Overview of Pediatric Genetics

7/29/2019 Overview of Pediatric Genetics

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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 xraysee image).

Celiac diseaseo Associated ocular problems include:

Congenital cataracts Strabismus Refractive errors

o Other associated problems include: Hypothyroidism Atlantoaxial instability Leukemia (especially ALL) Autism/developmental delay


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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 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


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Holoprosencephaly Heart defects (80% of patients) Hypoplastic or absent ribs Genital abnormalities

o Median survival for these patients is 2.5 days; ~80% of patients die within the 1st month andonly 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 comesfrom the long arm, it is denoted as q-.

5p- or CRI-DU-CHAT SYNDROMEo 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

15q11-13o This deletions phenotypic appearance depends solely on whether it is maternally (Angelman)

or paternally (Prader-Willi) derivedgenomic 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


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o 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.


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Sex Chromosome Abnormalites

47, XXY (KLINEFELTER SYNDROME)o Occurs in 1/500 to 1/1000 newborn maleso Characteristics include:

Behavior problems (clinical scenarios onexams like to mention fire-setting behavior)

Tall stature Gynecomastia Small testes Delayed puberty Azoospermia and infertility Learning disabilities

FRAGILE X SYNDROMEo 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


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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 autoimmunethyroid disease)

Hearing deficits

Skeletal Dysplasias

ACHONDROPLASIAo 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 IMPERFECTAo 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


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Stature (usually near normal or normal) Multiple fractures (most occur before puberty and are rare at birth) Dental abnormalities

o 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)

o 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)

o 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 SYNDROMEo 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


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of the lens of the eye)

Dilation and dissection of theascending 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 SYNDROMEo 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 nervesheath 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 presentslater (in adulthood); maps to chromosome 22.


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o 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 SCLEROSISo 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

Other Commonly Tested Syndromes

CHARGE ASSOCIATIONo Coloboma, congenital Heart defects, choanal Atresia, growth and mental Retardation, GU

anomalies (hypogonadism), and Ear anomalies.

VATER ASSOCIATIONo 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 limbdefects).

o Also associated with a single umbilical artery. BECKWITH-WIEDEMANN SYNDROME

o Occurs in 1/14,000 birthso 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


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Wilms tumor Hepatoblastoma Cryptorchidism Hemihypertrophy Hypoglycemia in infant Neonatal polycythemia

NOONAN SYNDROMEo Usually occurs sporadically, although some autosomal dominant inheritance has been

demonstrated.

o Clinical features include: Short stature Unusual facies

Epicanthal folds, hypertelorism, low nasalbridge, 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 ofFallot, coarctation of the aorta.

Cryptorchidism Bleeding disorders

Usually mild; a variety of defects in the coagulation and platelet systems havebeen described.

TREACHER-COLLINS SYNDROMEo Autosomal dominant disordero 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 SYNDROMEo Autosomal dominant inheritance pattern; 50% are new mutations.o Clinical features include:

Microcephaly Micrognathia Low hairline Synophrys (unibrow)


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

Maternal Teratogens

FETAL ALCOHOL SYNDROMEo Small for gestational ageo Microcephalyo Cardiac abnormalitieso

Mental retardationo Characteristic facies (smooth philtrum, thin upper lip, small palpebral fissures)

FETAL WARFARIN SYNDROMEo Hypoplastic nasal bridgeo Stippled epiphyses secondary to calcifications (chondrodysplasia punctata)

LITHIUMo Ebstein anomaly(abnormality of the tricuspid valve often associated with ASD)

FETAL EXPOSURE TO ANTICONVULSANTS(VALPROIC ACID, ETC)o Microcephalyo Intrauterine growth retardationo Hypoplastic nailso 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 asymmetryo Microtiao Cardiac abnormalitieso Mental retardation

INFANTS BORN TO DIABETIC MOTHERSo Macrosomiao 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


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o Polycythemiao Hypoglycemiao Small left colon syndromeo 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

Overview of Pediatric Genetics

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