BY DR.KIRUTHIKA.S

DR.LATHA RAVICHANDRAN,SRI RAMACHANDRA MEDICAL COLLEGE.

UNUSUAL CAUSE FOR MACROCEPHALY

HISTORY

Ruthiresan 13 yr old male born out of non-consanguinous marriage

Large headChest deformityMultiple skin lesions over trunk & extremities

No symptoms of raised ICPNo bony abnormalities / Fractures

PAST HISTORY

Parents noticed increase in the size of head since 9 months of age

But he was evaluated only at 4 yrs of age

Serial CT Scans done in various centres thereafter were normal

No significant medical illnesses

HISTORY

Antenatal H/O : No H/O fever with rash / Systemic Illnesses / radiation exposure / drug intake. AN USG scans - Normal

Natal H/O: FTNVD,b.wt 3kg. cried immediately

Postnatal H/O: uneventfulDevelopmental H/O: Early developmental

milestones were delayed. Poor Scholastic performance

Immunization H/O: Immunized Up To Date. Optional vaccines not given.

GENERAL EXAMINATION

Afebrile, alert, no pallor / icterus/ cyanosis/ clubbing/ lymphadenopathy/ pedal edema

Vitals : RR 20/min PR 102/min BP 100/70 right UL sitting

posture CFT < 3 sec PP well felt

ANTHROPOMETRY

ANTHRO. INDICES

CURRENT VALUE

EXPECTED VALUE

CENTILE INTERPRETATION

WT 30.5 40 < 3RD Undernutrition

HT 147 155 25TH Normal

HC 58 52 >97TH Macrocephaly

BMI 13 18 - 25 <3RD Undernutrition

SMR Stage 4 Postpubertal

GENERAL EXAMINATION

HEAD TO FOOT EXAMINATIONMacrocephalyPectus excavatumMutiple Café-au-lait spots >10 in no. >15mm size

Nipple & areola enlargedAxillary freckling left side

SYSTEMIC EXAMINATION

RS –normal vesicular breath sounds presentCVS – S1 S2 present, no murmurABDOMEN –soft, no warmth, non tender genitalia well developed, pubic

hair thick ,plenty• CNS –higher function normal cranial nerves normal motor /sensory/autonomic normal spine ,cranium normal

INVESTIGATION

Blood routine – normalRenal function test – normalThyroid function test – normal Urine routine – normalX ray wrist AP view for bone age –

normalUSG abdomen – normal Urine spot calcium, phosphorus -

normal

FURTHER WORKUP

OPTHALAMIC EVALUATION : slit lamp examination revealed Lisch nodules in both eyes, fundus was normal, no evidence of optic glioma.

PSYCHOLOGICAL ASSESSMENT: his IQ was 55% with learning disability.

MRI BRAIN: showed Unidentified bright objects (UBOs) in the left frontal and hypothalamus.Size of ventricles were normal

MRI BRAIN

UBO

FINAL DIAGNOSIS – NEUROFIBROMATOSIS - 1

CRITERIA FOR DIAGNOSIS :Café-au-lait spotsAxillary or Inguinal frecklingLisch nodulesNeurofibromaDistinctive osseous lesionOptic gliomaIst degree relative with NF1Our patient satisfied 3 out 7 criterias hence

diagnosed as NEUROFIBROMA TYPE I

LITERATURE REVIEW

NEUROFIBROMA TYPE I

Also known as Von reckling hausen diseaseAutosomal Dominant Inheritance Neurocutaneous syndrome – defect in

differentiation of primitive ectodermConsequence of abnormality of neural crest

differentiation and migration during early stages of embryogenesis

NF1 gene – 17q11.2 encodes all mRNA of 11 – 13 kb containing atleast 59 exons that produce a protein Neurofibromin.

More than 300 independent mutation reported.Majority of mutations in paternal germline

CLINICAL MANIFESTATION AND DIAGNOSTIC CRITERIA

1. Café-au-lait macules 6 or more over 5mm in greatest diameter in

prepubertal individualOver 15mm in postpubertal individuals Hallmark of NF1 almost 100% in patients with

predilection over trunk, extremities with sparing of face

2. Axillary or inguinal freckling multiple hyperpigmented areas 2-3 mm in diameter3. Lisch nodules 2 or more, hamartomas located within the iris. Best identified by a slit lamp examination.>74%

patients of NF1.

4. Neurofibroma Small rubbery lesion with a slight purplish

discoloration of the overlying skin 2 or more or one plexiform neurofibroma.Neurofibroma typically involve skin but may also

involve peripheral nerves, blood vessels within viscera.

characteristically appear during adolescence or pregnancy suggesting a hormonal influence.

Plexiform neurofibroma Evident at birth and result from diffuse thickening of

nerve trunks frequently located in orbital or temporal region of

face.Produce overgrowth of extremity and a deformity of

the corresponding bone.

5. Optic glioma • 15% patients,relatively benign tumour consisting of glial cells and a mucinous material.•Mostly asymptomatic. 20%have visual disturbance and precocious puberty.•MRI –a distinct focal mass originating from optic nerve or chiasma.

6. First degree relative with NF1 ,whose diagnosis was based on aformentioned criteria

7. DistinctiveOsseousLesion•Sphenoid Dysplasia causing pulsating exophthalmos. Cortical thinning of long bones.•Scoliosis most common orthopedic deformity

CAFÉ-AU-LAIT SPOTS

AXILLARY AND INGUINAL FRECKLING

LISCH NODULES

NEUROFIBROMA

OSSEOUS LESION

OPTIC GLIOMA

LEFT OPTIC N GLIOMA

COMPLICATIONS OF NF1

Cognitive abnormalities like learning disabilities are common and occur in 40 – 60% of NF1 patients.

Complex partial and generalised tonic clonic seizures are a frequent complications.

Hydrocephalus is a rare manifestation secondary to adueductal stenosis.Whereas macrocephaly with normal ventricles is a common finding.

MRI – hyperintense signals in optic track,brainstem,internal capsule, Cerebellum.These are ‘UNIDENTIFIED BRIGHT OBJECTS’(UBOs) that tend to disappear by 30yrs of age.

.

•Cerebral vessels may develop aneurysms or stenosis resulting in moyamoya disease.Neurologic sequelae of this vascular abnormality include transient ischemic attacks ,hemiparesis,cognitive defects.

•Precocious puberty become evident in the presence or absence of lesions in optic chiasma and hypothalamus

•Malignant neoplasms are also significant in NF1. Neurofibroma occasionally differentiates in to a neurofibrosarcoma or malignant schwannoma.

•Patient with NF1 at risk for hypertension,resulted from renal vascular stenosis or a pheochromocytoma.Incidence of pheochromacytoma, rhabdomyosarcoma, leukemia,wilms tumour is higher than in general population.

•Unusual association involving myeloid leukemia, juvenile xanthogranuloma and NF1.

UBOs

UBO

WORKUP

Molecular testing- in patient with a single clinical finding without positive family h/o

Linkage analysis in a patient with multiple affected family members.

Prenatal diagnosis via chorionic villus sampling when specific gene mutation is known

Preimplantation genetic diagnosis using in vitro fertilisation with selection of unaffected embryos for transfer.

24 hr urinary free catecholamine EEG

Imaging studies

X ray long bones to visualise lytic lesionsMRI - UBOs are thought to represent areas

of dysmyelination or focal areas of increased water content,not detected by CT Scan. Do not cause mass effect.

Gallium 67 scintigraphy – for patients with a large plexiform neurofibroma undergo malignant transformation

Myelography – to clarify the extent of a spinal cord tumor.

MANAGEMENT

MEDICAL CARE :Detailed history,physical examination by a

pediatrician.Thorough annual ophthalmic examination by a

pediatric opthalmologist until the age of 10.then routine visual assessment is recommended for early detection of optic glioma

Cutaneous examination at each visit to look for new lesions, or progression of prexisting ones.

Skeletal involvement should be determined.Blood pressure checked at each visit and treated

promptly if detected.

To be continued…..

Interval h/o should focus on subtle sensory or motor symptoms such as paresthesia, radiculopathy , weakness or muscle atrophy.

Chemotherapy to treat malignant peripheral nerve shealth tumors (MPNSTs) that are unresectable or metastatic.

Medications used -Farnesyl transferases with Lovastatin, Sorafenib,Rapamycin complex 1 inhibitor with Erlotinib,Carboplatin, Hyaluronan oligomers with Doxorubicin

MANAGEMENT

Surgical care :Neurofibroma that press on vital organs,obstruct

vision,grow rapidly deserve immediate attention.Plastic surgery consultation is advisable for areas of

great cosmetic concern like face.Symptomatic peripheral nerve sheath tumors located

along the nerve of brachial or pelvic plexus sometimes require surgical resection.

Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia

Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.

FROM ABTRACTS

Macrocephaly in NF1 patients is related to increased grey matter volume and white matter volume and corpus callosum enlargement

-Margariti PN, Blekas K, et al; Department of Radiology, University of Ioannina, Ioannina, Greece; Eur Radiol .2007;17(2):433-8

Delayed developmental apoptosis results in macrocephaly and delay in the development of appropriate neuronal connection in children with NF1.

-Moore BD, Slopis JM, Jackson EF,et al; Division of Paediatrcs, University of Texas Medical division, Anderson Cancer Centre,Houston. Neurology.2000;54(4): 914-20

The short stature was evident in adolescents girls of NF1 than NF1 boys but macrocephaly was evident in both sexes 31%.The 97th centile of the affected NF1 were above the 97th centile of healthy persons

-Rafia S,Garcia Pena JJ.et al; Serviciode neurologia pediatrica, Hospital Infantil Universitario Lapaz, Madrid, Spain; Rev Neurol.2004; 38(1):1009-12

REFERENCES

Nelson textbook of peditrics -18th edition

Textbook of pediatric neurology –Fenichel

Neurofibromatosis center of New Jersey, Author Beth A Pletcha. Deparment of Pediatrics, University of medicine, New Jersey

THANK YOU