“[Minors] should not be tested except under the following specific circumstances:

1. 
   

   there are immediate medical benefits, such as institution of measures that can prevent the disease, delay its onset, limit its severity, or prevent secondary disabilities, or

   
   
2. 
   

   there is a benefit to another family member and no anticipated harm to the minor.

   
   

   When the results of genetic testing will be used solely for future reproductive decisions or when parents request it and there are no benefits to the child, in most circumstances it should be deferred until the child can request such testing as an autonomous individual who is able to appreciate the emotional and social consequences, as well as the genetic facts, of the results.”

Syndrome, Association, and Sequence

• Syndrome: A recognizable pattern of signs or symptoms that “run together.” Typically differs from association in that a molecular cause has been elucidated. Examples include Turner, Marfan, and CHARGE syndromes (previously charge was an association prior to discovery of a causative gene).
  
• Sequence: A pattern of deformations and malformations which is a consequence of a single malformation. Examples include Pierre Robin and Potter sequences.
  
• Association: A group of malformations that occur together more than would be expected by chance alone. Examples include VACTERL and MURCS associations.

Inheritance

Mendelian Patterns of Inheritance

• Autosomal dominant
  
  
  
  • Classic description: Carriers of one mutant allele exhibit the trait or disease and pass it to their offspring with 50% probability regardless of gender (eg, male-to-male inheritance is possible).
    
  • Allele characteristics: Point mutations (leading to a gain of function), nonsense mutations, insertions, or deletions (in genes that exhibit haploinsufficiency). Protein products are often structural proteins or regulatory signaling proteins.
    
  • Pitfalls in interpretation: Many individuals with autosomal dominant diseases appear without family history because of a de novo mutation. Incomplete penetrance and variable expressivity may lead to difficulty in determining who in a family is affected. Gonadal mosaicism in one parent may lead to multiple affected children of unaffected parents.
    
  • Examples: Neurofibromatosis, tuberous sclerosis, Marfan syndrome, achondroplasia.
  
  
• Autosomal recessive
  
  
  
  • Classic description: Disease manifests in individuals with two mutant alleles. More common in inbred populations or consanguineous unions. Full siblings of an individual with the disease have a 25% chance of having the disease, 50% chance of being carriers, and 25% of having no mutant allele, and parents are unaffected carriers.
    
  • Allele characteristics: Deletions, insertions into functional sites, or point mutations usually leading to decreased or dysfunctional protein products. Protein products are often enzymatic.
    
  • Pitfalls in interpretation: Variable expressivity may lead to differences in severity or specific organ involvement of these diseases. Uniparental disomy may lead to autosomal recessive disease inherited from one carrier parent (Am J Hum Genet 1988; 42:217).
    
  • Examples: Sickle cell anemia, cystic fibrosis, galactosemia, congenital adrenal hyperplasia.
  
  
• X-linked dominant
  
  
  
  • Classic description: Only females are affected because of male lethality (rare exceptions exist, eg, X-linked hyposphatemic rickets), and affected females have variable involvement depending on the pattern of X inactivation.
    
  • Allele characteristics: Deletions or loss of function mutations in essential X-linked genes.
    
  • Pitfalls in interpretation: High rates of de novo mutations in these disorders; males may exhibit the disease if there is mosaicism.
    
  • Examples: Incontinentia pigmenti, Goltz syndrome, Aicardi syndrome.
  
  
• X-linked recessive
  
  
  
  • Classic description: Mostly males are affected. The disease cannot be passed from father to son but only from carrier mother to son (no male-to-male transmission)
    
  • Allele characteristics: Deletions, insertions, or point mutations leading to loss of function.
    
  • Pitfalls in interpretation: Pattern of X inactivation in females may lead to effects in females. Gonadal mosaicism in the mother may lead to multiple affected sons but negative carrier status. Variable expressivity may lead to differences in the severity or specific organ involvement of these diseases.
    
  • Examples: Duchenne muscular dystrophy, hemophilia A and B, Wiskott-Aldrich syndrome.

Non-Mendelian Patterns of Inheritance

• Multifactorial or complex inheritance
  
  
  
  • Description: Diseases in which multiple genes, gene–gene interactions, and environmental factors influence disease presence.
    
  • Keydisease examples: Diabetes mellitus; obesity; nonsyndromic birth defects, including cleft lip and palate, neural tube defects, and congenital heart defects.
  
  
• Chromosomal aneuploidy (present in 0.7% of live births)
  
  
  
  • Description: Diseases caused by excess or deficiency of chromosomal material, affecting entire chromosomes and therefore multiple genes, mostly sporadic and the result of nondisjunction events or chromosomal rearrangement.
    
  • Examples: Down syndrome, Turner syndrome (monosomy), trisomy 18 (Edward’s syndrome), trisomy 13 (Patau syndrome).
  
  
• Genomic disorders (Trends in Genetics 1998;14(10):417)
  
  
  
  • Description: Structural characteristics of the human genome predispose to genomic alterations that may lead to the complete loss or gain of a gene sensitive to a dosage effect or may disrupt the structural integrity of a gene.
    
  • Examples: VCFS/DiGeorge, Williams, Smith-Magenis syndromes.
  
  
• Mitochondrial (maternal) inheritance
  
  
  
  • Classic description: Affected females pass the disease on to all of their offspring, and affected males do not pass on the disease.
    
  • Allele characteristics: Point mutations, deletions, or duplications on the mitochondrial genome (present outside the nucleus, encoding part of the mitochondrial machinery for energy metabolism).
    
  • Pitfalls in interpretation: Heteroplasmy, or variation between cells of the percentage of mitochondria with mutations, may lead to large variations in the severity and degree of phenotypes. Autosomal genes also encode for the majority of mitochondrial proteins, and these will not exhibit mitochondrial inheritance.
    
  • Examples: Kearns-Sayre syndrome, Leber hereditary optic neuropathy, Myoclonic epilepsy with ragged red fibers (MERRF).
  
  
• Parent of origin effects (genomic imprinting)
  
  
  
  • Description: Specific areas of the genome contain genes that are differentially expressed depending on whether the allele was inherited from the mother or the father; these effects are caused by epigenetic DNA modifications (eg, methylation) that does not change the DNA sequence but enhances or represses function. Deletions of these regions on one parent’s allele, abnormal persistence of previous methylation patterns, and uniparental disomy may lead to disease.
    
  • Inheritance: Complex with epigenetic, genetic, de novo, and inherited factors (Ann Rev Genom Hum Genet 2004;5:479). Consider when a pedigree has distantly related individuals with identical phenotypes separated by healthy family members.
    
  • Pitfalls in interpretation: DNA mutations can produce the same disease phenotypes in some of these diseases. Uniparental disomy may lead to inheritance of an autosomal recessive disease from a carrier parent (Am J Hum Genet 1988;42:217).
    
  • Examples: Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome, Russell-Silver syndrome.
  
  
• Triplet repeat expansion disorders
  
  
  
  • Inheritance: Genetic anticipation, a phenomenon that reflects a progressive shift in the pedigree in which later generations have an earlier onset and more severe manifestations of the disease (not always observed; may be stable between generations).
    
  • Allele description: Unstable areas of the genome with repetitive trinucleotides in the proximity of a gene, which are subject to abnormal expansion of the number of repeats, leading to a change in the expression, RNA processing, or protein product of the gene.
    
  • Pitfalls in interpretation: The expansion of the repeat and resulting anticipation may only occur in one gender. Repeats on the X chromosome may affect females depending on the pattern of X inactivation.
    
  • Key disease examples: Fragile X syndrome, Friedrich’s ataxia, myotonic dystrophy, Huntington’s disease (currently 14 documented disorders exist)

Morphogenesis

• Zygote to blastocyst development (wk 1 and 2): Vigorous cell proliferation; implantation; formation of the two-layered embryonic disc, chorion, amnion, and yolk sac
  
• Teratogen effects: Loss of the pregnancy
  
• Embryonic development (wk 3–8): Gastrulation, organ system development

Teratogen Effects

• Major structural birth defects
  
• Fetal development (wk 9+): Growth of the organs and structures of the embryo
  
• Will not cause major structural defects but can lead to growth retardation; mental retardation; neuronal migration abnormalities, and eye, ear, and limb abnormalities

Chromosomal Disorders

Trisomy 21 (Down Syndrome)

• Most common chromosomal cause of mental retardation.
  
• Three distinct cytogenetic abnormalities can lead to Down syndrome.
  
  
  
  • 95% of cases are attributable to trisomy 21 (47, XX, +21 or 47, XY, +21) caused by a maternal nondisjunction (an event with a higher risk at advanced maternal age). 75% of these errors are in meiosis I and 25% in meiosis II (Am J Hum Genet 1992;50(3):544).
    
  • 4% are attributable to Robertsonian translocations resulting in a third copy of chromosome 21 translocated onto another acrocentric chromosome (13, 14, 15, 21, or 22).
    
  • 1% are attributable to mosaicism.
  
  
• Clinical manifestations by organ system
  
  
  
  • Respiratory: Sleep apnea caused by hypotonia or airway narrowing
    
  • Facial dysmorphology: Epicanthal folds, Brushfield spots, upslanting palpebral fissures, short neck with excess nuchal skin, protruding tongue
    
  • CNS: Hypotonia, mental retardation
    
  • Cardiac defects in 50% of patients (in order of frequency):
    
    
    
    • Endocardial cushion defect
      
    • Ventricular septal defect
      
    • Secundum atrial septal defect
      
    • Patent ductus arteriosus
      
    • Tetralogy of Fallot
    
    
  • Endocrine: Hypothyroidism; women can be fertile
    
  • Extremities: Short hands, hypoplastic midphalanx of fifth finger, single transverse palmar crease, sandal gap toe, hallucal arches
    
  • GI: Duodenal atresia, annular pancreas, imperforate anus, tracheoesophageal fistulas, Hirschsprung’s disease
    
  • Growth retardation: Special growth charts are used for patients with Down syndrome (Pediatrics 1988;81:102, Am J Med Genet 1992;42: 61)
    
  • Hematologic (Am J Med Genet 1990;46(6):1034)
    
  • Transient myeloproliferative disorder: Neonatal presence of blasts on peripheral smear; disappears by age 3 mo
    
  • Acute myelocytic leukemia (FAB M7 subtype)
    
  • Marked increased risk of acute lymphoblastic leukemia (ALL).

• Etiology: Majority caused by trisomy of chromosome 18 secondary to maternal meiotic nondisjunction (advanced maternal age is a risk factor); small proportion caused by mosaicism or translocations.
  
• Prevalence: 1.29/10,000 live births; 61% female.
  
• Clinical manifestations by organ system
  
  
  
  • CNS: Major CNS malformations in 8%, including spina bifida, anencephaly, hydrocephalus, or microcephaly. Those without a major structural CNS anomaly usually have a developmental delay or mental retardation and hypertonia.
    
  • HEENT: Aniridia, microphthalmia, cataracts, prominent occiput, micrognathia, choanal atresia, cleft lip, cleft palate, abnormal ears, ptosis.
    
  • Cardiac: Congenital heart disease in 45% (in order of frequency): VSD, ASD, tetralogy of Fallot, coarctation, transposition, endocardial cushion, hypoplastic left heart, pulmonic stenosis, aortic stenosis, pulmonary atresia, truncus arteriosus, tricuspid atresia, Ebstein’s anomaly.
    
  • GI: Present in 8%; includes tracheoesophageal fistulas, Hirschsprung’s disease, rectal atresia, abdominal wall defects (in 4%), failure to thrive (uniform finding).
    
  • GU: Present in 4%; includes hypospadias, epispadias, obstructive uropathy, renal agenesis.
    
  • Musculoskeletal: “Rocker bottom” feet, overlapping digits, polydactyly, syndactyly, short sternum.
  
  
• Survival: Mean survival is 14.5 days.
  
  
  
  • However, 5.6% will survive beyond 1 year. The mean is highly influenced by the large number of deaths in the first 24 hours.
    
  • Survival beyond 48 hours is a significant predictor of survival to 1 week and 1 month but possibly not to 1 year (J Med Genet 2002;39:e54). Other contributors may be female gender, mosaicism, and presence of a heart defect.
    
  • Causes of death include cardiac disease, CNS-related hypoventilation, respiratory infections, sepsis, and renal failure.

• Etiology: Majority caused by trisomy of chromosome 13 caused by maternal meiotic nondisjunction (advanced maternal age is a risk factor); small proportion caused by mosaicism or Robertsonian translocations.
  
• Prevalence: 0.85/10,000 live births.
  
• Clinical manifestations by organ system
  
  
  
  • CNS: 11% have a major CNS anomaly such as anencephaly, encephalocele, hydrocephalus, microcephaly, or spina bifida; others have developmental delay or mental retardation or holoprosencephaly.
    
  • HEENT: Aniridia, microphthalmia, coloboma, ocular hypotelorism (ranging to the severity of cyclopia), low-set and abnormal ears, cleft lip, cleft palate.
    
  • Cardiovascular: Congenital heart disease present in 35% in order of frequency: VSD, ASD, tetralogy of Fallot, transposition, coarctation, hypoplastic left heart, endocardial cushion defect, pulmonic stenosis, pulmonic atresia, truncus arteriosus, aortic stenosis, tricuspid atresia, Ebstein’s anomaly.
    
  • GI: Present in 2%; includes tracheoesophageal fistulas, Hirschsprung’s disease, abdominal wall defects (in 2%), failure to thrive (uniform finding).
    
  • GU: Present in 7% and includes obstructive uropathy, renal agenesis, hypospadias, epispadias.
    
  • Musculoskeletal: Flexed fingers, postaxial polydactyly, narrow fingernails.
  
  
• Survival: Mean survival is 7 days.
  
  
  
  • 5.6% live beyond 1 year.
    
  • Survival beyond 48 hours is a significant predictor of survival to 1 week and 1 month but possibly not to 1 year (J Med Genet 2002;39:e54); other contributors may be female gender, mosaicism, and presence of heart defect.
    
  • Causes of death include cardiac disease, CNS-related hypoventilation, respiratory infections, sepsis, and renal failure.

• Range from abnormal chromosome structure (eg, ring chromosomes) to deletions and duplications caused by rearrangement.

Definitions

• Balanced: An exchange of chromosomal material has occurred between at least two sites, but the resulting total chromosome complement is normal.
  
• Unbalanced: An exchange of chromosomal material has occurred between at least two sites, and the result is added or deficient chromosomal material.
  
• Marker chromosome: Small additional chromosomes of unclear origin that do not correspond to any of the normal human chromosomes.
  
• Ring chromosome: Chromosomal breaks at both ends of a chromosome with subsequent fusion lead to a ring-shaped chromosome.
  
• Isochromosome: A chromosome in which one arm is missing and the other arm is duplicated in mirror image fashion (eg, Pallister-Killian syndrome).
  
• Terminal deletion: Loss of a segment of a chromosome arm from a point, leading to loss of all the genes distal to that point.
  
• Interstitial deletion: A loss of a segment of chromosome from one point to another point, leaving the terminal portion (telomere) of the chromosome arm intact.
  
• Duplication: A rearrangement leading to extra chromosomal material for a particular segment (this is the opposite of a deletion [see above], and similar to a deletion, it can be terminal or interstitial; eg, cat-eye syndrome, duplication of 22q11distinct from the DiGeorge region; Charcot Marie Tooth IA).
  
• Inversion: A segment of chromosomal material that is rearranged in the reverse orientation relative to the surrounding chromosomal material. Two breaks are needed, and the inversion can be paracentric (two breaks in one arm, not including the centromere) or pericentric (one break in each arm, including the centromere). (eg, inv (8)(p23.1-q22.1) karyotype).
  
• Translocation: Exchange of chromosomal material between two chromosomes.
  
• Robertsonian translocation: A special type of translocation in which acrocentric chromosomes (13, 14, 15, 21 or 22) fuse at the centromere, losing their short arms.

Definitions

• Deletion: A chromosomal deletion visible on routine or high-resolution karyotype.
  
• Microdeletion or submicroscopic deletion: A chromosomal deletion not typically visible on karyotype (detected by fluorescence in situ hybridization or chromosomal microarray).
  
• Contiguous gene syndromes: Recognizable syndromes caused by a deletion involving multiple adjacent genes; these deletions are usually submicroscopic.

Inheritance

• Any large deletions that affect fertility arise de novo. Smaller deletions may have a Mendelian inheritance pattern. Other deletions may have parent-of-origin effects such as the deletions in Angelman and Prader-Willi syndromes.

Examples

• 1p36 deletion syndrome: Moderate to severe intellectual disability, seizures, FTT, hypotonia, speech delay, malformations, hearing and vision impairment, distinct facies.
  
• Wolf-Hirschhorn syndrome: 4p- microdeletion causing hypertelorism, frontal bossing, microcephaly, cleft lip and palate, mental retardation, hypospadias, low-set abnormal ears, and 5th finger clinodactyly.
  
• Cri-du-chat: 5p- (critical region is 5p15, often paternal deletion) microdeletion causing hypotonia, “cat’s meow” cry in the first few weeks of life, microcephaly, hypertelorism, epicanthal folds, low-set ears, micrognathia, mental retardation.
  
• Williams syndrome (Williams-Beuren syndrome): Microdeletion of 7q11.23 causing mild microcephaly, round “elfin” face with long philtrum, depressed nasal bridge and epicanthal folds, stellate iris, strabismus, supravalvar aortic stenosis, hypercalcemia, mental retardation with preserved language or social (“cocktail party personality”) abilities, nephrocalcinosis, progressive joint limitation, hypertension. (AAP Health Care Supervision for Children with Williams Syndrome: Pediatrics 2001;107:1192).
  
• WAGR Syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation): 11p13 deletion also causing glaucoma, abnormal tone, proteinuria, asthma, and obesity (Pediatrics 2005;116:984).
  
• Prader-Willi syndrome and Angelman syndrome: 15q11-13 deletions (disorders of imprinting).
  
• Chromosome 17 deletions: Four major locations
  
  
  
  • Smith-Magenis syndrome: 17p11.2 deletion causing short stature, brachycephaly, midface hypoplasia, cleft palate, mental retardation.
    
  • Neurofibromatosis type I: 17q11.2 deletion (see Neurofibromatosis).
    
  • Hereditary neuropathy with liability to pressure palsy: 17p12 deletion.
    
  • Miller-Dieker syndrome: 17p13.3 deletion causing microcephaly; intractable seizures; lissencephaly; pachygyria; profound mental retardation; and dysmorphic facies with a high forehead, small nose, and upslanting palpebral fissures.
  
  
• Alagille syndrome: 20p12 deletion causing cholestasis because of bile duct paucity, peripheral pulmonic stenosis, posterior embryotoxon (opacification at margin of cornea), butterfly vertebrae, deep-set eyes, broad forehead.
  
• DiGeorge syndrome or velocardiofacial syndrome: Deletions 22q11.2 leading to a broad spectrum of features, including parathyroid agenesis with refractory hypocalcemia (→ neonatal seizures), thymic agenesis (→ immunodeficiency), cardiac defects (VSD, right aortic arch, tetralogy of Fallot), cleft palate, prominent nose with narrow palpebral fissures.

Turner Syndrome (45,X)

• Diagnosis: Depends on the presence of clinical features of Turner syndrome and cytogenetic findings compatible with loss of X chromosome material.
  
  
  
  • Clinical pitfalls: All are phenotypically female; some are mosaic for 46,XY cell lines, requiring orchiectomy (risk of gonadoblastoma). Must have features beside primary amenorrhea to be considered Turner syndrome.
    
  • Cytogenetic pitfalls: Most are 45,X, but some patients have X chromosome deletions. Xq22.3 terminal deletions have been reported to cause Turner syndrome, but no deletions distal to that have been reported.
  
  
• Physical findings by organ system
  
  
  
  • HEENT: Inner canthal folds, ptosis, blue sclera, low-set ears, high arched palate, micrognathia, low posterior hairline, webbed neck, hyperopia, strabismus, conductive hearing loss, chronic otitis media.
    
  • CNS: Normal intelligence with a relative deficit in visuospatial skills.
    
  • Cardiac: Bicuspid aortic valve is most common; also coarctation of the aorta, hypoplastic left heart, partial anomalous pulmonary venous connection. Increased risk of aortic dissection and increased risk of QTc prolongation.
    
  • Endocrine: Autoimmune thyroid disease; GH is useful in increasing final adult height. Most need estrogen replacement starting at age 12 yr (streak gonads).
    
  • Musculoskeletal: Shield chest, short stature (SHOX gene deficiency), Madelung deformity (growth deficiency of radius), cubitus valgus, scoliosis, short fourth metacarpal.
    
  • Genitourinary: ⩽40% with structural kidney anomalies.
    
    
    
    • Classic 45,X is more likely to have renal abnormalities; mosaics are more likely to have lower GU tract anomalies.
      
    • Streak gonads with primary amenorrhea.
    
    
  • Skin: Multiple nevi.
  
  
• Management: AAP screening and health supervision in turner syndrome (Pediatrics. 111(3):692–702).

Klinefelter Syndrome (47, XXY; Most Common Cause of Male Hypogonadism)

• Epidemiology: One in 1000 males (many are never diagnosed).
  
• Diagnosis: Neonates and children are phenotypically normal. Scenarios for diagnosis include:
  
  
  
  • Adolescent male with gynecomastia noted to have tall stature, long limbs, and small testes.
    
  • Workup for male infertility (↑ FSH, ↓ testosterone).
  
  
• 47,XYY: Tall stature, mild developmental delay, normal puberty. Association with criminal activity is controversial.

Fragile X

• See triplet repeat disorders

General Principles

• Greatest susceptibility to structural malformations is when teratogens present during the embryonic period (3rd to 8th wk). Mental retardation and growth retardation can still result from exposure in the fetal period.
  
• Teratogenicity is related to timing, duration of exposure, and dose of exposure. Clinically recognizable patterns are often apparent.
  
• For a specific list of teratogens and associated defects, see Chapter 36.

Pierre Robin Sequence

• Description: Hypoplasia of the mandible → posterior positioning of the tongue and failure of the palate shelves to meet in the midline → cleft palate → resulting airway prone to posterior obstruction.
  
• Management considerations
  
  
  
  • Anticipate severe upper airway obstruction.
    
  • Consider early ENT referral
    
  • Monitor closely initially for hypoxia.
    
  • Consider sleep study looking for apnea.
    
  • Look for associated syndromes such as Stickler syndrome and chromosomal abnormalities.

Potter Sequence

• Description: Oligohydramnios (multiple causes, including bilateral renal agenesis, renal cystic dysplasia, lower urinary tract obstruction, chronic amniotic fluid leak) → compression on the fetus → limb position defects, flattened nose, wrinkled skin, severe pulmonary hypoplasia (caused by a lack of the mechanical effects of the amniotic fluid on the developing lungs).
  
• Management considerations
  
  
  
  • Anticipate severe respiratory insufficiency and possible need for high-frequency oscillatory ventilation, or ECMO.
    
  • Examine the placenta looking for amnion nodosum (suggestive of oligohydramnios).
    
  • Consider detailed imaging evaluation of genitourinary tract looking for renal agenesis, dysplasia, and urinary obstruction.
    
  • Early urology referral if indicated.
    
  • Pursue genetic causes of renal abnormalities such as chromosomal disorders and branchiootorenal syndrome.

Amniotic Band Sequence (Actually a Disruption, See Definitions)

• Description: Bands of ruptured amnion encircle developing structures → circumferential constrictions, amputations → decreased fetal movements with development of contractures.
  
• Management considerations (NeoReviews. 2005;6(12):e567): Plastic surgery involvement for circumferential constrictions; placental examination for bands.

Associations

Charge

• This is now considered a syndrome since the molecular cause was discovered.
  
• The incidence is one in 10,000.
  
• Features (NeoReviews. 2008;9(7):e299)
  
  
  
  • Colobomas: Retinal is more common than of the iris.
    
  • Cranial nerves: Particularly VII, VIII.
    
  • Heart defects: Tetralogy of Fallot, interrupted aortic arch, AV canal, double-outlet RV, truncus arteriosus, ASD, VSD.
    
  • Atresia choanae: Causes neonatal respiratory distress, chronic sinorespiratory infections. May be complete or partial and unilateral or bilateral. Clues to diagnosis: inability to pass NG tube, polyhydramnios.
    
  • Retarded somatic growth and mental retardation.
    
  • Genitourinary anomalies: Generally genital but also unilateral renal agenesis, obstructive uropathy.
    
  • Ear anomalies: Outer, middle, or inner.
  
  
• Evaluation
  
  
  
  • Ophthalmology evaluation for retinal colobomas
    
  • CT maxillofacial bones for choanal atresia
    
  • Echocardiography
    
  • Renal US
    
  • Hearing screen, temporal bone CT for Mondini dysplasia
    
  • Chromosomal microarray (CMA)
    
  • Chromodomain helicase DNA-binding protein 7 (CHD7) mutation testing: Confirmatory molecular test for CHARGE syndrome (in consultation with specialist)
  
  
• Health maintenance
  
  
  
  • Eye exam every 6 months
    
  • Prompt surgical correction of choanal abnormalities
    
  • Cardiology, ENT, renal referrals if indicated

Vater/VACTERL Association

• Should be treated as an epidemiologic phenomenon rather than as a diagnosis until chromosomal abnormalities and other syndromes have been ruled out.
  
  
  
  • Vertebral defects
    
  • Anal atresia
    
  • Cardiac defects
    
  • TracheoEsophageal fistulas
    
  • Renal anomalies
    
  • Limb defects, particularly of the radius

• There are more 300 disorders classified based on clinical features, radiographic findings, biochemical abnormalities, genetic mutations, and perturbations in embryonic development. Diagnosis requires consultation with a specialist.

Key Descriptors and Nomenclature (Pediatr Radiol. 2003;33:153)

• Dysostosis: Generalized multifocal defects of bone that remain static and will not evolve to affect previously uninvolved bones.
  
• Dysplasia: Intrinsic abnormality of bone or cartilage that can progress over time to involve previously normal bones.

Achondroplasia

• Autosomal dominant disorder: Mutation in the fibroblast growth factor receptor 3 (FGFR3). ∼75% are new mutations in the father’s germline (associated with advanced paternal age).
  
• Most common cause of severe short stature; occurs in one in 15,000 to one in 40,000.
  
• Radiographic findings (often sufficient for diagnosis): Rhizomelic shortening of the long bones, trident hands, square-shaped pelvis, short vertebral pedicles.
  
• Complications: Cervicomedullary compression, apnea resulting in sudden death.
  
• AAP: Health supervision for children with achondroplasia (Pediatrics. 2005;116(3):771)

• Diseases caused by an abnormal increase in the number of copies of a repetitive three-nucleotide element (eg, CGG). This increase (expansion) generally occurs during meiosis or mitosis at an early embryonic stage.
  
• May exhibit anticipation, a phenomenon in which severe phenotypes or an earlier age of onset occur with each generation.
  
• Fragile sites are constrictions or breaks that become visible on metaphase chromosomes when the cells are exposed to particular agents; they are unstable repeats. Not all unstable repeats are fragile sites.
  
• Most are inherited in an autosomal dominant pattern.

• Disease may be caused by:
  
  
  
  • Expansions of repeats that are not in the coding region, leading to decreased RNA expression.
    
  • Expansions of repeats within coding region, leading to altered protein function.
    
  • Expansion in an RNA regulatory region, leading to altered RNA function.

Fragile X Syndrome

• Definition: X-linked syndrome caused by mutations in the fragile X mental retardation 1 gene (FMR1) on Xq27.3. CGG trinucleotide repeat expansion in 5′ untranslated region of the FMR1 gene → gene methylation → lack of expression (although point mutations have been described).
  
  
  
  • Normal alleles: Six to 50 repeats
    
  • Premutation: 50 to 200 repeats
    
  • Mutation: 200+ repeats (classically from transmission of premutation allele from mother to child)
  
  
• Incidence: 25 per 100,000 in males; 12 per 100,000 in females (∼50% of females with full mutation express the syndrome depending on the pattern of X inactivation).
  
• Clinical features: Mental retardation of variable severity, hyperactivity, autistic features, ADHD, long face, prominent jaw, large ears, joint laxity (generalized connective tissue dysplasia), postpubertal macroorchidism.
  
• Diagnosis: Molecular testing for number of repeats.

Definitions

• Monoallelic gene expression: Despite a diploid chromosomal complement, a particular gene is only expressed from one allele.
  
• Uniparental disomy: Inheritance of two copies of a particular chromosome from one parent and none from the other parent. In some cases caused by nondisjunction in one of the parents’ gametes, with an initially trisomic embryo and subsequent “rescue” through degradation of one of the three chromosomes.
  
  
  
  • Heterodisomy: Nondisjunction in meiosis I with the child inheriting both of the chromosomes of one parent.
    
  • Isodisomy: Nondisjunction in meiosis II with the child inheriting two copies of one of the chromosomes of one parent.
  
  
• Many cases are believed to have genetic and epigenetic etiologies. Angelman syndrome (Am J Hum Genet 2002;71(1):162) and Beckwith Wiedemann syndrome (Am J Hum Genet 2003;72(1):156) have been associated with in vitro fertilization.