating Seronegative Autoimmune Encephalitis in Indian Children. 2018;61:875–8.

Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Expert Review of Neurotherapeutics systematic review Immune therapy in autoimmune encephalitis� : a systematic review. Expert Rev Neurother. 2015;15(12):1391–419. Available from: http://dx.doi.org/10.1586/14737175.2015.1115720

1.

2.

3.

4.

13

"BCGosis: an early clue to inborn errors of immunity- Report oftwo cases"

1 1 1 1 2 3Authors: Arunima Ashok , Abdul Rauf , Ajay Vijayan , CK Sasidharan , Neena Mampilly , Sudarshana J

1- Dept of Pediatrics, Baby Memorial Hospital, Calicut, 2- Dept of Pathology, Baby Memorial Hospital, Calicut

3- Dept of Microbiology, Baby Memorial Hospital, Calicut

Correspondence to: Dr CK Sasidharan, Senior consultant, Dept of Pediatrics, Baby Memorial Hospital, Calicut, email-cksasidharan@gmail.com

Inborn errors of immunity (IEI) are genetic disorders with absent or abnormal

functioning immune system resulting in unusually severe, recurrent and

persistent infections. A disseminated infection caused by the BCG vaccine

(BCGosis) often occurs in babies with IEI and it can be the first clinical

manifestation of their immune deficiency. Here we report two infants who

presented with BCGosis and were diagnosed with IEI on further workup. First

infant had Severe Combined Immuno Deficiency (T- B+ NK-), while the second

had Chronic Granulomatous Disease. BCGosis can serve as an early clue to

underlying IEI and warrants workup.

KEYWORDS: Inborn error of immunity, Primary Immunodeficiency,

BCGosis, Severe Combined Immuno Deficiency

Abstract:

Introduction:

Bacillus Calmette-Guérin (BCG) vaccine is

recommended for newborns at birth in some

countries including India. Though it is well known

that BCG can cause some local reactions, the

systemic spread of BCG is rare.[– ] BCG

complications can range from a regional-localized

disease(BCGitis) to a more severe, life-threatening

disseminated form (BCGosis).[2,3] Disseminated

infection by BCG occur usually in children with

underlying immune deficiency. Inborn errors of

immunity (IEI), previously called primary

immunodeficiency disorders [PIDs]) refer to a

group of heterogenous genetic disorders

characterised by poor or absent function of one or

more components of the immune system. Children

with these diseases tend to have infections with

unusual organisms, or unusually severe and

recurrent infections with common organisms.[4]

Here, authors report two cases which presented

with BCGosis and an underlying IEI was proved on

further workup.

Calicut Journal of Pediatrics 2020;1:14-17

14

Figure 1- Reulcerated BCG scar Figure 2- Abdominal distension with rashes

Figure 3- Chest X ray showing absent thymic shadow

Case Description 1:

A 6 month old boy, second born of a non-

consanguineous marriage with no significant

family history presented with BCG scar ulceration 4

weeks back ; developed rashes for 3 weeks, fever and

cough for 10 days. Infant had tachycardia and

tachypnea on examination, with pallor, maculo-

papular rashes (over trunk and limbs) and BCG scar

ulceration (Fig 1). Abdomen was grossly distended

(Fig 2) and massive hepatosplenomegaly was

present.

P r e l i m i n a r y Investigations revealed

anaemia with lymphopenia and thrombocytopenia

(Hemoglobin : 7 g/dl, Total count : 11,000/�L

(86%N,10%L) and platelets : 96,000/mm3).

Inflammatory parameters were high (CRP:

175mg/L, Procalcitonin: 202 ng/ml). His liver and

renal function tests were within normal limits.

Chest X ray revealed absence of thymic shadow. His

CT abdomen showed expansile lytic lesions in left

pubis and proximal femur, multiple bulky

mesenteric and retroperitoneal lymph-nodes with

massive hepatosplenomegaly and dif fuse

infiltrative lesions in the spleen with ascites.

Differential diagnosis of sepsis was considered and

proceeded but blood culture was sterile. Gastric

Aspirate-was positive for Mycobacterium

Tuberculosis (MTB) by Truenat PCR. Workup for

Hemophagocytic lymphohistiocytosis (HLH) was

done in view of the bicytopenia and it showed

hypofibrinogenemia (Ferritin-2359ng/ml),

h y p o f i b r i n o g e n e m i a ( 8 5 m g / d l ) a n d

hypertriglyceridemia (279 mg/dl ). Bone marrow

biopsy showed granulomas with surrounding

eosinophils and CD1a immunohistochemistry was

negative (done to rule out possibility of Langherhan

cell histiocytoisis considered in view of the lytic

lesions in bones and cytopenia). Bone marrow also

showed AFB positivity. Skin biopsy from the

papular rash showed foamy aggregates of

macrophages and AFB. Child did not have any

contact of TB and HIV serology was negative. The

absence of TB contact and presence of BCG scar

ulceration raised the suspicion that AFB could be

Mycobacterium

by AFB culture). Possibility of underlying Severe

Combined Immunodeficiency Disorder (SCID)

was suspected in view of the lymphopenia and

absent thymic shadow in chest X ray. Lymphocyte

subset analysis was suggestive of (T- B+ NK-) type

of SCID (Absolute CD 3-/ CD (16+56):

0.83% (3-15%),CD 19 (B Cell) : 87.5% (14%- 37%),

Cd3 (T Cell) : 9.2 % (49-76%).Child was

managed with broad spectrum antibiotics, IVIg and

methylprednisolone pulse for HLH,supportive

treatment including mechanical ventilation and

blood products. Antituberculosis therapy for the

disseminated BCGiosis was also started. His

condition deteriorated and he succumbed on day 5

due to septic shock. His final diagnosis was Severe

Combined ImmunoDeficiency {SCID} (T- B+

NK-) wi th Disseminated BCGosis wi th

Hemophagocytic Lympho Histiocytosis (HLH).

15

Case Description 2:

A 5month old male presented as acute febrile illness

with refractory status epilepticus.On examination,

he had an ulceration of BCG scar (Fig 4) and

significant lymphadenopathy (left axillary and right

cervical lymph nodes). Abdomen was distended

with hepatosplenomegaly.

Preliminary investigations showed anaemia with

leucocytosis (Hemoglobin:7.1 g/dl, Total WBC

count - 27100/microL (P58 % L31 %)and elevated

inflammatory markers (CRP :120.65 mg/L,

Procalcitonin: >200 ng/ml). Ultrasound abdomen

revealed hepatosplenomegaly. Cerebrospinal fluid

(CSF) study showed elevated CSF proteins- 128.7

mg/dl, normal glucose 104 mg/dl, WBC 5

cells/mm3 (100% lymphocytes). CSF-PCR was

positive for Gram negative bacteria. He was

mechanically ventilated for 48 hours and

appropriate antibiotics and antiepileptics were

given. Child was extubated after 2 days and he was

neurologically normal by day 7. He developed

pneumonia on day 7. His lymph node FNAC - PCR

was positive for Mycobacterium. Occurrence of

gram negative meningitis, pneumonia and presence

of BCG scar ulceration prompted to test for IEI.

Immunoglobulin profile was normal apart from

elevated IgG. Lymphocyte subset flow cytometry

was normal. Nitroblue Tetrazolium (NBT) dye

reduction was found absent and Dihydro

rhodamine (DHR) neutrophil respiratory burst

assay was markedly reduced, suggesting Chronic

Granulomatous disease. He was treated with broad

spectrum antibiotics including anti-staphylococcal,

anti-tubercular drug and antifungal therapy. Child

improved gradually and he was discharged on ATT,

voriconazole and cotrimoxazole prophylaxis. His

clinical exome suggested mutation of CYBB gene.

He is presently doing well on follow up and planned

for hematopoietic stem cell transplant.

DISCUSSION:

A high index of suspicion regarding the possibility

of IEI should be kept in every infant who present

with disseminated BCG infection (BCGiosis).[5]

BCGiosis is most commonly reported in IEI like

SCID, CGD, Mendelian susceptibil i ty to

Mycobacterial Diseases (MSMD). SCID is a type

of primary combined antibody and cellular

immunodeficiency and is a true pediatric

emergency. The usual clinical features are persistent

diarrhoea, pneumonia, otitis media, sepsis, and

cutaneous infections. Definitive treatment is HLA

identical/ haploidentical HSCT.Patients with CGD

(inherited as X linked recessive or autosomal

recessive) have defective intracellular killing of

phagocytosed organisms due to a defective

oxidative burst in the neutrophils. Catalase positive

organisms like Staphylococcus aureus and

Aspergillus species are the most common

organisms reported to cause infections.Children

with CGD also need HSCT for definitive cure.

There is a need for development and ensuring the

accessibility of more advanced facilities for

diagnosis and management of IEI in India and

population and hospital based registries needs to be

established.[6]Another interesting point to be noted

from the first case is that Truenat PCR can detect

any species among Mycobacterium tuberculosis

complex, which included Mycobacterium Bovis

too.

16

Conclusion

BCGosis can be the first clinical manifestation of

inborn error of immunity (IEI) and hence warrants

workup for the same.

REFERANCES:

1.Sellami K, Amouri M, Kmiha S,met al. Adverse

Reactions Due to the Bacillus Calmette-Guerin

Vaccine: Twenty Tunisian Cases. Indian J

Dermatol.2018; 63: 62–65

2.Kourime M, Akpalu ENK, Ouair H, et al.

BCGitis/BCGosis in children: Diagnosis,

classification and exploration. Arch Pediatr.

2016;23:754–9.

3.Norouzi S, Aghamohammadi A, Mamishi S,

Rosenzweig SD, Rezae N. Bacillus Calmette-

Guérin (BCG) complications associated with

primary immunodeficiency diseases. J

Infect.2012;64:543–54.

4 . Re u s t C E . E va l u a t i o n o f P r i m a r y

Immunodeficiency Disease in Children. Am

Fam Physician. 2013; 87:773–8.

5.Mandal A, Singh A, Kaur Sahi P, Rishi B.

Disseminated BCG Disease in an Infant with

Severe Combined Immunodeficiency. J Clin

Infect Dis Pract.2016;01.

6.Madkaikar M, Mishra A, Desai M, et al

C o m p r e h e n s i v e R e p o r t o f P r i m a r y

Immunodeficiency Disorders from a Tertiary

Care Center in India. J Clin Immunol

2013;33:507-12.

17

C1q Nephropathy Presenting as Recurrent Gross Hematuria

K. Sasidharan, Soja Vijayan, Mukesh C.V. Department of Pediatrics, Malabar Medical College Hospital and Research Centre,

Calicut, Kerala, India.

A six-year-old boy presented with recurrent gross hematuria. He had normal renal

function tests, blood pressure and urine output. He had proteinuria, elevated

cholesterol, normal C3 and C4, and ANA was negative. Light microscopy and

immunofluorescence study of his renal biopsy specimen showed features of C1q

nephropathy.

Key words: C1q nephropathy, recurrent gross hematuria, proteinuria.

Abstract:

Introduction:

Some familiar causes of recurrent glomerular

h e m a t u r i a a r e I g A n e p h r o p a t h y, t h i n

basement membrane disease, Alport syndrome,

Goodpasture disease and benign familial

hematuria.[1] We present the case of a six year old

boy with recurrent gross hematuria and proteinuria

without hypertension and normal renal function

tests whose renal biopsy showed C1q nephropathy.

Case Report:

A six-year-old male, the only child of a non-

consanguineous marriage, presented with

complaints of cola colored urine, peri-orbital

puffiness and pedal edema; all on and off for the

past one month. There was no decrease in his urine

output; no dysuria, headache, vomiting, fever, joint

pain or abdominal pain; no history of trauma. The

symptoms were not preceded by any respiratory

symptoms. He had a past history of allergy to eggs

and insect bite reactions on the skin. He had a

urinary tract infection treated with parenteral

medication at the age of three years and he was

circumcised after that. His perinatal period was

uneventful and development normal. There was no

family history of renal disease.

On examination he was moderately built and

nourished. His BP was 90/70 mm of Hg. His weight

was 19 kg, height 114 cm with a body surface area of 20.77 m . There was no pedal oedema, no pallor,

only mild periorbital puffiness. He had multiple

lower limb scars (of insect bite reaction).

Examination of systems was unremarkable. Investigations done from outside as well as our

hospital showed numerous RBCs in the urine with

varying degrees of albumin (1+ to 3+), and granular

casts. Urine culture and sensitivity was sterile. His

complete blood count was normal (hemoglobin 11 3

g/dL, total count 7600 cells/mm , differential

count-polymorphs 57%, lymphocytes 40%, 3

eosinophils 3%; platelet count 3.6 lakhs/mm ) with

a high ESR (85 mm/1st hour). His blood urea was

34 mg%, serum creatinine was 0.5 mg%. ASO titre

and serum electrolytes were normal. Serum C3 was

normal (106 mg%). 24-hour urine protein was

elevated (679 mg). Mantoux test was non-reactive

Correspondence to: Dr. Soja Vijayan, Assistant Professor, Department of Pediatrics, Malabar Medical College Hospital, P.O. Modakkalloor, Calicut, Kerala – 673315

Calicut Journal of Pediatrics 2020;1:18-20

18

and chest x-ray normal. Ultrasonogram of the

abdomen showed bilaterally enlarged kidneys with

mild increase in echotexture.

However the child did not come for follow up and

he was next brought four months later. Recurrent

gross hematuria was still present but there was no

pedal edema or facial puffiness. Urine output was

good. Physical examination was unremarkable and

BP normal. Detailed ENT and Ophthalmology

evaluation showed no evidence of Alport

syndrome. Investigations showed numerous RBCs

in the urine, 24 hour urine protein was high (1840

mg) and in the nephrotic range and 24 hour urine

calcium was normal. The blood counts were

normal with high ESR (75mm /1st hour). Blood

urea and serum creatinine were normal, serum

cholesterol was 260 mg/dL and serum total protein

and albumin was low. Serum C3 and C4 were

normal and ANA was negative. Tests for HIV and

HBsAg were negative. Ultrasonogram of the

abdomen showed evidence of bilateral grade 1

medical renal disease. After consultation with the

nephrologist renal biopsy was done which showed

mild enlargement of glomeruli,mild mesangial

hypercellularity and patent capillary loops on light

microscopy. Granular deposits of C1q 2+ and IgM

1+ were seen on immunofluorescence study (no

IgG, IgA or C3 deposits seen), finding suggestive of

C1q nephropathy. Electron microscopy could not

be done due to financial and technical issues.

The patient was started on prednisolone and

losartan. On follow up a month later he was

symptomatically better. Urine analysis showed

RBC 4-5/HPF, albumin nil and urine protein

creatinine ratio 0.6. He received steroids for total 12

weeks duration which was later tapered off. He was

further followed up by a nephrologist. He later had

two relapses which responded to treatment with

steroids. For the past two years he is asymptomatic,

urine tests normal and off medications.

Discussion:

C1q nephropathy was first described by Jennette

and Hipp [2] in 1985 in biopsies exhibiting

dominant or codominant mesangial staining for

C1q in glomeruli and confirmation of such

mesangial deposits by electron microscopy in

patients with no clinical or serological features of

systemic lupus erythematosus or in the absence of

type 1 membranoproliferative glomerulonephritis

(MPGN) pattern. [3] Several reports about this

disease have been published since then.[4,5,6,7] It is

seen in 0.2-2.5% of renal biopsies from children and

adults.[2,4] In clinicopathological studies, C1q

nephropathy is characterized by its onset in older

children and young adults (mean age 17.8 years),

100% proteinuria, 40% hematuria.[2] It has been

picked up as asymptomatic microscopic hematuria

on screening.[7,8] It has been seen in children as

young as one year and a case of congenital nephritic

syndrome with C1q deposits has been described.[9]

A study by Markowitz et al showed edema

in 58.8% pat ients, hematur ia in 22.2%,

hypertension in 29.4%, nephrotic range proteinuria

in 78.9%, hypoalbuminemia in 50% and

hypercholesterolemia in 88.9%.[4] Serological

examination reveals no antinuclear antibodies or

complement abnor mal i t i e s. [2 ] On l i gh t

microscopy, minimal change disease, proliferative

g lomer ulonephr i t i s and focal segmenta l

glomerulosclerosis were noted in variable

frequencies.[4,7,8] Representative renal biopsy

images (h is topathology and IF) of C1q

nephropathy are given in figures 1 and 2

respectively. Some studies show a good prognosis

w i t h i m p r o v e m e n t o n t r e a t m e n t w i t h

prednisolone and/or immunosuppressive drugs

and d i sappearance o f C1q de pos i t s on

follow up [4,7] but cases with focal segmental

glomerulosclerosis showed poorer prognosis. Index

child responded well to steroids and had good

outcome probably because of absence of features of

proliferative glomerulonephritis and focal

segmental glomerulosclerosis in the renal biopsy. In

India, C1 q nephropathy has been noted in pediatric

biopsies. [10] In spite of being reported since 1985,

C1q nephropathy continues to remain a challenge

due to its diverse clinical presentation and varied

response to treatment.

19

Phadke KD, Vijayakumar M, Sharma J, Iyengar

A. Consensus Statement on Evaluation of

Hematuria. Indian Pediatric Nephrology Group,

Indian Academy of Pediatrics. Indian Pediatr.

2006; 43:965-73

Jennette JC, Hipp CG. C1q nephropathy: A

distinct pathologic entity usually causing

nephrotic syndrome. Am J Kidney Dis.

1985;6:103-10.

Jenette JC, Hipp CG. Immunohistopathologic

evaluation of C1q in 800 renal biopsy specimens.

Am J Clin Pathol. 1985;83:415-20.

Markowitz GS, Schwimmer JA, Stokes MB,

Nasr S, Seigle RL, Valeri AM, et al. C1 q

nephropathy: A variant of focal segmental

glomerulosclerosis. Kid Int. 2003;64:1232-40.

Iskander SS, Browning MC, Lorentz WB. C1q

nephropathy: A pediatric clinicopathologic

study. Am J Kidney Dis. 1991;18:459-65.

Vizjak A, Ferluga D, Rozic M, Hyala A, Lindic J,

Levar t TK, e t a l . Pa tho log y, c l in i ca l

p r e s e n t a t i o n s, a n d o u t c o m e s o f C 1 q

nephropathy. J Am Soc Nephrol. 2008;19:2237-

44.

Hisano S, Fukuma Y, Segawa Y, Niimi K, Kaku

Y, Hataeet K, et al. Clinicopathologic correlation

and outcome of C1q nephropathy. Clin J Am Soc

Nephrol.2008;3:1637-43

Fukuma Y, Hisano S, SegawaY, Niimi K, Tsuru

N, Kaku Y, et al. Clinicopathological correlation

of C1q nephropathy in children. Am J Kidney

Dis. 2006;47:412-8.

Kuwano M, Ito Y, Amamoto Y, Aida K. A case

of congenital nephritic syndrome associated

with positive C1q immunofluorescence. Pediatr

Nephrol.1993;7:452-4.

Kanodia KV, Vanikar AV, Nigam LK, Patel RD,

Suthar KS, Gera DN, et al. Pediatric Renal

Biopsies in India: A Single-Centre Experience of

Six Years. Nephrourol Mon. 2015 ;7:e25473.

References:

FIGURES

Fig.1 Histopathology of C1q

nephropathy (H&E X 400)

Fig.2 Immunofluorescence Using

Antiserum to C1q X 400

1.

2.

3.

4.

5.

20

6.

7.

8.

9.

10.

Achalasia cardia in infancy – a case report

1 1 1 2 1 1V.K.Gopi , P.R.Babu , M.Narayanan , Shaji Thomas John , K.T. Muralikrishnan , T.P.Joseph

Achalasia cardia is an unusual chronic disease of esophagus. It is a neuromuscular

disorder of unknown etiology affecting esophageal body and lower esophageal

sphincter. It is unusual in children and extremely rare in infants. We report an infant

who had his symptoms from first month of life and underwent multiple sittings of

pneumatic balloon dilatation and was still on nasogastric feeds. We did

laparoscopic Heller's cardiomyotomy and anti-reflux procedure resulting in total

relief of symptoms.

Keywords: Achalasia cardia, infancy, laparoscopic cardiomyotomy, anti-reflux

procedure

Abstract:

1- Department of Pediatric Surgery, Baby Memorial Hospital, Calicut

2- Department of Pediatrics, Baby Memorial Hospital, Calicut

Correspondence to: Dr VK Gopi, Department of pediatric Surgery,

Baby Memorial Hospital, Calicut. Email: gopivk99@gmail.com

Figure 1:

Esophagogram

showing total

obstruction at

GE junction

and absent

fundic gas.

Introduction:

Achalasia is a Greek word that means 'failure of

relaxation'. It is a functional obstruction affecting

the propulsive activity of esophagus in response to

swallowing. Idiopathic achalasia is characterized

by esophageal aperistalsis and failure of lower

esophageal sphincter (LES) relaxation due to loss of

inhibitory nitrinergic neurons in the esophageal

myenteric plexus [1]. Macroscopically the entire

esophagus is dilated, often tortuous with narrowing

at the lower end. The goal of management is relief

of obstruction at lower esophagus and gastro-

esophageal junction and can be accomplished by

either of the following; medication, injection of

Botox (botulinum toxin type A),pneumatic

dilatation or Heller's cardiomyotomy. When non-

operative measures fail to bring in lasting and

satisfactory results, surgical intervention is being

instituted as a final resort.

Case Description:

A two year old male child was admitted with

clinical, radiological and endoscopic features of

achalasia cardia.

His symptoms started from first

month of life. He had vomiting,

regurgi tat ion and repeated

aspirations. He was on nasogas-

tric feeds most of the time and had

multiple sittings of pneumatic

dilatation but without lasting

results. As he continued to be

symptomatic and unable to be off

nasogastric tube, he was referred

to us. He was taken up for Heller 's cardiomyotomy. At

laparoscopy lower esophageal

narrowing was remarkable.

Cardiomyotomy and Dor fund-

oplication was carried out.

Calicut Journal of Pediatrics 2020;1:21-24

21

Figure 2: Per-op picture showing esophageal narrowing atGE junction

Figure 3: Post-op esophagogram showing complete esophageal emptying and presence of fundic gas

Discussion:

Achalasia cardia is a motility disorder of the esophagus featuring aperistalsis and dilatation, often with tortuosity of body of esophagus and failure of relaxation of lower esophageal sphincter(LES). In an established case, esoph-agus is in a state of functional obstruction. Achal-asia is an uncommon disorder with an annual incidence of approximately 1.6 cases per 1,00,000

individuals and a prevalence of 10 cases per 1,00,000 individuals [2]. Though it can affect any age group, it is commonly seen between 30 and 60 years and it is exceedingly rare in rst two decades of life. Achalasia cardia is uncommon in children and extremely rare in infants [3]. Only a few cases are reported in new born babies. Sir Thomas Willis rst described achalasia cardia in 1674. Even after 300 years, the understanding on the etiopathogenesis of achalasia cardia remains unclear. Various hypotheses have been postulated including autoimmune process, loss of ganglion cells in the lower esophagus, Wallerian degeneration of extra esophageal nerve bres and a reduction in the dorsal motor nuclei of vagus nerve [4]. Experimental and autopsy studies demonstrated that achalasia results from degeneration of esophageal nerve plexus particularly inhibitory bres [5]. According to the etiology, the disease can be classied in to a primary neurogenic abnorm-ality with failure of the inhibitory nerves suppl-ying the sphincter and progressive degener-ation of ganglion cells and a deciency of myenteric plexus cells secondary to gastro-esophageal reux disease, Chagas disease or viral infection. The common presenting features of achalasia are dysphagia, regurgitation of feeds, emesis, failure to thrive, weight loss, heart burn, chest pain and recurrent lower respiratory tract infections [6]. Clinical suspicion is important for initiating investigations. Plain radiograph of chest and abdomen may show absence of fundic air bubble and presence of mediastinal air uid level. Barium esopha- gogram will be remarkable with esophageal dilatation and smooth narrowing of distal esophagus and gastro-esophageal junction, often described as “bird beak” sign. Esophageal Manometry is an useful tool of investigation. It will show high resting pressure of lower esophageal sphincter and aperistalsis of esophageal body will be discernible. High Resolution Manometry (HRM) has a denite role in the surveillance after therapy. Endoscopy (OGD) is required for the evaluation of suspected case of esophageal achalasia. The descriptive rules for achalasia of esophagus published by the Japanese Society of esophageal diseases in 2012

Postoperative period was smooth and oral feeds started after repeat esophagogram.

There was steady improvement and child later could accept a normal diet. He was reviewed after one year and was found to be doing well. He remained asymptomatic two years after the procedure (as reported by his mother during recent telephonic contact)

22

describe the different endoscopic features of achalasia; dilatation of esophageal lumen, abnormal liquid and or food retention food in esophagus, thickening and whitish changes of the mucosal surface, functional stenosis of esophagogastric junction, abnormal contraction of esophageal body [7]. Endoscopy is required to exclude other causes of esophageal obstruction. Early diagnosis and prompt management is important in achalasia. Neglect and improper management can lead to end stage achalasia which can end up with esophagectomy and resultant morbidity. Achalasia is a risk factor for the development of esophageal squamous cell carcinoma and esophageal adenocarcinoma. Patients with achalasia have 50 times higher risk of esophageal squamous cell carcinoma than the general population. Multiple mechanisms are related to the development of esophageal squamous cell carcinoma and they include bacterial overgrowth, food stasis, genetic alterations and chronic inammation. Regarding the risk of esophageal adenocarcinoma, in achalasia patients, most cases are associated with Barrett's esophagus due to uncontrolled chronic acid reux [9].

The treatment of achalasia is palliative in nature and normalcy is never reinstated. The goal of treatment is relief of obstruction at LES, enabling esophageal emptying and over all symptomatic improvement. Various management options include medications (nitrates, calcium channel blockers, anticholinergic agents, beta agonists and phosphodiesterase inhibitors), Botox injection, Pneumatic balloon dilatation and Surgical cardiomyotomy. Out of all management options, pneumatic balloon dilatation and surgical esophagomyotomy are considered as preferred treatment options. Pharmacological agents and Botox injection fail to give consistent long lasting results apart from tolerance, side effects and complications. Although pneumatic dilatation has a role in the treatment of patients with achalasia, laparoscopic Heller myotomy is considered by many experts as the best treatment modality for most patients with newly diagnosed achalasia.10 When a fundoplication is not

performed after myotomy, 47% to 100% of pat ients have postoperat ive pH-metry conrmed GERD[10]. On the other hand, given the total absence of esophageal peristalsis in patients with achalasia, the risk of performing a total fundoplication is to have persistent or recurrent dysphagia . This was demonstrated in a prospective study that compared total (Nissen) versus partial anterior (Dor) fundoplication after Heller myotomy; it showed equal GERD control but higher dysphagia rate (15% versus 2.8%) for the total fundoplication group after 5 years of followup

Emerging newer trends in the management of achalasia cardia are Lapro-endoscopic Single Site Surgery (LESS), Robot assisted myotomy and Per Oral Endoscopic Myotomy (POEM) and they have to withstand the test of time in terms of efcacy, cost effectiveness, reproducibility and above all be truly evidence based.

Conclusion:

Achalasia is a clinical challenge. Non-bilious vomiting and regurgitation along with respiratory symptoms should arouse suspicion of the disease. Barium esophagogram, high resolution manometry (HRM) and endoscopy (OGD) should culminate in appropriate management. Laparoscopic Heller's cardiom-yotomy with anti-reux procedure is the well accepted and effective treatment option in achalasia cardia.

23

Park W, Vaezi MF. Etiology and pathogenesis of achalasia: the current understanding. Am J Gastroenterol. 2005;100:1404-14

Sadowski DC, Ackah F, Jiang B, Svenson LW. Achalasia: incidence, prevalence and survival. A population-based study. Neurogastroenterol Motil. 2010;22:e256-e261.

Chatterjee S, Gajbhiye V, De A, Nath S, Ghosh D, Das SK. Achalasia cardia in infants: report of two cases. JIMA. 2013;44:44-1-9260.

Shettihalli N, Venugopalan V, Ives NK, Lakhoo K. Achalasia cardia in a premature infant. BMJ Case Rep. 2010;2010:bcr0520103014.

Ghoshal UC, Daschakraborty SB, Singh R. Pathogenesis of achalasia cardia. World J Gastroenterol. 2012;18:3050-7.

Myers NA, Jol ley SG, Taylor R. Achalasia of the cardia in children: a worldwide survey.J Pediatr Surg.1994; 29:1375-9.

Minami H, Isomoto H, Miuma S, et al. New endoscopic indicator of esophageal achalasia: "pinstripe pattern". PLoS One. 2015;10:e0101833.

Torres-Aguilera M, Remes Troche JM. Achalasia and esophageal cancer: risks and links. Clin Exp Gastroenterol.

2018;11:309-316.

Torres-Villalobos G, Martin del-Campo LA. Surgical Treatment of Achalasiaof Esophagus: Laparoscopic Heller Myotomy. Gastroenterol Res Pract. 2013:708327.

Acknowledgments

Authors acknowledge Dept of Anesthesiology, Baby Memorial Hospital, Calicut for their support offered in the management of the child

References:

1.

2.

3.

4.

5.

6.

7.

8.

9.

24

Incomplete Kawasaki Disease in Infants: A Diagnostic Challenge - Case Series

1 1 1 2 3Abdul Latheef , Sayyid Sabik , Yassar Andru , Renu P Kurup , Abdul Rauf

1-Department of Paediatrics, Santhi Hospital, Omassery

2- Dept of Pediatric Cardiology, Santhi Hospital, Omassery 3- Dept. Of Pediatrics, Baby Memorial Hospital, Calicut

Calicut Journal of Pediatrics 2020;1:25-27Correspondence to: Dr Abdul Latheef KM, Consultant Pediatrician, Santi Hospital, Omassery, Calicut

Diagnosis of Kawasaki Disease (KD) in infants may be extremely challenging when may

present as incomplete KD, without the classical clinical features given in the diagnostic

criteria. Here we describe four cases of incomplete KD with variable presentation in whom

high index of suspicion and serial monitoring of symptoms and investigations helped in

reaching the diagnosis. All cases were treated with IVIG and Aspirin. Extended spectrum

of clinical presentation goes beyond the classical diagnostic criteria for KD.

Key words: Incomplete Kawasaki Disease, Infants, Atypical Kawasaki Disease

Abstract:

Introduction:

Kawasaki disease (KD) is an acute medium vessel

vasculitis of unknown etiology seen predominantly

in infants and young children. It was first described

in Japan by Tomisaku Kawasaki [1]. KD can result

in coronary artery abnormalities (CAA) in up to

25% of untreated patients and 3–5% of treated cases

[2]. Kawasaki disease in infants is always a

diagnostic challenge because infants may not often

manifest the complete form of disease (incomplete

KD) [3]. Approximately 35% of infants can have

incomplete KD, thereby resulting in delayed clinical

recognition and treatment [4]. Incomplete forms of

KD in infants should not be assumed as milder

forms of KD as they do have predilection for CAA

[2,4, 5-6].

Here we describe four cases of incomplete KD with

variable presentation in whom high index of

suspicion and serial monitoring of symptoms and

investigations helped in reaching the diagnosis.

Case descriptions

Case 1:

A 7 months old female infant presented with fever

of 1-week duration along with cough and rashes of

2 days duration. At time of admission, she was

febrile (102°F) and was irritable. Her initial

systemic examination was unremarkable. Her

initial blood parameters showed haemoglobin of

10.4 gm/dl with elevated leukocyte count (TLC) of 3

21000/mm with 77% neutrophils. Child had 3

thrombocytosis (6.2 lakhs/mm ), elevated ESR

(67mm/hr) and high CRP (56mg/L). As urine

routine showed 10-15 pus cells, a diagnosis of UTI

was considered and hence started on IV antibiotics

(Inj. Ceftriaxone and Inj. Amikacin). Even after 48

hours of initiation of antibiotics, she continued to

be febrile and her urine culture was sterile. She

developed skin desquamation in axilla on day 5.

Her repeat blood investigations showed increase in 3platelet count to 8.1 lakhs /mm with further rise in

ESR (72 mm/hr). Considering sterile pyuria,

irritability, rashes and desquamation over axilla

25

with features of systemic inflammation, possibility

of incomplete KD was considered. Accessory lab

parameters showed Serum sodium of 131 mEq/L

and serum albumin of 2.9 gm/dl. IV Ig 2 g/kg was

given over 15 hours. Her echocardiography showed

normal coronaries and fever subsided following

IVIG administration

Case 2:

An eight months old male infant was admitted with

complaints of persistent low-grade fever of 10 days

duration. It was associated with excessive cry in

initial few days and was treated with oral antibiotics

with probable diagnosis of otitis media. At time of

admission, vitals were stable, child had pallor and

systemic examination was unremarkable. His

initial blood investigations showed haemoglobin of 39.3 gm%, and leucocytosis (TLC-24500/mm ) with

45% polymorphs and 54% lymphocytes. His ESR

(135mm/hr) was grossly elevated and platelet count 3

was 10.35 lakh/mm . Urine routine showed 6-8 pus

cells/HPF and chest x-ray was normal. Initial

differential diagnosis considered were partially

treated meningitis/ complicated UTI. Urine

culture was sterile. Child continued to have low

grade fever and hence possibility of incomplete KD

was considered (sterile pyuria, thrombocytosis,

elevated inflammatory parameters). Echocardio-

graphy done showed coronary artery dilatation

(LMCA 2.9 mm (+3.6 Z score) and RCA 2.1 mm

(+1.9 Z score). He was treated with IVIG 2gm/kg

and Aspirin.

Case 3:

A 3-month old female infant was admitted with

cough for 7 days with fever present on initial 2 days

of illness. History of irritability for initial 2 days of

illness was present. Child was admitted with

provisional diagnosis of viral pneumonia/ UTI. On

examination she was playful and afebrile.

Examination of other systems was unremarkable.

Initial blood investigations showed haemoglobin of

37.8gm/dl and TLC- 20,120 cells/mm with

polymorphs of 40% and 55% lymphocytes. Her 3

platelet count was 6.19 lakhs/mm and ESR was 80

mm/hr. Chest X-ray showed infiltrates on right side

and urine routine showed 6-8 pus cells/hpf. After 5

days of iv antibiotics, hemogram was repeated -

TLC 18700/ mm3 with neutrophils of 43% and

platelet count -6.79 Lakh/mm3. Her serial ESR

also showed increasing trend (110mm/hr) and CRP

was also grossly elevated (103.7mg/L). As her urine

culture was sterile and blood investigations

showed e levated inf lammator y markers,

a possibilityof incomplete KD was considered. 2D

echocardiogram was done, which showed dilated

LMCA – 4.8mm (+ 8 Z scores), LAD- 2mm (+3 Z

scores) and RCA– 3 mm (+5 Z scores). She was

given IVIG 2 gm/kg and anti-inflammatory dose of

aspirin. She was also given dual anti-coagulant

therapy (aspirin and clopidogrel). as treated with

IVIG 2gm/kg and Aspirin.

Case 4:

A 10 months old female infant presented with high

grade continuous fever for 5 days. History of

irritability and 4-5 episodes of loose stools on initial

2 days of illness was present. Mother had also

noticed maculopapular rash over body on initial 2

days of illness. At admission, her vitals were stable

and systemic examination was unremarkable. Her

urine routine showed numerous pus cells and hence

iv antibiotics were initiated with provisional

diagnosis of UTI. Initial blood investigations

showed haemoglobin – 8.6 gm/dl, TLC of 23460 3

/mm with 67 % polymor phs and 28 % 3

lymphocytes. Her platelet count was 3.6 lakh/mm

and ESR was elevated (70mm/hr). Though her

fever subsided after 3 days of iv antibiotics, her

repeat hemogram showed further rise in platelet 3

count (4.4 Lakh /mm ) and ESR (88mm/hr). Her

CRP was also grossly elevated (93 mg / L) and urine

culture was sterile. Possibility of Incomplete KD)

was considered at this time. On 7th day of illness

26

her platelet count further raised to 9.5 lakh and

clinical examination showed desquamation in

perineal area. Her 2D echocardiography showed

normal coronaries and was treated with IVIG 2 gm

/kg after which inflammatory markers decreased.

Discussion:

The diagnosis of incomplete Kawasaki disease may

be made in cases with fewer classical diagnostic

criteria and with several compatible clinical,

laboratory or echocardiographic findings and on

exclusion of other aetiology of febrile illness. We

reported clinical details of four infants with

incomplete KD where timely administration of

IVIG resulted in resolution of signs and symptoms

Our cases had few clinical features of classical KD.

The clinical features were fever, rash, irritability

..etc. Desquamation happened in two kids. None of

the children had eye changes or oral cavity changes.

Sterile pyuria was a common finding. The practice

of clinicians to label a diagnosis of UTI just based

on presence of pyuria, is to be discouraged.

Monitoring inflammatory markers (CRP, ESR)

serially and documenting the increasing trend

helped us to establish the diagnosis. It is notable that

two children had coronary involvement, of whom

one had giant aneurism.

It is notable that fever was not a prominent sym-

ptom in two children. Though fever is mandatory

for diagnosis in AHA criteria, it's just another

criteria (not mandatory) in Japanese criteria for

KD.[7]. There are many reports of afebrile KD with

coronary involvement in literature. These children

did had elevated inflammatory markers (CRP,

ESR) which guided the treating team to make the

diagnosis.

Conclusions:

Possibility of KD needs to be considered in children

presenting with fever of 4 or more days without any

other localising signs in infants, especially when the

initial acute phase reactants are elevated. Extended

spectrum of clinical presentation in KD goes beyo-

nd the classical diagnostic criteria.

References

Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi. 1967 Mar;16(3):178-222.

McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment and Long-term Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017 Apr 25;135:e927-e999.

Singh S, Agarwal S, Bhattad S, Gupta A, Suri D, Rawat A, Singhal M, Rohit M. Kawasaki disease in infants below 6 months: a clinical conundrum? Int J Rheum Dis. 2016 Sep;19:924-8.

Rosenfeld EA, Corydon KE, Shulman ST. Kawasaki disease in infants less than one year of age. J Pediatr. 1995 ;126:524-9.

Sundel RP, Petty RE. Kawasaki disease. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB (eds) Textbook of Pediatric Rheumatology, 6th edn, pp 505–20. Elsevier Saunders, Philadelphia.

Choo HL. Kawasaki disease in infants. Southeast Asian J Trop Med Public Health. 2014;45 Suppl 1:75-8.

JCS Joint Working Group:Guidelines for Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease (JCS 2013).Circ J 2014; 78: 2521–62

1.

2.

3.

4.

5.

6.

7.

27

Anti NMDA receptor encephalitis in children - A Case series

Jayakrishnan MP, Krishnakumar P, Sabitha S, Rajesh TV

Department of Pediatrics, Government medical college, Kozhikode

Correspondence to: Dr Jayakrishnan MP, Additional Professor, Dept of Pediatrics,

Government medical college, Kozhikode, email- mp.jayakrishnan@gmail.com

Anti NMDAR encephalitis is a immune mediated encephalitis which can occur as

paraneoplastic syndrome or following infections. We report 3 cases of anti

NMDAR encephalitis, of which one was associated with neoplasm.Anti NMDAR

encephalitis should be considered and ruled out in any child presenting with

behaviour changes and memory problems associated with abnormal movements

and seizures.

Key words: anti NMDAR encephalitis, children, paraneoplastic syndrome,

neuropsychiatric manifestations

Abstract:

Introduction:

Anti N-methyl D-aspartate (NMDA) receptor encephalitis is a type of immune mediated encephalitis, first reported in 2007, with most of the cases occurring in young women in the 14-35 year age group [1]. Underlying ovarian teratoma was present in a large number of cases above the age of 12 years [2]. NMDA receptor encephalitis has been reported in association with other neoplasms and also following infections and vaccinations [3,4].

We report three cases of anti NMDA receptor encephalit is, each with different cl inical presentation. The case of a 7 year old girl who developed antiNMDA encephalitis associated with ovarian teratoma is described in detail and the other two cases are given in table 1

Case 1:

A seven year old girl presented with history of memory lapses, frequent episodes of agitated behaviour and poor speech output of 5 days duration. In spite of having good school functioning, she showed little interest in her recent class examination and after the examination had no memory of the event. At home she kept silent most

of the time but exhibited episodes of behaviour outbursts with agitation and shouting. One week prior to the present symptoms she had fever and head ache which lasted for 2 days. On admission she had motor aphasia and showed repeated pill rolling movements involving fingers of both hands. Cranial nerves and motor system examination were normal except for the movement disorder. There were no signs of meningeal irritation and other systems were normal.

Subsequently her irritability and agitation increased and she developed episodes of dystonic posturing with arching of the trunk and orofacial dyskinesia.

Initial investigations revealed normal blood glucose, blood count, serum electrolytes, liver and renal function tests and cerebrospinal fluid (CSF) analysis. Serum and CSF viral studies were also normal. Electroencephalogram (EEG) done at the time of admission was normal.

Repeat EEG after 4 days showed generalised slowing with epileptiform discharges from right fronto-temporal area. Magnetic resonance imaging (MRI) of brain showed diffuse grey matter oedema. Thyroid function was normal. Antinuclear antibody (ANA), antithyroid peroxidise antibody

Calicut Journal of Pediatrics 2020;1:28-32

28

(anti TPOAb) and serology for HIV were negative. Computerised tomography (CT) scan of abdomen showed benign cystic teratoma of left ovary (Figure 1).

A clinical diagnosis of autoimmune encephalitis was made and serum was sent for anti NMDA receptor antibodies which came as positive. She was treated with intravenous immunoglobulin 400mg/kg per day for 5 days followed by a 5 day pulse of methyl prednisolone 30mg/kg and continued with oral prednisolone. By the 10th day of treatment, behaviour symptoms improved and dystonia reduced significantly with occasional abnormal movements.

Surgical removal of the ovarian tumour was done and the biopsy confirmed benign cystic teratoma. After discharge steroids were continued for 3 months. Follow up at one year showed no neurological deficits and no cognitive impairment. An interesting finding was that she had no memory of the illness.

Discussion:

Anti NMDA receptor encephalitis, a disease characterized by autoantibody mediated reaction against NMDA receptor, was first described by Dalmau et al in 2007 [1]. Though originally reported in relatively young women between the second and fifth decades of life subsequently it was shown that the disease can occur in children and

adolescents [1, 5].

Studies from India and abroad have reported that anti NMDAR encephalitis is more common in females [5-7]. However in a recent series, only 33% of children with NMDAR encephalitis were females (8). In the present sample all were females in the 7-10 year age group.

It is reported that children with anti NMDAR encephal i t is present predominantly with neurological symptoms while psychiatric symptoms are prominent in adults [7]. Our experience shows that children with anti NMDA encephalitis can present with both neurological and psychiatric symptoms. Frank psychosis as in adults is not reported in children probably because of the difficulty in eliciting delusions and hallucinations in children.

The role of neoplasms and infections predisposing to anti NMDAR encephalitis is well documented. Anti NMDAR encephali t is can occur as paraneoplastic syndrome or as non paraneoplastic syndrome [1, 3, 7]. Probable association of NMDAR encephalitis with immunisation has been recently reported [4]. Prodromal symptoms like headache, fever, nausea, vomiting, diarrhea and upper respiratory tract symptoms are reported in 48% to 70% of patients with anti NMDAR encephalitis [2,5]. Our experience shows that multiple factors like neoplasms or infection can predispose to anti NMDAR encephalitis.

The finding that in addition to anti NMDAR antibodies, other auto antibodies like anti TPO antibodies and antinuclear antibodies are present in children with anti NMDAR encephalitis suggest the possibility of increased predilection to develop autoantibodies in these children [5]. In our sample Anti TPO antibody and anti-nuclear antibody were positive in one child. This child had no tumour association and no history of preceding infection. It is probable that multiple factors like gender, race and genetics are involved in the aetiology of anti NMDA encephalitis and infections, neoplasms or vaccination triggers auto antibody production in vulnerable individuals [3].

Figure 1- CT image showing benign cystic

teratoma of left ovary

29

Clinical presentation

Age

Gender

Preceding illness

Symptoms at presentation

Neuropsychiatric symptoms

Focal neurologic deficits

Movement abnormalities

Case 1

7 years

Female

Upper respiratory infection 1 week prior to onset

Memory loss, excessive anger

Memory loss, agitation, poor speech output

No

Pill rolling movements of fingers, Orofacial dyskinesia, Tonic posturing of limbsOpisthotonic posturing

Case 2

8 years

Female

Upper respiratory infection 2 weeks prior to onset

Unusual sleepiness, fearfulness, excessive anger, seizures

Fearfulness, excessive anger, unusual sleepiness

Left hemiparesis

Orofacial dyskinesia, tonic posturing of limbs, opisthotonic posturing

Case 3

10 years

Female

Nil

Excessive anger, memory loss, not interested in going to school

Excessive anger, memory loss, not interested in going to school

No

Orofacial dyskinesia, tonic posturing of limbs, opisthotonic posturing, choreoathetoid movements

Even though the exact incidence of anti NMDAR

encephalitis is not known recent reports suggest that

it is a relatively frequent disorder. In a recent study

on the aetiology of encephalitis, anti NMDAR

encephalitis was the leading cause of encephalitis

[9]. Early identification and initiation of prompt

treatment is crucial. Anti NMDAR encephalitis

should be considered and ruled out in any child

presenting with mood changes, behaviour changes

and memory problems associated with abnormal

movements and seizures.

The finding that in addition to anti NMDAR

antibodies, other auto antibodies like anti TPO

antibodies and antinuclear antibodies are present in

children with anti NMDAR encephalitis suggest

the possibility of increased predilection to develop

autoantibodies in these children [5]. In our sample

Anti TPO antibody and anti-nuclear antibody were

positive in one child. This child had no tumour

association and no history of preceding infection. It

is probable that multiple factors like gender, race

and genetics are involved in the aetiology of anti

NMDA encephalitis and infections, neoplasms or

vaccination triggers auto antibody production in

vulnerable individuals [3].

Even though the exact incidence of anti NMDAR

encephalitis is not known recent reports suggest that

it is a relatively frequent disorder. In a recent study

on the aetiology of encephalitis, anti NMDAR

encephalitis was the leading cause of encephalitis

[9]. Early identification and initiation of prompt

treatment is crucial. Anti NMDAR encephalitis

should be considered and ruled out in any child

presenting with mood changes, behaviour changes

and memory problems associated with abnormal

movements and seizures.

30

Intense erythema of palms

Diffuse grey matter oedema

Generalized slowing with epileptiform discharges

Positive

Negative

Negative

CT Abdomen: cystic teratoma left ovary

IVIG,Methyl prednisolone followed by oral prednisolone

36 days

24 days

No neurologic deficits. Normal cognitive function.Total amnesia about the illnesss

Pelvic MRI normal

Nil

Normal

Generalized slowing

Positive

Negative

Negative

CT Abdomen:Normal

IVIG,Methyl prednisolone followed by oral prednisolone

48 days

40 days

No neurological deficits. Normal cognitive function. Total amnesia about the illnesss

Pelvic MRI normal

Intense erythema of palms

Normal

Frequent epileptiform discharges right frontocerbral area

Positive

Positive(268 IU/ml )

Positive

MRI Abdomen, pelvis: Normal

IVIG,Methyl prednisolone followed by oral prednisolone

40 days

30 days

No neurological deficits. Normal cognitive function. Total amnesia about the illnesss

Pelvic MRI normal

Autonomic dysfunction

MRI brain

EEG during first week

NMDA receptor antibody (serum)

Anti TPO antibody

Antinuclear antibody

Pelvis imaging

Treatment

Hospital stay

PICU stay

Follow up at 1 year

Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi

JE, Voloschin A et al. Paraneoplastic anti-N-

methyl-D-aspartate receptor encephalitis

associated with ovarian teratoma. Ann Neurol

2007; 61:25e36.

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE,

Peng X, Lai M et al. Anti-NMDA-receptor en-

cephalitis: Case series and analysis of the effects

of antibodies. Lancet Neurol 2008; 7:1091-8.

Dalmau J, Lancaster E, Martinez-Hernandez E,

Rosenfeld MR, Balice-Gordon, R .Clinical

experi-ence and laboratory investigations in

patients with anti NMDAR encephalitis. Lancet

Neurol. 2011; 10: 63-74.

References

1.

2.

3.

31

Hofmann C, Baur MO, Schroten H. Anti-

NMDA receptor encephalitis after TdaP-IPV

boost-er vaccination: cause or coincidence? J

Neurol. 2011; 258: 500-1. doi: 10.1007/s00415-

010-5757-3. Epub 2010 Sep 30.

Florance NR, Davis RL, Lam C, Szperka C,

Zhou L, Ahmad S et al. Anti-N-methyl-D-

aspartate re-ceptor (NMDAR) encephalitis in

children and adolescents. Ann Neurol. 2009; 66:

11-8. doi: 10.1002/ana.21756

Chakrabar ty B, Tripathi M, Gulat i S,

Yoganathan S, Pandit AK, Sinha A et al . Pediat-

ric Anti-N-Methyl-D-Aspartate (NMDA)

Receptor Encephalitis: Experience of a Tertiary

Care Teaching Center From North India.J Child

Neurol. 2013 Oct 4. [Epub ahead of print]

Titulaer MJ, McCracken L, Gabilondo I,

Armangué T, Glaser C, Iizuka T et al. Treatment

and prognostic factors for long-term outcome in

patients with anti-NMDA receptor encephalitis:

an observational cohort study. Lancet Neurol.

2013; 12: 157-65. doi: 10.1016/S1474-

4422(12)70310-1. Epub 2013 Jan 3.

Armangue T, Titulaer MJ, Málaga I, Bataller L,

Gabilondo I, Graus F et al. Spanish Anti-N-

methyl-D-Aspartate Receptor (NMDAR)

Encephalitis Work Group. Pediatric anti-N-

methyl-D-aspartate receptor encephalitis-

clinical analysis and novel findings in a series of

20 patients. J Pediatr. 2013; 162: 850-856.e2. doi:

10.1016/j.jpeds.2012.10.011. Epub 2012 Nov

16.

Gable MS, Sheriff H, Dalmau J, Tilley DH,

Glaser CA. The Frequency of autoimmune N-

Methyl-D-Aspartate receptor encephalitis

surpasses that of individual viral etiologies in

young individu-als enrolled in the California

Encephalitis Project. Clin Infect Dis. 2012;

54:899–904.

6.

7.

8.

9.

4.

5.

32

A Case of Prader-Willi Syndrome diagnosed in neonatal period

Jitesh Pillai, Balraj G, Cherian NC, Anjali T

Department of Paediatrics, KMCT Medical College, Calicut

Case Report

Prader-Willi syndrome (PWS) is a rare genetic disease manifesting with complex

neurodevelopmental issues comprising of multiple cognitive, behavioural and endocrine

abnormalities. The natural history of the disease has been described as having successive

phases which start during the last trimester of pregnancy. After birth, this syndrome is

characterized by neonatal hypotonia and poor sucking that results in feeding difficulties.

They may require nasogastric tube feeding in most cases. Many affected babies fail to thrive

in early infancy. Subsequently, in the absence of early care, spontaneous excessive weight

gain occurs at about 3 years even without an increase in food intake, followed by severe

obesity with hyperphagia and a satiety deficit which is typical of this disease.We report a

case of Prader-Willi syndrome diagnosed in the neonatal period

Abstract:

CASE REPORT

16 days old female baby was admitted with

complaints of difficulty in feeding and decreased

activity since birth. The baby was born to non-

consanguineous parents. Maternal age was 33 and

she had noticed decreased foetal movement

compared to previous pregnancy right from early

stage. She also had polyhydramnios in 3rd

trimester. Baby was delivered by LSCS. She cried

immediately after birth. Baby was shifted to NICU

in view of poor sucking activity. Expressed breast

milk was given using “paladai” which baby

continued to receive when admitted to the hospital.

Elder sibling was normal. There was no similar

history in any family member.

On admission infant appeared to be lethargic, lying

in frog like posture. Weight on admission was 2.06

kg, length-48cm and head circumference-33cm.

Vitals were stable. On head to toe examination, face

appeared dull, deep set eyes with strabismus and

retrognathia with inverted 'v' shaped upper lip.

Normal female genitalia was present. No

contractures seen in upper or lower limbs. No

fasciculations in tongue was seen. On examination,

cranial nerves examination was normal. Muscle

bulk appeared normal and symmetr ical .

Generalised hypotonia was present in all four limbs

(Rag doll phenomenon, slipping through on vertical

suspension, positive Scarf sign and increased

Amiel- Tison angles). Deep tendon Reflexes were

diminished and plantar was extensor. Sucking

reflex was poor, rooting reflex absent, Moro reflex

was incomplete.

In view of central hypotonia, baby was investigated

further. MRI (brain) showed T1 hyper intensity

areas in subdural region of left occipital convexity.

Metabolic screening (tandem mass spectrometry)

and Sepsis screening were found to be normal.

DNA Methylation Analysis using Multiple

ligation-dependent probe amplification (MLPA)

Correspondence to: Dr Anjali T, Senior resident, Dept of Pediatrics, KMCT Medical College, Calicut

Calicut Journal of Pediatrics 2020;1:33-35

33

showed negative result for microdeletion 15q11 but

positive for hypermethylated SNRPN gene. This

finding was consistent with the diagnosis of Prader-

Willi syndrome due to uniparental disomy/

imprinting centre mutation of chromosome 15.

Fluorescence in situ Hybridization (FISH) Analysis

was done which again showed absence of deletion

of 15q11.2 region. Absence of deletion and

presence of methylation abnormality was

suggestive of Prader-willi syndrome due to

uniparental (maternal) disomy. Chromosomal

microarray with SNP and CNV probes were also

done for further delineation of the genetic

abnormality.

Infant was fed with expressed breast milk and

formula milk via nasogastric tube and occasionally

via paladai for 6 months, following which

complementary feeds were started. Sucking

remained poor and child was not able to feed

directly from breast. As baby started gaining weight

at a faster rate, dietary modification was advised

and now, at 10 months, baby weighs 8.3 kg. Baby

also have delay in gross motor development.

Parents and caregivers were counselled regarding

the disease and care of the baby also had delay in

gross motor development.

DISCUSSION

Prader-Willi Syndrome (PWS) is a rare neurodevel-

opmental genomic imprinting disorder. The

condition is named after Swiss physicians Andrea

Prader and Heinrich Willi who, together with

Alexis Labhart, described it in detail in 1956 [1] The

disease frequency is about 1 in 15,000 individuals

[2] Overall life expectancy is shortened such that

13–20% of people with PWS have died by 35years

in previously published cohorts [3]

In the case of PWS, most of the genes from

chromosome 15q11-q13 region are subject to

genomic imprinting and only the alleles from the

paternally derived chromosome are active. These

same alleles from the maternally derived

chromosome 15 are silenced by epigenetic factors,

primarily through methylation. The second most

common genetic cause of PWS in about 35% of

individuals is referred to as maternal disomy 15.

Older mothers have a greater chance of having a

child with PWS due to maternal disomy 15

compared with those having the typical 15q11-q13

deletion [4]

The course of PWS is historically divided into two

clinical stages with failure to thrive representing the

first stage and hyperphagia with the onset of obesity

representing the second stage. Recent studies have

shown more gradual and complex progression with

the development of nutritional phases. Cardinal

clinical features are craniofacial anomalies;

Intellectual disability; Infantile hypotonia; Growth

h o r m o n e d e f i c i e n c y ; H y p o g o n a d i s m /

H y p o ge n i t a l i s m ; B e h av i o r a l p r o b l e m s ;

Hyperphagia leading to obesity in early childhood

[5]. In our case, central hypotonia in infantile

period, poor suck and characteristic facies with

deep set eyes helped us suspect PWS and hence

appropriate Lab investigation were sent.

Genetic testing for PWS include DNA methylation

analysis (Include polymerase chain reaction (PCR)

along with Southern blotting of the SNRPN probe

for the chromosome 15q11-q13 region or

Methylation-Specific Multiplex Ligation-

Dependent Probe Amplification (MS-MLPA)

approaches utilizing several imprinted probes from

this chromosome region[6]. Detection of the

chromosome 15 deletion or other anomaly

(undertaken if the deletion status is normal and

methylation is abnormal) can also be done.

Chromosomal microarrays with SNP and CNV

probes can assist in determining the maternal

disomy 15 subclass status.

34

Management include medical and behavioural

supervision, extensive lifestyle modification by

caregivers and families of affected individuals.

Assisted feeding techniques are often required

for in fant s wi th poor suck . Cur rent

comprehensive and multidisciplinary care

using Human Growth Hormone (hGH) and

dietary management can help the child with

PWS achieve BMI values within normal range,

and this is a clinical goal[7]. Prognosis depends

on transition from stage 1 (failure to thrive) to

stage 2 (hyperphagia and obesity) of clinical

course development; monitoring obesity status

and managing with food and dietary control.

Psychological food security and mandatory

exercise for calorie expenditure; determining

mental capacity and identifying and treating

neurological/psychiatric findings; monitoring

the endocrine, orthopedic, cardiopulmonary

and gastrointestinal systems to avoid health

related complications and death[8]. In our

patient, there was exaggerated weight gain after

introduction of complementary feeds hence

diet modification was done by reducing fat

content and increasing fibre content in food.

And child was followed up and noted to have

only minimal weight ga in fo l lowing

modification.

Conclusion

Possibility of PWS should be kept in mind in an

infant with hypotonia, poor suck and

characteristic facies. Early diagnosis and

management can reduce the complications

associated with PWS

References

[1] Butler MG, Miller JL, Forster JL. Prader-

Willi Syndrome - Clinical Genetics, Diagnosis

and Treatment Approaches: An Update. Curr

Pediatr Rev. 2019;15:207-44.

[2] Butler M.G. Prader-Willi syndrome:

Obesity due to genomic imprinting. Curr.

Genomics. 2011;12:204–15

[3] Liont i T, Reid SM, Rowel l MM.

Prader-Willi syndrome in Victoria: Mortality

and causes of death. J. Paediatr. Child Health

2012; 48: 506–11

[4] Butler MG, Hartin SN, Hossain WA, et al.

Molecular genetic classification in Prader-Willi

syndrome: a multisite cohort study. J Med

Genet. 2019; 56:149-53

[5] Gunay-Aygun M, Schwartz S, Heeger S,

O'Riordan MA, Cassidy SB. The changing

purpose of Prader-Willi syndrome clinical

diagnostic criteria and proposed revised

criteria. Pediatrics 2001; 108: E92

[6] Angulo MA, Butler MG, Cataletto. Prader-

Willi syndrome: a review of clinical, genetic,

and endocrine findings. MEJ Endocrinol

Invest. 2015;38:1249-63.

[7] Deal CL, Tony M, Hoybye C, et al. Growth

Hormone Research Society workshop

summar y : Consensus gu ide l ines fo r

recombinant human growth hormone therapy

in Prader-Willi syndrome. J. Clin. Endocrinol.

Metab. 2013; 98: E1072–87

[8] Butler M.G., Lee P.D.K., Whitman B.Y.

Management of Prader-Willi Syndrome. 3rd

ed. New York, NY: Springer Verlag Inc.; 2006.

35

A Rare Case Of CGD With Chromobacterium Violaceum Abscess

Amrutha Visalakshi, Athulya E P, Geeta Govindaraj, Ajith Kumar V T

Department of Pediatrics, Government Medical College, Kozhikode

Case Report

Chronic Granulomatous Disease is a rare inborn error of immunity characterized by

granulomatous lesions in skin, lymph nodes ,lung, liver, GIT, bones . A rare case of CGD

in a 7 month old male child is reported here who presented with prolonged fever ,failure to

thrive,firm hepatosplenomegaly. Investigations revealed multiple liver abscesses and skin

abscess which grew Chromobacterium violaceum- an unusual pathogen which prompted

us to workup the case for CGD. Clinical suspicion and appropriate investigations could

identify the underlying PID and ensure proper followup and counselling that could alter

the outcome in these children.

Key words : Chronic Granulomatous Disease, Chromobacterium violaceum

Abstract:

Introduction

Chronic granulomatous disease is a rare inborn

error of immunity with defective phagocyte

bactericidal function characterized clinically by

granulomatous lesions in the skin, lymph nodes,

lung, liver, GIT and bones. Incidence approximates

1 in 2-2.5 lakh live births. ESID gives criteria for

diagnosis as at least one among the following 7

clinical criteria with absent/significantly decreased

respiratory burst as suggested by NBT or DHR

:deep seated infection due to bacteria and/or fungi

(abscesses, osteomyelitis, lymphadenitis), recurrent

p n e u m o n i a , l y m p h a d e n o p a t h y a n d / o r

hepatomegaly and/or splenomegaly, obstructing /

diffuse granulomata, chronic inflammatory

manifestations, failure to thrive, affected family

member.

Here we report a rare case of CGD in a 7 month old

male child in his first presentation)

Case Report:

A 7 month old male child, first child of more than

third degree consanguineous parentage belonging

to Muslim community was referred to our institute

with complaint of high grade fever with rigor and

dry cough for 10 days .He had been running high

fever despite being treated with oral antibiotics from

another hospital and was becoming more lethargic

and lean,hence was the referral on day 10 of illness.

On enquiring he had no significant past medical

history except for having a febrile upper respiratory

illness of 4 days duration at his 5 months of age. His

birth history was uneventful- born at term with a

birth weight of 2.7kg. On examination the child was

toxic, lean with grade 2 PEM,had tachycardia and

tachypnoea with gross abdominal distension due to

firm hepatosplenomegaly-tender liver of span 12

cm with palpable left lobe and 1 cm spleen palpable

below left costal margin.

He was investigated initially with USG abdomen

Correspondence to: Dr Geeta Govindraj, Professor,Department of Pediatrics, Government Medical College,Kozhikode

Calicut Journal of Pediatrics 2020;1:36-38

36

which showed multiple well defined hypoechoeic

lesions in liver confirmed with CECT abdomen as

multiple liver abscesses. Blood investigations

showed a TC 22,470 , DC- P82 L5.6, Hb -6.6 gm% ,

PLT - -6.64 L, CRP -83 mg/dL, SGPT -36 IU/L.

Child was started on broad spectrum IV antibiotics

but fever persisted as high grade. On day 5 of

hospitalization he developed an abscess over

dorsum of foot for which incision and drainage was

performed. The pus grew a rare Gram negative

coccobacillus - Chromobacterium violaceum on

culture. In view of persisting fever USG guided

aspiration of liver abscess was also performed and

the aspirate also grew the same rare pathogen. In

the background of consanguineous parentage,

failure to thrive, presentation with multiple

abscesses and having grown a rare organism, we

suspected CGD. Nitroblue Tetrazolium (NBT) test

and Dihydrorhodamine flow cytometric test done

were suggestive of CGD.Serum Immunoglobulin

profile performed was normal. Hence diagnosis of

CGD was confirmed in this child. Samples of

parents and child has been sent for genotypic

diagnosis and is awaited. Child was then started on

IV Ciprofloxacin -being the sensitive antibiotic for 2

weeks on 7th day of which child became afebrile.

He was also continued on oral Levofloxacin for

another 4 weeks and also on cotrimoxazole

prophylaxis. At present the child is under regular

followup in our PID clinic gaining weight slowly.

Uunstimulated NBT (A) , stimulated NBT normal (B) , stimulated NBT abnormal (C)Growth of Chromobacterium violaceum

in blood agar

A

B

C

37

DHR flow cytometry report

References

Segal BH, Romani L, Puccetti P.

Chronic granulomatous disease. Cell

Mol Life Sci. 2009; 66:553-8.

Johnston RB Jr. Clinical aspects of

chronic granulomatous disease. Curr

Opin Hematol. 2001; 8:17-22.

Martinez CA, Shah S, Shearer WT,

Rosenblatt HM, Paul ME, Chinen J, et

al. Excellent survival after sibling or

unrelated donor stem cell transpla-

ntation for chronic granulom-atous

disease. J Allergy Clin Immunol.

2012;129:176-83.

Rapid determination of chimerism

status using Dihyrorhodamine Assay in

a patient with X-linked chronic

granulomatous disease following

hematopoietic stem cell transplantation.

Annals of Laboratory medicine

2013;33:288-92

Conclusion

In a child presenting with an unusually severe

infection or infection due to unusual organism an

inborn error of immunity should be suspected. In

infections with Chromoba-cterium violaceum the

diagnosis of CGD should be ruled out.

1.

2.

3.

4.

38

Frontal Encephalocele in a neonate

1 2Shamnad M , Muralikrishnan KT

1-Dept of Pediatrics and Neonatology 2- Dept of Pediatric Surgery Baby Memorial Hospital, Calicut

Clinical Image

A male neonate born at 38 weeks of gestation with

birth weight of 3.46 kg by LSCS with 5 X 4 cm soft

cystic pedunculated frontonasal swelling in the

midline. MRI Brain showed 5 X 4 X 3 cm

protuberant mass with soft tissue pedicle having

intracranial extension attached to right basifrontal

lobe through bony defect between right frontal

bone, nasal bone and cribriform plate suggestive of

frontanasal encephalocele. There was no facial

dysmorphism or associated anomalies. Surgical

removal of the mass was done uneventfully;

histopathological report of the excised tissue was

consistent with the clinical diagnosis.

Encephaloce le i s an open neural defect

characterized by herniation of brain and/or neural

tissue through a defect in calvarium, most common

site being occipital. Majority of cases are sporadic

although associations with syndromes (Meckel

Gruber, Walker-Warburg etc) have been reported.

Encephaloceles are associated with 60-80% risk of

associated structural abnormalities like optical,

choroidal and retinal dysplasia, ocular alterations,

central nervous system anomalies and dermoid

cyst. More than 60% may require V-P shunt for

hydrocephalus. Treatment of choice is surgical;

despite surgical advances, morbidity and mortality

still remains high. Plan is to follow the index baby

for growth, development and do serial neurological

monitoring.

Figure1: Pre-operative Figure 2: MRI Brain (Pre-op) Figure 3: Post-operative

Calicut Journal of Pediatrics 2020;1:39

39

MERS (Mild encephalitis with reversible splenial lesion)

1 2Smilu Mohanlal , Aleena Naushad

2 3Suresh Kumar E K , Rekha Narayanan

1. Department of Neurology and pediatric Neurosciences, Aster MIMS, Kozhikode

2. Department of Pediatrics, Aster MIMS, Kozhikode

3. Department of Radiology, Aster MIMS, Kozhikode

A 7-year-old boy presented with one day

history of fever and status epilepticus. On

examination he was active and alert with no

neurological deficits. Blood investigations

revealed neutrophilic leukocytosis with normal

inflammatory markers. MRI brain showed a

lesion in the splenium of corpus callosum

(Figure 1 a, b. c). Dengue serology was

negative, CSF analysis was normal and

respiratory panel was positive for Influenza A.

He was managed symptomatically with no

neurological deficits on follow up.

MERS are of two types, type 1 where lesions

are confined to the splenium of corpus

callosum and type 2 where there is additional

white matter involvement. The differentials

include posterior reversible encephalopathy

syndrome, ischemia, multiple sclerosis,

lymphoma, Infections like Influenza A,

rotavirus, measles, herpes, adenovirus, dengue,

E. coli, mumps, varicella. The mechanism is

thought to be due to angiogenic edema. MERS

has good prognosis with complete remittance

in 2-3 weeks.

Figure 1 a,b,c (clockwise from right) : a) MRI Brain Diffusion weighted imaging showing a tiny circumscribed area of diffusion restriction in the splenium of corpus callosum b) MRI Brain apparent diffusion co efficient map showing ADC reversals in the splenium of corpus callosum c) MRI T2 weighted flair sequence showing circumscribed T2 hyperintensity in the splenium of corpus callosum

Clinical Image

Calicut Journal of Pediatrics 2020;1:40 - 41

40

Compiled by: Dr Vinodkumar MS, Additional Professor, Govt Medical College, Kozhikode

PG QUIZ

Specific antidote used in a child with

significant QRS widening following TCA

(Tricyclic antidepressant) poisoning is

Name the condition with severe urinary

frequency during the day, without dysuria,

UTI,daytime incontinence, or nocturia

Unfractionated Heparin is monitored using

the aPTT .What test is used to monitor

LMWH effect

Endocrine disorder associated with low

levels of vWF

Genetic disease for which egg therapy is

indicated

HIV positive children with history of severe

adverse reaction to cotrimoxazole or other

sulfa drugs & children with G6PD

deficiency should not be initiated on

Cotrimoxazole Preventive Therapy (CPT).

Name the alternative drug to be used in such

situations :

Children with chronic hookworm disease

acquire a yellow-green pallor known as :

What is the diagnosis in this 16 month old

child who had hypotonia, head lag in 1st few

weeks of life followed by macrocephaly,

spasticity & seizures . MRI & MRS is shown

Helmet therapy is used in

Sad old man facies is seen in

Microcytic anemia, osteoporosis, neutro-

penia are seen in which trace element

deficiency

Which LSD is associated with joint

swellings thus mimicking JIA ?

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

41

PG QUIZ

Sodium bicarbonate

Pollakiuria

Anti–factor Xa activity

Hypothyroidism

Smith Lemli-Opitz syndrome

Dapsone/Aerosolised Pentamidine

Chlorosis.

Canavan disease

Deformational Plagiocephaly

SSSS

Copper

Farber disease

Answers

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

42

Calicut Journal of PediatricsOfficial Journal of IAP Kozhikode

Author Instructions Editorial Process

Editorial Process A manuscript will be reviewed for possible publication with the understanding that it is being submitted to Calicut Journal of Pediatrics alone at that point in time and has not been published anywhere, simultaneously submitted, or already accepted for publication elsewhere. The journal expects that authors would authorize one of them to correspond with the Journal for all matters related to the manuscript. All manuscripts received are duly acknowledged. On submission, editors review all submitted manuscripts initially for suitability for formal review.

Manuscripts with insufficient originality, serious scientific or technical flaws, or lack of a significant message are rejected before proceeding for formal peer-review. Manuscripts that are found suitable for publication in Journal of Calicut Journal of Pediatrics will be sent to two expert reviewers. Journal will follow a double-blind review process, wherein the reviewers and authors will be unaware of each other’s identity. Every manuscript will be assigned to a member of the editorial team, who based on the comments from the reviewers takes a final decision on the manuscript. The comments and suggestions (acceptance/ rejection/ amendments in manuscript) received from reviewers will be conveyed to the corresponding author. If required, the author will be requested to provide a point by point response to reviewers’ comments and submit a revised version of the manuscript. This process is repeated till reviewers and editors are satisfied with the manuscript.

Manuscripts accepted for publication will be copy edited for grammar, punctuation, print style, and format. Page proofs wil l be sent to the corresponding author. The corresponding author is expected to return the corrected proofs within three days. It may not be possible to incorporate corrections received after that period. The whole process of submission of the manuscript to final decision and sending and receiving proofs will be

done onlinAuthorship Criteria

Authorship credit should be based only on substantial contributions to each of the three components mentioned below:

1. Concept and design of study or acquisition of data or analysis and interpretation of data;

2. Drafting the article or revising it critically for important intellectual content; and

3. Final approval of the version to be published.

Each contributor should have participated sufficiently in the work to take public responsibility for appropriate portions of the content of the manuscript. The order of naming the contributors should be based on the relative contribution of the contributor towards the study and writing the manuscript. Once submitted the order cannot be changed without written consent of all the contributors. Contributors should provide a description of contributions made by each of them towards the manuscript. Description should be divided in following categories, as applicable: concept, design, definition of intellectual content, literature search, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing and manuscript review. Authors' contributions will be printed along with the article

Conflicts of Interest

All authors must disclose any and all conflicts of interest they may have with publication of the manuscript or an institution or product that is mentioned in the manuscript.

Submission of Manuscripts

All manuscripts must be submitted to the editor or sub-edior by email (drsgireesh@gmail.com,

43

abdrauf06@gmail.com). The journal does not charge for submission and processing of the manuscripts. If you experience any problems, please contact the editor or sub editor by e-mail or phone

The submitted manuscripts that are not as per the "Instructions to Authors" would be returned to the authors for technical correction, before they undergo editorial/ peer-review.

Preparation of manuscript

A summary of technical requirements for preparing the manuscript is provided below:

Ÿ Use American (US) English throughout. Ÿ Double-space throughout, including title

page, abstract, main text, key messages, references, figure legends and tables. Start each of these sections (in same order) on a new page, numbered consecutively in the upper right hand corner.

Ÿ Use 12-point font size (Times New Roman) and leave margins of 1.75 cm (0.7 inch) on all sides. The whole manuscript should be formatted in 'portrait' layout.

Ÿ Units of measure: Conventional units are preferred. The metric system is preferred for the expression of length, area, mass and volume.

Ÿ Use non-proprietary names of drugs, devices and other products.

The manuscript should be submitted as Microsoft word file including following sections:

[1] Title Page:

This page should provide

1. The type of manuscript (original article, case report, review article, Letter to editor, Images, etc.) title of the manuscript, running title, names of all authors/ contributors (with their highest academic degrees, designation and affiliations) and name(s) of department(s) and/ or institution(s) to which the work should be credited.

2. The total number of pages, total number of photographs and word counts separately for

abstract and for the text (excluding the references, tables and abstract

3. Source(s) of support in the form of grants, equipment, drugs, or all of these;

4. Acknowledgement, if any. 5. If the manuscript was presented as part at a

meeting, the organization, place, and exact date on which it was done.

6. Registration number in case of a clinical trial and where it is registered (name of the registry and its URL)

7. Conflicts of Interest of each author/ contributor. A statement of financial or other relationships that might lead to a conflict of interest.

8. Criteria for inclusion in the authors'/ contributors' list

9. A statement that the manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.

10. The name, address, e-mail, and telephone number of the corresponding author, who is responsible for communicating with the other authors about revisions and final approval of the proofs

[2] Blinded Article: The main text of the article, beginning from Abstract till References (including tables) should be in these pages. These must not contain any mention of the authors' names or initials or the institution at which the study was done or acknowledgements. Do not incorporate images in these pages. The pages should be numbered consecutively.

3- Tables- Type each table with double-spacing on a separate sheet of paper. Do not submit tables as photographs. Number tables consecutively in the order of their first citation in the text, and supply a brief but self-explanatory title for each. Tables with only two columns or those with more than 7 columns should be avoided. Also avoid tables with more than 20 Rows as these are likely to cross-over to the next page during printing. Give each column a short or abbreviated heading in italic font style. Place explanatory matter in footnotes, not in the heading. Explain in footnotes all abbreviations that are used in each table. For footnotes use the

44

following symbols, in this sequence: *, #, $, and so on. Be sure that each table is cited in the text.

4: Illustrations (Figures)

Figures should be sent as separate files. It is preferable to have the photograph in portrait form rather than in landscape form to fit easily into one column. Letters, numbers, and symbols in photographs should be clearly legible. The electronically submitted images should be of high resolution (>300 dpi). Only JPEG files are acceptable. Figures should be submitted separately f r o m t h e t ex t f i l e. I f p h o t o g r a p h s o f individual/people are used, either they must not be identifiable or their pictures must be accompanied by written permission to use the photograph. It is advisable to cover the eyes unless specifically need to be shown. If a figure has been published, acknowledge the original source and submit written permission from the copyright holder to reproduce the material. Figures should be numbered consecutively according to the order in which they have been first cited in the text.

Figure legend: Type or print out legends for illustrations using double-spacing, in a separate page at the end of main text with Arabic numerals corresponding to the illustrations. When symbols, arrows, numbers, or letters are used to identify parts of the illustrations, identify and explain each one clearly in the legend.

5- The contributors' / copyright transfer form has to be submitted in original with the signatures of all the contributors within two weeks of submission via email as a scanned image/photo.

Types of Manuscripts-

Original articles: These include randomized controlled trials, intervention studies, studies of screening and diagnostic test, outcome studies, cost effectiveness analyses, case-control series, and surveys with high response rate. The text of original articles amounting to up to 3000 words (excluding Abstract, references and Tables) should be divided into sections with the headings Abstract, Key-words, Introduction, Material and Methods,

Results, Discussion, References, Tables and Figure legends.

Ÿ Introduction: State the purpose and summarize the rationale for the study or observation.

Ÿ Materials and Methods: It should include and describe the following aspects:

Ethics: When reporting studies on human beings, indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 2000. For prospective studies involving human participants, authors are expected to mention about approval of Ethics Committee or Review Board, obtaining informed consent from adult research participants and obtaining assent for children aged over 7 years participating in the trial. Ensure confidentiality of subjects by desisting from mentioning participants' names, initials or hospital numbers, especially in illustrative material. The journal will not consider any paper which is ethically unacceptable. A statement on ethics committee permission and ethical practices must be included in all research articles under the 'Materials and Methods' section.

Study design: Selection and Description of Participants: Describe your selection of the observational or experimental participants clearly, including eligibility and exclusion criteria and a description of the source population. Technical information: Identify t h e m e t h o d s , a p p a r a t u s ( g i ve t h e manufacturer 's name and address in parentheses), and procedures in sufficient detail to allow other workers to reproduce the results.. Reports of randomized clinical trials should present information on all major study elements, including the protocol, assignment of interventions (methods of randomization, concealment of allocation to treatment groups), and the method of masking (bl inding), based on the CONSORT S t a t e m e n t ( h t t p : / / w w w. c o n s o r t -statement.org).

45

Statistics: Whenever possible quantify findings and present them with appropriate indicators of measurement er ror or uncertainty (such as confidence intervals). Authors should report losses to observation (such as, dropouts from a clinical trial). When data are summarized in the Results section, specify the statistical methods used to analyze them. Specify the computer software used.

Ÿ Results: Present your results in a logical sequence in the text, tables, and illustrations, giving the main or most important findings first. Do not repeat in the text all the data in the tables or illustrations; emphasize or summarize only important observations.

Ÿ Discussion: Include summary of key findings (primary outcome measures, secondary outcome measures, results as they relate to a prior hypothesis); Strengths and limitations of the study (study question, study design, data collection, analysis and interpretation); Interpretation and implications in the context of the totality of evidence, what this study adds to the available evidence; Controversies raised by this study; and Future research directions. Do not repeat in detail data or other material given in the Introduction or the Results section. About 30 references can be included.

Case reports:

New, interesting and rare cases can be reported. They should be unique, describing a great diagnostic or therapeutic challenge and providing a learning point for the readers. Cases with clinical significance or implications will be given priority. These communications could be of up to 1000 words (excluding Abstract and references) and should have the following headings: Abstract (unstructured), Key-words, Introduction, Case report, Discussion, Reference, Tables and Legends in that order. The manuscript could be of up to 1000 words (excluding references and abstract) and could be supported with up to 10 references.

Review Articles:

It is expected that these articles would be written by individuals who have done substantial work on the

subject or are considered experts in the field. A short summary of the work done by the contributor(s) in the field of review should accompany the manuscript. The prescribed word count is up to 3000 words excluding tables, references and abstract. The manuscript may have about 90 references. The manuscript should have an unstructured Abstract (250 words) representing an accurate summary of the article. The section titles would depend upon the topic reviewed. Authors submitting review article should include a section describing the methods used for locating, selecting, extracting, and synthesizing data.

Interesting Images:

Only cl inical photographs with/without accompanying skiagrams or pathological images are considered for publication. Images of radiographs/histopathology slides alone (without accompanying clinical photograph) are not considered for this section. Image should clearly identify the condition and have the classical characteristics of the clinical condition. Clinical photograph of conditions that are very common, extremely rare, where diagnosis is obvious would not be considered. A short text of about 150 words should be provided in two paragraphs; first paragraph having description of condition, and second paragraph discussing differential diagnosis and management. No references are needed. See guidelines for preparing and submitting figures given later.

Other:

Editorial, PG Quiz Column, Book review/Journal scan will be solicited by the editorial board.

Reference Style References should be numbered consecutively in the order in which they are first mentioned in the text (not in alphabetic order). Identify references in text, tables, and legends by Arabic numerals in superscript with square bracket after the punctuation marks. References cited only in tables or figure legends should be numbered in accordance with the sequence established by the first identification in the text of the particular table or figure. Use the style of the examples below, which are based on the formats used by the NLM in Index Medicus. The titles of journals should be

46

abbreviated according to the style used in Index Medicus. Use complete name of the journal for non-indexed journals. The commonly cited types of references are shown here, for other types of references such as newspaper items please refer to ICMJE Guidelines (http://www.icmje.org or http://www.nlm.nih.gov/bsd/uniform_requirements.html).

Articles in Journals

1. Standard journal article (for up to six authors): Parija S C, Ravinder PT, Shariff M. Detection of hydatid antigen in the fluid samples from hydatid cysts by co-agglutination. Trans. R.Soc. Trop. Med. Hyg.1996; 90:255–6.

2. Standard journal article (for more than six authors): List the first six contributors followed by et al.

Roddy P, Goiri J, Flevaud L, Palma PP, Morote S, Lima N, et al. Field Evaluation of a Rapid Immunochromatographic Assay for Detection of Trypanosoma cruzi Infection by Use of Whole Blood. J. Clin. Microbiol. 2008; 46: 2029-31.

Books and Other Monographs

1. Personal author(s): Parija SC. Textbook of Medical Parasitology. 3rd ed. All India Publishers and Distributors. 2008.

2. Editor(s), compiler(s) as author: Garcia LS, Filarial Nematodes In: Garcia LS (editor) Diagnostic Medical Parasitology ASM press Washington DC 2007: pp 319-56.

3. Chapter in a book: Nesheim M C. Ascariasis and human nutrition. In Ascariasis and its prevention and control, D. W. T. Crompton, M. C. Nesbemi, and Z. S. Pawlowski (eds.). Taylor and Francis,London, U.K.1989, pp. 87–100

47

A journey of a thousand milesbegins with a single Step.- Lao Tzu

48

www.iapcalicut.org