Terminology

1. Malformations are defects that result from the intrinsically abnormal development of a structure or set of structures (e.g., anencephaly, congenital heart disease).

2. Deformations occur when extrinsic (mechanical) forces impinge on the development of otherwise normal tissue (e.g., clubfoot).

3. Disruptions occur when normal tissue is irreparably destroyed, altering the subsequent formation of the structure (e.g., amniotic bands).

4. Syndromes are recognizable patterns of symptoms or abnormalities that suggest a specific underlying disorder.

Trisomy syndromes

1. Trisomy 21 (Down syndrome) most common chromosomal disorder. Incidence is about 1:700 live births. The risk increases in advanced maternal age, with a sharper rise in prevalence rates seen every

year after the age of 35 years. Atlantoaxial instability (1–2%) Brachycephaly Anemia Epicanthal folds Upslanting palpebral Brushfield spots (speckled irides) Protruding tongue Clinodactyly Wide space between first and second toes (sandal gap) Duodenal atresia omphalocele Pyloric stenosis Cardiac defects (40%) Endocardial cushion defects (most common Diagnosis is on the basis of clinical features and genetic testing that demonstrates three copies

of chromosome 21. Note that about 3–4% of individuals have Down syndrome due to a translocation. A karyotype is

needed to distinguish full trisomy 21 from a translocation. If a parent carries a translocation, the recurrence risk for subsequent children with Down syndrome is higher.

2. Trisomy 18 (Edwards syndrome) severe intellectual disability prominent occiput low-set ears micrognathia congenital heart disease rocker-bottom feet

clenched hands with overlapping digits. Prognosis is poor, as 90% of children die by 1 year of age.

3. Trisomy 13 (Patau syndrome) severe intellectual disability cutis aplasia microphthalmia coloboma congenital heart disease polydactyly midline defects such as agenesis of the corpus callosum and cleft lip and palate. Prognosis is poor, as 50% die by 1 month of age and 90% die by 1 year of age.

Sex chromosome syndromes

1. Turner syndrome (XO) occurs in females with complete or partial absence of a second X chromosome. Epidemiology: Monosomy X is found in 45% of affected individuals, remainder of cases are due

to either a structural abnormality of the second X chromosome or mosaicism. Incidence is 1:2500–3000 female live births.

Short stature is present in 95% of individuals with Turner syndrome. Webbed neck with low posterior hairline Broad chest with widely spaced nipples (shield chest) Congenital lymphedema. May have swelling of the hands and/or feet at birth Cardiac defects: coarctation of the aorta, bicuspid aortic valve, hypoplastic left heart Ovarian dysgenesis leads to primary amenorrhea and lack of secondary sex characteristics in

most patients. Most individuals have normal intelligence. Renal malformations, hypothyroidism, diabetes, and hearing loss are also associated with Turner

syndrome.

2. Klinefelter syndrome (XXY) most common genetic cause of male infertility. Epidemiology The incidence is 1:500–1000 male live births. Tall stature, thin, with relatively long legs gynecomastia Hypogonadism results in small testicles, underdeveloped secondary sex characteristics, oligo- or

azoospermia, and decreased bone density. Learning disabilities are common, especially in the areas of verbal comprehension and reading. Icreased risk of psychosocial and behavioral problems. increased risk for developing mediastinal germ cell tumors (starting in adolescence) and breast

cancer.

3. XYY males may be taller than average but have normal sexual development. Intelligence is usually normal, but there is increased risk for learning disabilities and behavioral problems.

Chromosomal (micro) deletion syndromes

1. 22q11.2 deletion syndrome (DiGeorge, velocardiofacial syndrome) portion of the q arm of chromosome 22 is missing. Deletion can be de novo or inherited. CATCH-22 can be used to remember the findings of this disorder (Cardiac defects, Abnormal

facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, and deletion on chromosome 22) Epidemiology. The incidence of 22q11.2 deletion syndrome is about 1 in 4000 live births. Cardiac: congenital heart disease, especially conotruncal malformations (tetralogy of Fallot,

ventricular septal defect) Palatal abnormalities: velopharyngeal incompetence, cleft palate, submucous cleft, and bifid

uvula Abnormal facies: hooded eyelids, hypertelorism, overfolded or squared off helices, prominent nasal root, bulbous nasal tip, and micrognathia

Thymic hypoplasia can result in immunodeficiency. Parathyroid hypoplasia can result in severe hypocalcemia, and therefore, calcium should be

monitored in any newborn with suspected 22q11.2 deletion. Intellectual and learning disability Other associations include renal anomalies, hearing loss, and gastrointestinal anomalies.

2. Williams syndrome deletion on chromosome 7 (7q11.23) that includes the elastin gene. Epidemiology: Incidence of Williams syndrome is about 1 in 20,000 births. Distinctive facial features (“Elfin facies”) include prominent forehead, widely spaced eyes,

upturned and full nasal tip, long philtrum, distinctive wide mouth, and stellate/lacy iris pattern. Cardiovascular disease (elastin arteriopathy): Supravalvar aortic stenosis is the most common

location. Abnormalities of connective tissue may result in a hoarse voice or hernias. Intellectual disability, with a very friendly personality Endocrine problems include hypocalcemia, hypercalcuria, and hypothyroidism.

3. Cri du chat syndrome deletion of the short arm of chromosome 5 (5p). catlike cry in infancy, microcephaly,

downslanting palpebral fissures, developmental delay, and intellectual disability.

Imprinting disorders

Genomic imprinting results in differences in gene expression depending on whether the gene is inherited from the mother or father.

Disease occurs when the copy from the appropriate parent cannot be expressed. An example occurs in an imprinted region of chromosome 11q

o Angelman syndrome occurs when there is a deletion or other mechanism that causes a missing maternal copy of the region

o Prader–Willi syndrome occurs if there is a missing paternal copy of the region.

The mnemonic “P is for Prader–Willi and paternal deletion” may be used to remember the molecular basis of these conditions.

Uniparental disomy (UPD) occurs when both copies of one chromosome come from the same parent.

1. Prader–Willi syndrome hypotonia and feeding difficulties in infancy, usually resulting in failure to thrive. Early childhood: hyperphagia leading to obesity. Almond-shaped eyes, strabismus, down-turned mouth, hypopigmentation, small hands and feet, short stature, and hypogonadism Behavioral problems, intellectual disability, and learning disabilities Most common cause is a deletion in a region within the paternally inherited chromosome 15.

2. Angelman syndrome Severe developmental delay, speech impairment happy demeanor with inappropriate laughter and smiling. Jerky movements and ataxic gait is sometimes described as “puppetlike.” Microcephaly, seizures, large mouth, widely spaced teeth prognathia (prominent mandible most common cause is a deletion in a region within the maternally inherited chromosome 15.

3. Beckwith–Wiedemann syndrome Overgrowth disorder characterized by macrosomia, macroglossia, and visceromegaly hemihyperplasia, ear creases/pits omphalocele Increased risk for embryonal tumors (Wilms tumor, neuroblastoma, etc.) Several different etiologies, all of which affect imprinting on chromosome 11p15.5.

4. Russell–Silver syndrome Intrauterine growth retardation/small for gestational age (SGA) short stature normal head circumference asymmetry (limb, body, or face) Triangular facies, frontal bossing, or prominent forehead. Café-au-lait macules.

Triplet repeat expansion disorders.

number of repeats can increase with each generation, disorder only occurs once the number of nucleotide repeats in a gene expands beyond a specific

threshold. expansion can become even larger, causing earlier onset and more severe symptoms, which is a

phenomenon known as anticipation.

1. Fragile X syndrome number of CGG repeats in the FMR1 gene on the X chromosome. X-linked recessive mode of inheritance. Full mutation = >200 repeats Developmental delay and mild to severe intellectual disability. Behavioral abnormalities including autism and attention deficit/hyperactivity disorder Macrocephaly, long face, prominent jaw, protruding ears. Macroorchidism develops in adolescence. Females with full mutation may have behavioral problems and developmental delays, but most

have normal intelligence quotient (IQ).

2. Myotonic dystrophy

Severe form is caused by expansion of the number of CTG repeats in the DMPK gene. Expansion of the repeats occurs much more frequently in mothers. Progressive muscular weakness starting at any time during childhood Cataracts cardiac conduction abnormalities.

Connective tissue disorders

1. Marfan syndrome Autosomal dominant disorder caused by mutations in the gene that codes for fibrillin. Mutations can either be inherited or sporadic. Myopia, lens dislocation, and retinal detachment Tall stature with long extremities long fingers (arachnodactyly) pectus deformity scoliosis pes planus decreased upper-to-lower segment ratio increased arm span-to-height ratio Aortic root dilatation mitral valve prolapse and valvular regurgitation. Patients are at risk for spontaneous pneumothorax.

2. Ehlers–Danlos syndrome classic type: autosomal dominant disorders caused by mutations in genes that code for type V

collagen. Mutations can be inherited or sporadic. skin hyperextensibility, abnormal wound healing, and joint hypermobility. Skin may be described as soft and/or velvety in texture, with bruising caused by fragile blood

vessels.

Skeletal disorders

1. Achondroplasia Autosomal dominant disorder caused by mutations in FGFR3. majority of cases result from a sporadic mutation. Advanced paternal age (>45 years old) increases the risk of having an affected child. Most common cause of disproportionate short stature. Craniofacial findings include macrocephaly, prominent forehead, low nasal bridge, and midface

hypoplasia.

Rhizomelic (proximal limb) shortening of the limbs, bowed legs, and trident appearance of the hands. Lumbar gibbus deformity (structural, sharp-angled kyphosis resulting in a prominent “hump” on

the back) in infancy that resolves once the patient starts walking. Lumbar lordosis then develops. Normal intelligence with delayed acquisition of motor milestones Recurrent middle ear dysfunction obstructive sleep apnea Increased risk for foramen magnum stenosis and compression of the craniocervical junction. Patients should therefore be monitored for signs of hydrocephalus and spinal cord compression.

2. Osteogenesis imperfecta (OI) Most cases are due to autosomal dominant mutations in genes that encode for chains of type I

collagen. Type I is the most common and the mildest form of OI. Type II OI are the most severely affected, and rarely survive beyond the first weeks of life. Type III is the most severe type among those who survive the neonatal period. Blue sclera and frequent fractures after minimal or no trauma. Easy bruising. Fractures usually heal without resulting deformity. Normal stature or slightly shorter than the rest of the family May have yellow or grayish brittle teeth (dentinogenesis imperfecta) which are at increased risk

for breakage. Progressive hearing loss in adulthood

Additional disorders

1. Noonan syndrome Autosomal dominant disorder caused by mutations in certain genes involved in the RAS/MAPK

pathway. Short stature congenital heart defect pectus deformity characteristic facies in infancy low-set, posteriorly rotated ears, wide-spaced eyes (hypertelorism), eyelid ptosis downslanting palpebral fissures. Pulmonary valve stenosis is the most common cardiac defect. risk for developing hypertrophic cardiomyopathy during their lifetime. Patients can have short, webbed neck with low posterior hairline, and broad chest with widely spaced nipples.

Affected females are sometimes initially misdiagnosed with Turner syndrome (which is associated with left-sided heart defects vs. Noonan syndrome with right-sided heart defects).

Patients may have developmental delay and/or intellectual disability.

2. VACTERL (VATER) association A group of malformations generally observed as a sporadic occurrence in an otherwise healthy

family. Etiology is unknown. Clinical findings overlap with those seen in Fanconi anemia, which should be ruled out in anyone

presenting with VACTERL. V—vertebral defects A—anal atresia C—cardiac defects TE—tracheoesophageal (TE) fistula R—renal dysplasia L—limb/radial defects

3. CHARGE Syndrome: An autosomal dominant disorder most often caused by a spontaneous mutation C—colobomas of the iris or retina. Usually results in impaired vision H—heart defects such as conotruncal defects and aortic arch abnormalities A—choanal atresia or stenosis R—retarded growth and development G—genital abnormalities, including genital hypoplasia E—ear anomalies, including abnormal outer ear shape, hearing loss, and ossicular and temporal

bone abnormalities Cranial nerve dysfunction is another important feature.

4. Cornelia de Lange syndrome Generally observed as a sporadic occurrence in an otherwise healthy family. Autosomal dominant and X-linked mutations have been found. Characteristic facies include synophrys (single eyebrow resulting from both eyebrows growing

into one another) long eyelashes small upturned nose microcephaly. SGA, failure to thrive, and small stature Hirsutism Upper limb malformations Developmental delay, intellectual disability, and behavioral problems

5. Potter syndrome A deformation sequence that results from compressive forces exerted on a developing fetus

subjected to prolonged oligohydramnios. The oligohydramnios may have resulted from bilateral renal agenesis, other urinary tract

defects, or a chronic leak of amniotic fluid. Lung hypoplasia, abnormal limb positioning, and characteristic “Potter facies” (compressed facial appearance, with large ears flattened against

the head).

6. Pierre Robin sequence A sequence that can be seen as an isolated finding or as part of a specific multiple malformation

syndrome. Clinical findings result from mandibular hypoplasia, which leads to a cascade of other features. micrognathia, glossoptosis (posterior displacement of the tongue), and cleft palate (often a U-shaped cleft).

7. Amniotic band syndrome occurs when rupture of the amniotic sac during pregnancy results in small strands of amnion

wrapping around areas of the fetus’s body, causing deformation and/or amputation.

Syndromes caused by teratogens

1. Fetal alcohol syndrome (FAS) FAS is caused by maternal alcohol consumption during pregnancy. Prenatal exposure to alcohol can cause a wide range of findings, with FAS being the most severe.

No amount of alcohol is considered safe, but the risk for FAS is higher with binge drinking or chronic alcohol consumption during pregnancy.

Microcephaly, short palpebral fissures, smooth philtrum, and thin upper lip Developmental delay, intellectual disability, and attention deficit hyperactivity disorder Infants may be SGA. Cardiac defects may occur (ventricular septal defects are most common).

2. Fetal Hydantoin syndrome

Infants born to mothers taking phenytoin during pregnancy are at increased risk for specific malformations.

Microcephaly, wide anterior fontanelle, hypertelorism, short nose, wide mouth Low hairline, short neck, hypoplastic nails Developmental delays