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Overview of Pediatric Genetics/Dysmorphology

Heather M. Taylor, MD

Trisomy Syndromes TRISOMY 21 (DOWN SYNDROME) o Most common autosomal chromosome abnormality in humans, occurring in 1/800 live births. o 94% of Down syndrome patients have 3 copies of the whole chromosome 21; 3% have only part of the long arm due to translocations, and the remaining 3% have mosaicism. o Associated risk factor is increasing maternal age. o Classic features include: Hypotonia Small ears Brachydactyly (short, broad fingers and toes) Increased space between 1st and 2nd toes Microcephaly Up-slanted palpebral fissures Flat midface Epicanthal folds Single transverse crease (simian line) Speckled irises (Brushfield spots) High-arched palate Hypoplasia of the middle phalanx of the 5th finger Mental retardation o Associated heart defects are seen in 50% of patients and include: AV canal defects VSD ASD Tetralogy of Fallot o Associated GI defects occur in 5% of patients. Duodenal atresia (look for the classic double-bubble sign on abdominal xray see image). Celiac disease o Associated ocular problems include: Congenital cataracts Strabismus Refractive errors o Other associated problems include: Hypothyroidism Atlantoaxial instability Leukemia (especially ALL) Autism/developmental delay

2 Dementia or early-onset Alzheimer disease Diabetes Recurrent otitis media o Anticipatory Guidance for Children with Down Syndrome: Cardiac evaluation with echocardiogram in the newborn period before 3 months of age. Ophthalmology evaluation before 6 months of age. Hearing evaluation by 6 months of age and then every 6 months until age 3. Thyroid studies at 3, 6, and 12 months, and then annually. C-spine xrays between 3 and 5 years, and then as needed for Special Olympics Lateral views in the neutral, flexed, and extended positions are needed. The space between the posterior segment of the anterior arch of C1 and the anterior segment of the odontoid process of C2 should be measured. o <5mm: normal o 5-7mm: instability o >7mm: abnormal Celiac disease screening between 2 and 3 years of age. Dental evaluation at age 2 and then every 6 months thereafter. TRISOMY 18 (EDWARDS SYNDROME) o Occurs in ~1/6000 live births. o Ratio of girls to boys is 4:1. o Risk factors include increasing maternal age. o Characteristic findings include: Intrauterine growth retardation Mental retardation High forehead Microcephaly Small face and mouth Short sternum Rocker bottom feet Clubfoot Clenched fist (Hypertonicity) Overlapping fingers Hypoplastic nails Structural heart defects (90% of patients with most common lesion being VSD) o 50% of patients die in the 1st week of life; another 40% die by age 1. TRISOMY 13 (PATAU SYNDROME) o Occurs in ~1/20,000 1/25,000 live births. o Risk factors include increasing maternal age. o Associated clinical findings include: Bilateral cleft lip and palate Microphthalmia Postaxial polydactyly of the limbs

3 Holoprosencephaly Heart defects (80% of patients) Hypoplastic or absent ribs Genital abnormalities Median survival for these patients is 2.5 days; ~80% of patients die within the 1st month and only 5% survive the 1st 6 months.

Deletion Syndromes Note: if the deletion comes from the short arm of the chromosome, it is denoted as p-. If it comes from the long arm, it is denoted as q-. 5p- or CRI-DU-CHAT SYNDROME o Associated with the distinctive cats cry, which is due to an anatomic change in the larynx. o Other characteristics include: Moon face with hypertelorism (widely spaced eyes) Down-slanting palpebral fissures Hypotonia Short stature Microcephaly High-arched palate Wide and flat, nasal bridge Mental retardation Heart defects (in 30% of patients)

Microdeletion Syndromes 15q11-13 o This deletions phenotypic appearance depends solely on whether it is maternally (Angelman) or paternally (Prader-Willi) derived genomic imprinting. o ANGELMAN SYNDROME Classic findings include: Jerky, ataxic movements (the happy puppet) Hypotonia Fair hair and often pale, blue eyes Maxillary hypoplasia Prognathism (projecting jaw) Seizures Uncontrollable bouts of laughter Severe mental retardation

PRADER-WILLI SYNDROME Classic findings include: Severe hypotonia at birth Obesity Short stature Small hands and feet Hypogonadism Usually mild mental retardation 7q11.23- (WILLIAMS SYNDROME) o Characteristic features include: Periorbital fullness Prominent lips (especially bottom lip) with open mouth Friendly, cocktail party personality Stellate pattern of the iris Supravalvular aortic stenosis Enamel hypoplasia Mental retardation Renal abnormalities Nephrocalcinosis, asymmetry in kidney size, small or solitary pelvic kidney, bladder diverticuli, urethral stenosis, vesicoureteral reflux. o 95% of patients are missing the elastin gene from 1 of their copies of chromosome 7. 11p13- (WAGR SYNDROME) o WAGR: Wilms tumor, Aniridia, Genitourinary abnormalities (hypospadias, cryptorchidism, small penis, hypoplastic scrotum), and mental Retardation. 22q11.2- (DIGEORGE/VELOCARDIOFACIAL SYNDROME) o This deletion syndrome includes phenotypes referred to as DiGeorge syndrome, Velocardiofacial syndrome, or CATCH 22 (Cleft palate, Absent Thymus, Congenital Heart disease). o Characteristics include: Facial features (small mouth, narrow upslanted palpebral fissures) Cleft palate, velopharyngeal incompetence (VPI) Thymus agenesis or hypoplasia (leading to immune deficiencies) Parathyroid gland hypoplasia/agenesis (leading to hypocalcemia) Hypoplasia of the auricle and external auditory canal Cardiac defects (Tetralogy of Fallot>interrupted aortic arch>VSD>truncus arteriosus) Short stature Learning disabilities o Causes a developmental defect of derivatives of the 3rd and 4th pharyngeal pouches.

Sex Chromosome Abnormalites 47, XXY (KLINEFELTER SYNDROME) o Occurs in 1/500 to 1/1000 newborn males o Characteristics include: Behavior problems (clinical scenarios on exams like to mention fire-setting behavior) Tall stature Gynecomastia Small testes Delayed puberty Azoospermia and infertility Learning disabilities FRAGILE X SYNDROME o 2nd most common cause of mental retardation after Down syndrome; affects ~1/2500 males and has a female carrier rate of ~1/1500. o Characteristics include: Mild to profound mental retardation Autism (in 60% of patients) Long face Macrocephaly Prognathism Large, prominent ears Epicanthal folds Dental crowding Macro-orchidism o Female carriers may be normal (1/3), learning impaired (1/3), or mildly retarded (1/3). 45, X (TURNER SYNDROME) o Occurs in ~1/2000 live births. o 99% of affected fetuses spontaneously abort. o 50% of girls with Turner syndrome have 45, X abnormality; the rest of mosaics. o These patients are phenotypically female. o Characteristics include: Short stature Ovarian failure/gonadal dysgenesis or streak ovaries (with subsequent lack of secondary sexual development) Cardiac defects (Bicuspid aortic valves>coarctation of the aorta) Broad, webbed neck (from fetal cystic hygroma) Prominent ears Low posterior hairline Lymphedema of the hands and feet High arched palate

6 Broad chest with widely spaced nipples Cubitus valgus (outward deviation of the extended forearm) Hyperconvexity of the fingernails Renal abnormalities (pelvic kidney, horseshoe kidney, double collecting system, absence of a kidney) Thyroid abnormalities (10-20% will have autoimmune thyroid disease) Hearing deficits

Skeletal Dysplasias ACHONDROPLASIA o The most common skeletal dysplasia; occurs in 1/20,000 live births. o Autosomal dominant disorder with 90% having a de novo mutation of fibroblast growth factor receptor 3. Mutation rate increases with increasing paternal age. o Characteristics include: Disproportionately short stature (due to shortening of the most proximal segment of the upper arms and legs compared to the distal segments) Short, trident hands Macrocephaly Flat nasal bridge Prominent forehead Midfacial hypoplasia Small foramen magnum

Cartilage Anomalies OSTEOGENESIS IMPERFECTA o Group of autosomal dominant disorders caused by genetic defects affecting collagen. o OSTEOGENESIS IMPERFECTA TYPE I Most common and mildest form. Characteristics include: Blue sclera Delayed fontanelle closure Hyperextensible joints Hearing loss

7 Stature (usually near normal or normal) Multiple fractures (most occur before puberty and are rare at birth) Dental abnormalities OSTEOGENESIS IMPERFECTA TYPE II Most severe form. Results in death during the newborn period due to respiratory insufficiency. Almost all cases are due to a de novo autosomal dominant mutation of a gene which disrupts collagen formation. Characteristics include: Death in newborn period Numerous fractures and severe bone deformity Beaded ribs (due to callus formation) OSTEOGENESIS IMPERFECTA TYPE III Presents in the newborn period with numerous fractures. Characteristics include: Severe short stature Most cannot ambulate because of inability to bear weight Blue sclerae at birth (but lighten with age) Neurologic complications (hydrocephalus and basilar skull defects) OSTEOGENESIS IMPERFECTA TYPE IV Milder form. Characteristics include: White or near-white sclera Shorter-than-average stature Fractures present at birth Delayed fontanelle closure Tibial bowing Dental abnormalities

Connective Tissue Dysplasias MARFAN SYNDROME o Autosomal dominant disorder that affects 1/5000 individuals. o Results from a mutation in the gene that encodes fibrillin. o Clinical features include: Pectus excavatum Scoliosis Tall stature Joint hyperflexibility Ectopia lentis (displacement

8 of the lens of the eye) Dilation and dissection of the ascending aorta (this is the leading cause of death of these patients) Mitral valve prolapse High arched palate Recurrent or incisional hernias Spontaneous pneumothorax/apical blebs EHLERS-DANLOS SYNDROME o Mostly autosomal dominant disorder with 6 major types (there are a couple of types that have autosomal recessive inheritance). o Characteristics include: Hyperextensible skin Hyperextensible joints Mitral valve prolapse Proximal aortic dilatation Easy bruising Dystrophic scarring /poor wound healing Blue sclerae (in some patients)

Neurocutaneous Diseases NEUROFIBROMATOSIS TYPE I (von Recklinghausens disease) o Most common neurocutaneous disease and affects ~1/2000. o Most children have the diagnostic findings by age 10. o Nearly 60% of cases are sporadic or de novo autosomal dominant mutations; affected gene (neurofibromin maps to chromosome 17). o Clinical criteria include (diagnosis requires 2/7): >/= 6 caf au lait spots of >0.5cm in diameter in prepubertal children and >1.5cm in diameter in pubertal children >/= 2 neurofibromas (benign, peripheral nerve sheath tumors) or 1 plexiform neurofibroma Freckling in the axillary or inguinal areas Optic glioma >/= 2 Lisch nodules (iris hamartomas) Sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis 1st degree relative with the disease NEUROFIBROMATOSIS TYPE II o Autosomal dominant disorder that is much less common than Type I and typically presents later (in adulthood); maps to chromosome 22.

9 Clinical features include: Bilateral vestibular schwannomas (acoustic neuromas) Other CNS tumors (intracranial meningiomas, spinal schwannomas, cranial nerve schwannomas, and ependymomas) Lens opacities or cataracts TUBEROUS SCLEROSIS o Autosomal dominant disorder that affects ~ 1/6000 people. o Classic features include: Ash-leaf hypopigmented macules (enhance with a Woods lamp) Shagreen patches (oval-shaped nevoid plaque, skin-colored appearing on the trunk or lower back) Facial angiomas Caf-au-lait spots Forehead plaques Ungual and gingival fibromas Cardiac rhabdomyomas Infantile spasms/Seizures Glioma-angioma lesions in cortex and white matter o

Other Commonly Tested Syndromes CHARGE ASSOCIATION o Coloboma, congenital Heart defects, choanal Atresia, growth and mental Retardation, GU anomalies (hypogonadism), and Ear anomalies. VATER ASSOCIATION o Vertebral defects, Anal atresia, TracheoEsophageal fistula, Radial dysplasia, Renal malformations, and congenital heart defects o Also known as VACTERL (with C standing for congenital heart defects and L standing for limb defects). o Also associated with a single umbilical artery. BECKWITH-WIEDEMANN SYNDROME o Occurs in 1/14,000 births o Mode of inheritance is usually sporadic; there have been some reported autosomal dominant patterns as well. o Clinical features include: Coarse facies Macrosomia Macroglossia Ear lobe creases Posterior auricular pits Omphalocele

10 Wilms tumor Hepatoblastoma Cryptorchidism Hemihypertrophy Hypoglycemia in infant Neonatal polycythemia NOONAN SYNDROME o Usually occurs sporadically, although some autosomal dominant inheritance has been demonstrated. o Clinical features include: Short stature Unusual facies Epicanthal folds, hypertelorism, low nasal bridge, downslanting palpebral fissures, low-set ears, wide mouth, prominent/protruding upper lip, ptosis Short or webbed neck Low posterior hairline Shield chest Pectus excavatum Pulmonic valve stenosis Other heart defects include hypertrophic cardiomyopathy, ASD, tetralogy of Fallot, coarctation of the aorta. Cryptorchidism Bleeding disorders Usually mild; a variety of defects in the coagulation and platelet systems have been described. TREACHER-COLLINS SYNDROME o Autosomal dominant disorder o Clinical features include: Mandibular and maxillary hypoplasia Zygomatic arch clefts Ear malformations Down-sloping palpebral fissures Colobomata of lower eyelids Conductive hearing loss CORNELIA de LANGE SYNDROME o Autosomal dominant inheritance pattern; 50% are new mutations. o Clinical features include: Microcephaly Micrognathia Low hairline Synophrys (unibrow)

11 Long eyelashes Thin upper lip Low set ears Micromelia or phocomelia Syndactyly of toes Growth retardation

Maternal Teratogens FETAL ALCOHOL SYNDROME o Small for gestational age o Microcephaly o Cardiac abnormalities o Mental retardation o Characteristic facies (smooth philtrum, thin upper lip, small palpebral fissures) FETAL WARFARIN SYNDROME o Hypoplastic nasal bridge o Stippled epiphyses secondary to calcifications (chondrodysplasia punctata) LITHIUM o Ebstein anomaly (abnormality of the tricuspid valve often associated with ASD) FETAL EXPOSURE TO ANTICONVULSANTS (VALPROIC ACID, ETC) o Microcephaly o Intrauterine growth retardation o Hypoplastic nails o Characteristic facies (low-set ears, epicanthal folds, midfacial hypoplasia, micrognathia, small mouth) o Increased risk for cardiac defects, cleft lip, and neural tube defects THALIDOMIDE o Phocomelia (very short or absent long bones with flipper-like appearance of hands and feet) RETINOIC ACID o CNS defects (hydrocephalus, microcephaly, structural errors of neuronal migration) NOT meningomyelocele o Facial asymmetry o Microtia o Cardiac abnormalities o Mental retardation INFANTS BORN TO DIABETIC MOTHERS o Macrosomia o Increased risk for cardiac defects (VSD, transposition, dextrocardia) o Increased risk for CNS defects (anencephaly, holoprosencephaly, spina bifida, hydrocephalus) o Malformations of the lower spine or ribs

12 o o o o Polycythemia Hypoglycemia Small left colon syndrome Renal abnormalities (double ureter, hydronephrosis, renal agenesis)

References Smiths Recognizable Patterns of Human Malformation. 6th ed. Ed. Kenneth Lyons Jones, MD. 2006. Rudolphs Fundamental of Pediatrics. 3rd ed. Ed. Abraham M. Rudolph, Robert K. Kamei, Kim J. Overby. 2002: 184-220.

Edited 09/01/2009