Genetics
This chapter highlights the more common genetic disorders that are encountered in acute care practice.
CHARGE Syndrome
Lynn D. Mohr
Background/Definition
A congenital disorder described in 1979 with a characteristic set of congenital features categorized as major, minor, and occasional findings.
Leading cause of congenital deaf-blindness.
Etiology/Types
70% of children have mutation in the CDH7 gene on chromosome 8.
Autosomal dominant inheritance.
Pathophysiology
Arrest in embryonic differentiation during the second month of gestation, when the affected organs are in the formative stages.
Clinical Presentation
C: Coloboma of the eye (key-hole-shaped defect seen in eye).
H: Heart defects.
A: Atresia of the nasal choanae.
R: Retardation of growth and/or development.
G: Genital and/or urinary abnormalities.
E: Ear abnormalities and deafness (Figure 20.1).
Diagnostic Evaluation
Differentiate between other syndromes.
VACTERL, 22q11.2 deletion.
Major features (e.g., common in CHARGE syndrome and uncommon in other syndromes/conditions).
Coloboma.
Cranial nerve anomalies.
Choanal atresia/stenosis.
Ear anomalies.
Gene sequencing supports diagnosis.
Management
Congenital heart defect: surgical correction.
Choanal atresia repair.
Kidney function evaluation.
Feeding/nutritional support and gastroesophageal reflux therapy.
Hearing aid/assistive devices.
Hormone replacement for delayed puberty some cases.
PEARL
More information at CHARGE Syndrome Foundation: retrieved from http://www.chargesyndrome.org/
DiGeorge Syndrome (22q11.2 Deletion Syndrome)
Jeanne Little
Background/Definition
Deletion of chromos ome 22q11.2.
Most often results from a new mutation, but inherited in 10% of cases.
Inherited through an autosomal dominant pattern from a parent.
Etiology/Types
Common clinical features exist among DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome because they share a genetic deletion of chromosome 22q11.
Clinical Presentation
Cardiac outflow tract abnormalities (e.g., tetralogy of Fallot, interrupted aortic arch).
FIGURE 20.1 • CHARGE Syndrome. The characteristic ear anomalies include pinnae that are severely malformed (A), protruding (B), or small (C), as in this 5-year-old girl with very mild facial features and laryngotracheomalacia. She carries the CHD7 mutation and had a more severely affected brother, presumably representing gonadal mosaicism.
Dysmorphic features.
Hypertelorism.
Micrognathia.
Short philtrum.
Fish-mouth appearance.
Low-set ears.
Cleft palate with feeding and speech disorders, including velopharyngeal insufficiency.
Conductive hearing loss can occur secondary to cleft palate.
Frequent otitis media.
Absence or hypoplasia of the thymus, resulting in immune deficiency and increased susceptibility to infection.
Hypoplasia of the parathyroid gland, resulting in hypocalcemia.
Cognitive impairment and growth delay; hypotonia is common in infancy.
Skeletal abnormalities (e.g., cervical spine abnormalities, cervical spine instability, polydactyly, club foot).
Vertebral abnormalities (e.g., butterfly vertebrae, hemivertebrae, rib abnormalities).
Renal abnormalities (e.g., absent, cystic, or multicystic kidneys; vesicoureteral reflux).
Hypocalcemia
Diagnostic Evaluation
Fluorescence in situ hybridization (FISH) analysis or comparative genome hybridization (CGH) analysis for a deletion at chromosome 22q11.2 confirms the diagnosis.
Management
Congenital heart defect: surgical correction as indicated.
Cleft palate: surgical correction.
Immune dysfunction therapy: aggressive treatment of infection, avoidance of live vaccines.
Kidney anomalies: ultrasound evaluation.
Calcium replacement as needed.
Annual hearing screening.
Speech and physical therapy.
Cervical spine films at 4 years of age to evaluate for cervical spine abnormalities/instability.
PEARL
The acronym CATCH-22 is often used to describe the defect: cardiac, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia resulting from 22q11 deletion.
Fragile X Syndrome
Jeanne Little
Background/Definition
Most common cause of inherited intellectual disability.
Etiology
Caused by a fragile site on chromosome Xq27.3.
Fragile sites are areas of chromosomes that have a tendency to break, attenuate, or separate under growth.
Clinical Presentation
Males are affected more often and more severely than females.
Facial appearance is characterized by a long face and prominent jaw, forehead, and ears (Figure 20.2).
Macroorchidism may not be present until puberty.
Mild to profound cognitive impairment, autistic behavior, and developmental delays are evident.
Seizures may develop over time.
Poor eye contact, speech delays, hyperactivity, and aggressive tendencies.
Diagnostic Evaluation
Molecular observation of an expanded DNA segment of the FMR1 (fragile X mental retardation 1) gene.
Management
Medical management of seizures, if present.
Early intervention with behavioral therapy, educational evaluation, and support (e.g., speech and occupational therapy).
 FIGURE 20.2 • A. Prominent forehead and ears in a male with Fragile X syndrome. B. Long face with prominent ears and jaw in a male with Fragile X syndrome. |
Marfan Syndrome
Jeanne Little
Background/Definition
Autosomal dominant disorder resulting in connective tissue disease affecting the skeletal, cardiovascular, and ocular systems.
Etiology
Mutation in the fibrillin-1 (FBN1) gene with phenotypic variability of the disorder.
Clinical Presentation
Typically tall and thin with an arm span exceeding the height (Figure 20.3A).
Scoliosis, pectus excavatum, or pectus carinatum can develop.
Dural ectasia, an enlargement of the dura at the lumbosacral level, is common and is usually asymptomatic, but may cause back and leg pain.
Lens displacement (ectopia lentis) often occurs in the first decade of life. Severe myopia may also be present.
Steinberg thumb sign presence: protrusion of distal phalanx of thumb beyond the ulnar border when hand is in clenched fist position (Figure 20.3B).
Associated cardiac complications are progressive aortic root dilation with or without aortic regurgitation, mitral valve prolapse, and mitral regurgitation.
Diagnostic Evaluation
Diagnosis is based on major and minor clinical criteria involving primarily the skeletal, cardiovascular, and ocular systems.
FIGURE 20.3 • Marfan Syndrome. A: Marfan syndrome in a 14-year-old boy. Note arachnodactyly, relatively long limbs (dolichostenomelia), pectus carinatum, sparse subcutaneous fat, unilateral genu valgum, and pes planus. The patient also had scoliosis. This patient died of aortic rupture at age 15 years. B: A positive Steinberg thumb sign consists of protrusion of the distal phalanx of the thumb beyond the ulnar border of the clenched fist, and reflects both longitudinal laxity of the hand and a long thumb.
In general, a tall stature or an increased arm span to height ratio is the most consistent presenting finding.
Major criteria include:
Aortic root dilation for age or aortic dissection (Figure 20.4), ectopia lentis, lumbosacral dural ectasia, and skeletal findings.
Management
Prevention of complications and genetic counseling are most important.
Scoliosis and pectus abnormalities are often treated with bracing and/or surgery.
FIGURE 20.4 • Ascending Aortic Aneurysm (Marfan Syndrome). The anterior left portion of the heart in a patient who died suddenly with known Marfan syndrome. The aortic root is dilated (arrow), which is typical of Marfan aneurysms. The left ventricle is markedly dilated and moderately hypertrophied, consistent with chronic aortic insufficiency.
Dural ectasia can be serially followed with magnetic resonance imaging. Symptomatic children may require pain control therapy.
Annual ophthalmologic evaluations to screen for myopia, increased intraocular pressure, lens dislocation, or retinal detachment.
Cardiac, skeletal, and ocular monitoring.
Trisomy 18 (Edwards Syndrome)
Lynn D. Mohr
Background/Definition
Chromosomal disorder caused by an additional chromosome 18.
Etiology/Types
Females are more commonly affected than males.
Higher mortality in newborn period among males compared with females.
95% die before birth, 50% carried to term will be stillborn, <10% will survive to 1 year of age.
 FIGURE 20.5 • Rocker-Bottom Feet. |
Pathophysiology
Not an inherited condition.
Random events during egg and sperm formation.
Error known as nondisjunction.
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