approach to dysmorphic child
TRANSCRIPT
02/25/15 Sid 2
Congenital Anomalies
• 20 - 25% of perinatal deaths are due to lethal birth defects– 10% of deaths in infants weighing 500 - 1500
gm– 50% of deaths in infants > 1500 gm
02/25/15 Sid 3
Birth Defects Estimated Incidence Structural/Metabolic
Heart and circulation 1 in 115 births Muscles and skeleton 1 in 130 births Club foot 1 in 735 births Cleft lip/palate 1 in 930 births
Genital and urinary tract 1 in 135 births Nervous system and eye 1 in 235 births Anencephaly 1 in 8,000 births Spina bifida 1 in 2,000 births Chromosomal syndromes 1 in 600 births
Down syndrome (Trisomy 21) 1 in 900 births Respiratory tract 1 in 900 births Metabolic disorders 1 in 3,500 births PKU 1 in 12,000 births
Congenital Infections Congenital syphilis 1 in 2,000 births Congenital HIV infection 1 in 2,700 births Congenital rubella syndrome 1 in 100,000 births
Other Rh disease 1 in 1,400 births Fetal alcohol syndrome 1 in 1,000 births
March of Dimes, 2000.
02/25/15 Sid 4
Causes of Birth Defects
• Multifactorial: 20-30%• Single gene disorders: 10-20%• Chromosomal: 15%• Infection: 2.5%• Maternal diabetes: 1.5%• Maternal medications: 1-2%• Rest unknown
02/25/15 Sid 5
Empiric Recurrence Risks for for Birth Defects
Condition Affected Relatives(s) None 1 sib/parent 2 sibs / sib & parent Cleft lip/palate 0.1 4 10-11Cleft palate only 0.04 2-7 15 NTD 0.1 3 8 CHD (any) 0.3 4-5 10-11
VSD 3-4 10 Hypoplastic left heart 2 6
02/25/15 Sid 6
• Dysmorpholgy: study of abnormal forms• Dysmorphic: abnormal appearing
• Congenital: at birth• Anomaly: abnormality
• Just because it’s congenital it doesn’t mean it’s genetic
• One goal of the dysmorphologist is help determine the etiology of congenital anomalies
02/25/15 Sid 7
Who needs a dysmorphology evaluation?
•A history of intrauterine growth retardation or failure to thrive •Abnormal growth (short, excessive) •Abnormal or unusual facial features •Abnormal body and limb proportions or asymmetry •Major and/or minor congenital anomalies•Microcephaly, macrocephaly or craniosynostosis •Ambiguous or abnormal genitalia, early or late onset of puberty •Psychomotor delay or mental retardation •Hypotonia, hypertonia •A relative with problems similar to those of patient •Metabolic problems•Bleeding tendency •Blindness or deafness •A significant regression in developmental progress •An unusual body odor •Excessive unexplained vomiting •Unusual behaviors, especially when associated with minor malformations
02/25/15 Sid 8
Purposes of a Medical Genetics Evaluation:
New Patients:• Establish or confirm a specific diagnosis• Enable accurate, individualized counseling• Determine precise recurrence risks• Obtain necessary diagnostic tests• Provide specific education and support• Initiate appropriate referrals• Plan for focused medical management and follow-up
Established Patients (follow-up care):• Assess new medical problems and related concerns• Determine compliance with recommended management• Keep patients informed about new diagnostic and
management strategies• Provide ongoing age-appropriate education/support• Help coordinate necessary referrals and evaluations• Evaluate other at risk family members
02/25/15 Sid 9
Approach to Birth Defects &Congenital Anomalies
• Recognize associated abnormalities and medical problems• Make an accurate diagnosis• Give an accurate, realistic prognosis and natural history of
the disorder to the family• Discuss options and alternatives for management• Deliver appropriate medical care and/or treatment• Prevent subsequent related complications • Optimize quality of life • Determine and provide recurrence risks • Offer genetic and psychosocial counseling• Provide anticipatory guidance and education
02/25/15 Sid 10
1. Where are the problems? 2. What are the problems?3. What is the diagnosis?4. What are associated problems?5. When could they have happened?6. How did they arise?7. Why did they occur?8. Who is at risk?
02/25/15 Sid 11
Observable Differences of Human Phenotypes
• Normal variations• Minor anomalies • Major anomalies
Anomalies and normal variants can serve as indicators of altered morphogenesis and clues to patterns of malformation
02/25/15 Sid 12
A Range of Phenotypic Variation is Normal
• “Normal” spectrum of human variation of morphological features with absolutely no medical significance (eg. Epicanthal folds, ‘attached’ vs. ‘unattached ear lobes’,
• Observed in > 4% of the population
02/25/15 Sid 13
Minor Anomaly
• Minor variations of normal morphological features of little of no known medical, surgical, or cosmetic significance
• Observed in < 4% of the population
02/25/15 Sid 14
Copyright ©2002 Canadian Medical Association or its licensors
Hunter, A. G.W. CMAJ 2002;167:367-372
02/25/15 Sid 15
02/25/15 Sid 16
Major Anomaly
• Abnormality that has – Medical– Surgical or – Cosmetic significance
02/25/15 Sid 17
Suspect a genetic condition or syndrome when...
• Multiple anomalies• More than 3 minor anomalies• More than one major anomaly• One major anomaly and a few minor
anomalies
02/25/15 Sid 18
Variable Expression• Morphological features may be expressed at different
degrees of severity in individuals resulting in different levels of dysfunction and problems for individuals having the “same” abnormality, even when due to the same etiology
• Each individual with a particular syndrome, sequence, or association will not have every known feature of that disorder, or all the same features as one another, even if in the same family
• The degree of variable expression may correlate with the degree of pleiotropy in single gene disorders
02/25/15 Sid 19
Incomplete Penetrance• An “all or none” phenomena referring to the
presence or absence of observable phenotypic expression of features of a dominant disease in an individual known to have a mutant allele
• Some individuals with Tuberous Sclerosis appear to have incomplete penetrance
02/25/15 Sid 20
Sex-Influenced or Limited Expression
• Some congenital anomalies and/or genetic syndromes due to autosomal defects are more easily recognized, or only recognized, in individuals of a particular gender– Sex influenced: Genital hypoplasia, hypospadias,
virulization with hypertrophy of the clitoris– Sex limited: Hereditary prostate cancer
02/25/15 Sid 21
Types of Morphologic Abnormalities
• Malformation• Deformation• Disruption• Dysplasia
02/25/15 Sid 22
02/25/15 Sid 23
Malformation
• Defect of morphogenesis in an organ or structure due to an intrinsically abnormal problem with formation, growth, or differentiation of an organ or structure– hypoplasia of an organ or structure (microtia),
incomplete closure (NTDs, cleft palate), incomplete separation (syndactaly)
02/25/15 Sid 24
02/25/15 Sid 25
Timing is
everything!
02/25/15 Sid 26
Malformations are not specific
• The same morphological defect, or even a similar pattern of abnormalities, may occur as:– An isolated anomaly in an otherwise normal individual– A feature in a syndrome, sequence, or association– A feature of a chromosome disorder, a single gene
defect, multifactorial disorder, or secondary to a teratogenic effect
02/25/15 Sid 27
Deformation
• Abnormal form or position of a body or region of the body caused by extrinsic non-disruptive mechanical forces on a normally developing structure (fetal constraint)– clubfoot, congenital hip dislocation, craniofacial
asymmetry, over folded ear…..
02/25/15 Sid 28
Disruption• Defect of morphogenesis resulting from a
destructive breakdown of, or interference with, a normally developing structure resulting in death of cells or tissue destruction. May be secondary to mechanical forces, infections, or even vascular events. – Loss of digit due to amniotic bands, lack of normal
limb development due to intrauterine vascular accident
02/25/15 Sid 29
Dysplasia
• Error of morphogenesis due to the abnormal cellular organization of function in a specific type of tissue most often due to single gene defects– Achrondroplasia, ectodermal dysplasia,
osteogenesis imperfecta,
02/25/15 Sid 30
02/25/15 Sid 31
Recognizable Patterns of Anomalies
• Syndromes• Associations• Sequences or field defects
02/25/15 Sid 32
Syndrome
• Multiple anomalies in one or more tissues or structures thought to be pathologically related due to a specific etiologic mechanism (chromosome disorder, single gene defect, environmental agent, or unknown factor), not due to a related sequence of defects or field defect.– Down syndrome, Williams syndrome, FAS, Turner
syndrome, Gorlin syndrome….
• From Greek meaning “running together”
02/25/15 Sid 33
Genetic heterogeneity
• Even when phenotypically similar disorders have clear genetic etiologies, locus heterogeneity, and sometimes even allelic heterogeneity, may complicate laboratory testing and influence diagnosis, counseling, management, and prognosis– Locus heterogeneity: Tuberous Sclerosis, PKD– Allelic heterogeneity: Craniosynostosis, CF
02/25/15 Sid 34
Sequence/Field Defect• Constellation of defects derived from a cascade of
effects related to a single known, or presumed, localized abnormality (malformation, deformation, disruption)– Potter sequence
• Renal dysplasia, pulmonary hypoplasia, facial dysmorphisms
– Mandibular hypoplasia (Robin sequence)• Cleft palate
– Meningomyelocele• Club foot, hip dislocation, hydrocephalus
02/25/15 Sid 35
Association
• Non-random occurrence of a combination of several anomalies not yet identified as a specific sequence or syndrome that occur more often together than by chance alone.– VATER and CHARGE associations
02/25/15 Sid 36
General Caveats of Dysmorphology
• Having a diagnosis, even if bad, is more useful for families than having no diagnosis
• A wrong diagnosis is worse than no diagnosis• A diagnosis depends on the clinical recognition of
patterns of abnormalities as supported by appropriate laboratory and imaging tests
• Etiological heterogeneity and variable expression of abnormalities often makes the diagnostic evaluation challenging
• Time and library/database searches can provide clues to diagnosis
02/25/15 Sid 37
Reasons why difficulty in diagnosing Syndromes may be encountered
• Some are very rare disorders - not well described• Problems with lumping and splitting• Variable expression• Incomplete penetrance• Sex influenced or limited expression• Pleiotropy• Etiologic heterogeneity
02/25/15 Sid 38
02/25/15 Sid 39
Management of Congenital Anomaliesin the Fetus or Newborn
• Conduct careful clinical evaluation• Review family, prenatal history, and perinatal history• Obtain diagnostic studies
– Imaging studies: Photographs, X-rays– Laboratory studies: Chromosome, DNA, biochemical assays
• If deceased, request autopsy and specific pathological analyses• Provide parents an opportunity to see child
– Name, photograph,obtain hair, memorialize, bury...
• Provide referrals to social work/psychological services and support groups as appropriate
• Arrange follow-up genetic counseling
02/25/15 Sid 40
Talking with Families about Birth Defects
• Avoid delivery room diagnosis and counseling• Explain medical concerns openly and honestly• Humanize abnormal findings and note normal findings• Use diagnostic/medical terms only as appropriate• Avoid extensive differential diagnoses• Be careful about premature prognostication• Watch your facial expressions and body language• Listen to concerns and adhere to their agenda• Be supportive but not unrealistic or enmeshed• Provide frequent, honest updates of accurate information• Provide psychosocial support services
Ambiguous genitalia of a baby girl - the simple virilising form of congenital adrenal hyperplasia
02/25/15 Sid 42
Ogilvy-Stuart, A L et al. Arch Dis Child 2004;89:401-407
Differential virilisation of the external genitalia using the staging system of Prader, from normal female (left) to normal male (right). Sagittal (upper panel) and perineal (lower panel) views shown.
Ambiguous Genitalia
02/25/15 Sid 43
Ogilvy-Stuart, A L et al. Arch Dis Child 2004;89:401-407
Investigation flow plan for assessment of ambiguous genitalia
02/25/15 Sid 44
Down syndrome
02/25/15 Sid 46
Trisomy 21• Brachycephaly • Flat facial profile • Small ears • Folded helix • Conductive hearing loss • Upslanting palpebral fissures • Epicanthal folds • Iris Brushfield spots • Protruding tongue • Congenital heart defect • Atrioventricular canal • Duodenal stenosis/atresia• Imperforate anus• Hirschsprung disease • Atlanto-axial instability• Hypoplastic iliac wings • Shallow acetabulum
• Joint laxity • Short, broad hands • Fifth finger mid-phalanx hypoplasia • Single transverse palmar crease • Excess nuchal skin • Single transverse palmar crease • Mental retardation • Alzheimer disease • Hypotonia, poor Moro reflex • Hypothyroidism • Acute megakaryocytic leukemia • Increased recurrence risk with
parental translocation • Incidence, 1 in 650-1000 live births • Full trisomy 21, 94% • Mosaic trisomy 21, 2.4% • Translocation 21, 3.3%
02/25/15 Sid 47
Trisomy 18
02/25/15 Sid 48
Trisomy 18
• Incidence: 1 in 3000• Girls : Boys 3:1• Low birth weight infant • Mental deficiency • Low-set ears • Small jaw (micrognathia) • Clenched hands • Hypoplastic (underdeveloped)
fingernails • Umbilical hernia or inguinal hernia • Diastasis recti • Cryptorchidism
• Crossed legs (preferred position) • Congenital heart disease o VSD) o ASDo PDA Congenital kidney
abnormalities o Horseshoe kidney o Hydronephrosis o Polycystic kidney • Coloboma of iris • Microcephaly • Pectus carinatum
02/25/15 Sid 49
Trisomy 13
02/25/15 Sid 50
Trisomy 13
• Incidence 1 in 5000 live births• Mental retardation, severe • Seizures • Small head (microcephaly) • Scalp defects (absent skin) • Small eyes (microphthalmia) • Cleft lip and/or palate • Eyes close set (hypotelorism) --
eyes may actually fuse together into one
• Iris defects (coloboma) • low set ears • Simian crease
• Ventricular septal defect (VSD) • Atrial septal defect (ASD) • Patent ductus arteriosus (PDA)
• Hernias: umbilical hernia, inguinal hernia
• Undescended testicle (cryptorchidism)
• Hypotonia • Micrognathia o Skeletal (limb) abnormalities
• Extra digits (polydactyly)
02/25/15 Sid 51
Marfan syndrome
02/25/15 Sid 52
Marfan syndrome
• Autosomal dominant• Disproportionate tall stature, upper to
lower segment ratio less than 0.85 • Arm span to height > 1.05 • Dolichocephaly • Long, narrow face • Malar hypoplasia • Micrognathia • Retrognathia • Enophthalmos• Ectopia lentis • Myopia • Retinal detachment • Early glaucoma • Early cataracts • Down-slanting palpebral fissures
• High-arched palate • Aortic regurgitation • Mitral regurgitation • Mitral valve prolapse • Aortic root dilatation • APectus excavatum
• Pectus carinatum ortic dissection• Scoliosis • Kyphoscoliosis
• Thoracic lordosis • Spondylolisthesis
• Arachnodactyly • Caused by mutations in the fibrillin-1
gene• About 25% of cases due to new
mutations
02/25/15 Sid 53
02/25/15 Sid 54
Cornelia De Lange Syndrome • The incidence is 1 case per 10,000-
50,000 live births • Short stature • Microcephaly (98%) • Short neck (66%) • Hirsutism (78%)• Cutis marmorata and perioral cyanosis
(56%)• Hypoplastic nipples and umbilicus
(50%)• Micromelia (93%)• Undescended testes (73%) • Confluent eyebrows (synophrys) (99%) • Long curly eyelashes (99%) • Low anterior &posterior hairline (92%) • Underdeveloped orbital arches (100%)
• Neat, well-defined, and arched eyebrows (as though they had been penciled)
• Long philtrum • Anteverted nares (88%) • Down-turned angles of the mouth
(94%) • Thin lip (especially upper vermillion
border) • Low-set ears • Depressed nasal bridge (83%) • High arched palate (86%) and reports of
cleft palate • Late eruption of widely spaced teeth
(86%) • Micrognathia (84%)
02/25/15 Sid 55
02/25/15 Sid 56
Apert Syndrome
• Craniostenosis• Large late-closing
fontanels • Gaping midline defect • Flattened, often
asymmetric face • Maxillary hypoplasia with
retruded midface• Cardiovascular (10%)
– Atrial septal defect – Patent ductus arteriosus – Ventricular septal defect
• Syndactyly • Brachydactyly • Congenital cervical spinal
fusion (68%), especially C5-C6
• Aplasia or ankylosis of shoulder, elbow and hip joints
• Tracheal cartilage anomalies
• Rhizomelia
02/25/15 Sid 57
Turner syndrome(a) Puffy feet, (b) redundant skin at back of neck. (c) Histology of gonads: ovarian cortical stroma devoid of germ cell elements.
02/25/15 Sid 59
Turner Syndrome
• Short stature: • Ovarian failure: • Nails: Many patients have
hypoplastic or hyperconvex nails. • Nevi: Excessive numbers of nevi• Webbed neck: • Lymphedema • Cubitus valgus (increased carrying
angle): Short fourth metacarpal or metatarsal: Although this finding is of minimal clinical significance, it can be a clue to the presence of Turner syndrome.
• Shield chest:
• Eye: Ptosis, strabismus, amblyopia, and cataracts
• Gastrointestinal bleeding: • Hip dislocation: • Scoliosis: This occurs in 10% • Hypertension: • Murmurs: Cardiovascular
malformations include coarctation of the aorta, bicuspid aortic valve, and aortic dissection in adulthood
• Thyroid: 10-30% develop hypothyroidism.
• Cutis laxa:
02/25/15 Sid 60
02/25/15 Sid 61
02/25/15 Sid 62
Noonan syndrome• Autosomal dominant • Short stature • Failure to thrive in infancy • Triangular face with age • Low-set ears • Nerve deafness • Ptosis • Hypertelorism • Down-slanting palpebral
fissures • Epicanthal folds • Myopia • Mental retardation (25%)
• Malignant schwannoma
• High arched palate • Micrognathia • Dental malocclusion • Low posterior hairline • Webbed neck • Cystic hygroma • Atrial septal defects • Ventricular septal defects • Pulmonic stenosis• Shield chest, Pectus carinatum
superiorly, • Pectus excavatum inferiorly• Caused by mutations in the
protein tyrosine phosphatase, nonreceptor-type, 11 gene
02/25/15 Sid 63
02/25/15 Sid 64
Crouzon Syndrome
• Craniosynostosis: resulting in acrocephaly, brachycephaly, turricephaly, oxycephaly, flat occiput
• Shallow orbits • Face - Midface (maxillary)
hypoplasia• Eyes
– Exophthalmos (proptosis) secondary to shallow orbits resulting in frequent exposure conjunctivitis or keratitis
– Ocular hypertelorism – Divergent strabismus
• Choanal atresia or stenosis • Mandibular prognathism • Cervical fusion (18%), C2-C3
and C5-C6 • acanthosis nigricans• Central nervous system
– Approximately 73% of patients have chronic tonsillar herniation. Of these, 47% have progressive hydrocephalus.
– Syringomyelia may be present– Hydrocephalus (progressive in
30%)
02/25/15 Sid 65
Aarskog syndrome
02/25/15 Sid 66
02/25/15 Sid 67
Foetal Valproate syndrome
02/25/15 Sid 68
Prader-Willi syndrome (marked hypotonia)
02/25/15 Sid 70
02/25/15 Sid 71
Prader-Willi syndrome
• Failure to thrive • Central obesity • Dolichocephaly • Narrow bitemporal diameter • Almond-shaped eyes • Strabismus • Upslanting palpebral fissures,
Myopia • Thin upper lip • Small-appearing mouth • Down-turned corners of mouth • Thick, viscous saliva • Early dental caries • Hypoventilation
• Hypogonadotropic hypogonadism • Cryptorchidism • Osteoporosis • Scoliosis, Kyphosis• Small hands • Syndactyly • Small feet : • Frontal hair upsweep • mental retardation Learning
disabilities • Seizures • Global developmental delay • Childhood polyphagia • Microdeletion of 15q11 in 70%
02/25/15 Sid 72
(A); A) both chromosomes 15 are inherited from the mother and the PWS region from the father is missing (present in about 25 percent of patients) (B); and a defect in methylation inherited from the father (present in less than 5 percent of patients) (C). In this case, the genes in the PWS critical region on the chromosome 15 inherited from the father are inactivated, similar to those of the mother
Angelman syndrome
The 15q11q13 deletion in Prader-Willi or Angelman syndrome patients is sometimes just visible under the microscope in a standard cytogenetic preparation. In most cases a molecular test (FISH or PCR) is needed to make the diagnosis
Rubinstein-Taybi syndromea) The typical face, (b) broad thumb, and (c) characteristic appearance of large toes
Rett syndromecharacteristic hand-wringing.
02/25/15 Sid 77
45,X
02/25/15 Sid 78
47,XXY
02/25/15 Sid 79
47,XX,+13
02/25/15 Sid 80
47,XX,+18
02/25/15 Sid 81
47,XX,+21
02/25/15 Sid 82
46,Y,fra(X)(q27.3)
Thank you