Common Genetic Disorders

• Malformations


  Defects that result from the intrinsically abnormal development of a structure or set of structures (e.g., anencephaly, congenital heart disease)
• Deformations


  Occur when extrinsic (mechanical) forces impinge on the development of otherwise normal tissue (e.g., clubfoot)
• Disruptions


  Occur when normal tissue is irreparably destroyed, altering the subsequent formation of the structure (e.g., amniotic bands)
• Syndromes


  Recognizable patterns of symptoms or abnormalities that suggest a specific underlying disorder
• Trisomy 21 (Down syndrome)


  The most common chromosomal disorder. The 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.
• Down syndrome


  • Clinical features (see Table 5-1 and Figure 5-2)
  • Diagnosis is on the basis of clinical features and genetic testing that demonstrates three copies of chromosome 21
  • 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.
• Trisomy 18 (Edwards syndrome)


  Clinical features include:

  severe intellectual disability,

  prominent occiput,

  low-set ears,

  micrognathia,

  congenital heart disease,

  rocker-bottom feet, and clenched hands with overlapping digits. Prognosis is poor, as 90% of children die by 1 year of age.
• Trisomy 13 (Patau syndrome)


  Clinical features include severe intellectual disability, cutis aplasia, microphthalmia, coloboma, congenital heart disease, polydactyly, and 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.
• Turner Syndrome Epidemiology

  1. 
     

  • Monosomy X: 45% cases
  • Structural abnormality or mosaicism: rest of cases
  • Incidence: 1:2500–3000 female live births
• Turner syndrome


  • Short stature is present in 95% of individuals. Growth hormone can be used to increase final height.
  • 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. Estrogen therapy can be used to promote secondary sex characteristics.
  • Most individuals have normal intelligence.
  • Renal malformations, hypothyroidism, diabetes, and hearing loss are also associated with Turner syndrome.
• Klinefelter syndrome (XXY)


  The most common genetic cause of male infertility. The incidence is 1:500–1000 male live births. Risk increases with advancing maternal age.
• Klinefelter syndrome


  • Tall stature, thin, with relatively long legs, and 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. There is an increased risk of psychosocial and behavioral problems.
  • There is also an increased risk for developing mediastinal germ cell tumors (starting in adolescence) and breast cancer.
• 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.
• DiGeorge, velocardiofacial syndrome

  Occurs when a portion of the q arm of chromosome 22 is missing. The deletion can be de novo or inherited. The mnemonic 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). The incidence of 22q11.2 deletion syndrome is about 1 in 4000 live births.
• 22q11.2 deletion syndrome


  • 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, over-folded 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.
• Williams syndrome


  Results from a deletion on chromosome 7 (7q11.23) that includes the elastin gene. The incidence of Williams syndrome is about 1 in 20,000 births.
• Williams syndrome


  • 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, hypercalciuria, and hypothyroidism.
• Cri du chat syndrome

  Results from a deletion of the short arm of chromosome 5 (5p). It is characterized by catlike cry in infancy, microcephaly, downslanting palpebral fissures, developmental delay, and intellectual disability.
• 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.
• Uniparental disomy


  Occurs when both copies of one chromosome come from the same parent.
• Prader-Willi syndrome


  In infancy, patients demonstrate hypotonia and feeding difficulties, usually resulting in failure to thrive. In childhood, patients develop hyperphagia leading to obesity. Other features include almond-shaped eyes, strabismus, down-turned mouth, hypopigmentation, small hands and feet, short stature, and hypogonadism. Behavioral problems, intellectual disability, and learning disabilities are also common. The most common cause is a deletion in a region within the paternally inherited chromosome 15. The second most common cause is maternal UPD of the chromosome
• Angelman syndrome


  Clinical features include severe developmental delay, speech impairment, and happy demeanor with inappropriate laughter and smiling. Jerky movements and ataxic gait is sometimes described as "puppet-like". Other features include microcephaly, seizures, large mouth, widely spaced teeth, and prognathia (prominent mandible). The most common cause is a deletion in a region within the maternally inherited chromosome 15.
• Beckwith-Wiedemann syndrome


  An overgrowth disorder characterized by macrosomia, macroglossia, and visceromegaly. Can have hemihyperplasia, ear creases/pits, and omphalocele. Increased risk for embryonal tumors (Wilms tumor, neuroblastoma, etc.). This syndrome has several different etiologies, all of which affect imprinting on chromosome 11p15.5.
• Russell-Silver syndrome


  Characterized by

  intrauterine growth retardation/small for gestational age (SGA), short stature,

  normal head circumference, and asymmetry (limb, body, or face). Triangular facies, frontal bossing, or prominent forehead.

  The patient can also have café-au-lait macules.

  It has been associated with hypomethylation of a region that regulates expression of insulin-like growth factor 2.
• Triplet repeat expansion disorders

  Certain genes are sensitive to increasing (expanding) the number of nucleotide repeats in a specific gene segment. The number of repeats can increase with each generation, but the disorder only occurs once the number of nucleotide repeats in a gene expands beyond a specific threshold. Once the threshold is reached, this expansion can become even larger, causing earlier onset and more severe symptoms, which is a phenomenon known as anticipation.
• Fragile X syndrome


  Caused by expansion of the number of CGG repeats in the FMR1 gene on the X chromosome. It has an X-linked recessive mode of inheritance. Full mutation = >200 repeats.
• Fragile X syndrome


  • 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).
• Myotonic dystrophy


  The 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.
• Myotonic dystrophy


  • Progressive muscular weakness starting at any time during childhood
  • Other features include cataracts and cardiac conduction abnormalities.
• Marfan syndrome


  An autosomal dominant disorder caused by mutations in the gene that codes for fibrillin. Mutations can either be inherited or sporadic.
• Marfan syndrome


  • Characteristic findings involve the ocular, skeletal, and cardiovascular systems. Myopia, lens dislocation, and retinal detachment are common ocular findings.
• Fragile X syndrome


  Developmental delay and mild to severe intellectual disability, Behavioral abnormalities including autism and attention deficit/hyperactivity disorder
• Fragile X syndrome


  • Macrocephaly, long face, prominent jaw, protruding ears, Macroorchidism develops in adolescence
• Females with full mutation (Fragile X Syndrome)

  May have behavioral problems and developmental delays, but most have normal intelligence quotient (IQ)
• Myotonic dystrophy


  Caused by expansion of the number of CTG repeats in the DMPK gene
• Expansion of the repeats (in Myotonic Dystrophy) occurs much more frequently in mothers
• Myotonic dystrophy


  • Progressive muscular weakness starting at any time during childhood, Other features include cataracts and cardiac conduction abnormalities
• Marfan syndrome


  An autosomal dominant disorder caused by mutations in the gene that codes for fibrillin
• Marfan syndrome


  • 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
• Ehlers–Danlos syndrome, classic type

  An autosomal dominant disorder caused by mutations in genes that code for type V collagen