Hutchinson-Gilford Progeria Syndrome

Review
In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.
[updated ].

Excerpt

Clinical characteristics: Hutchinson-Gilford progeria syndrome (HGPS) is characterized by clinical features that typically develop in childhood and resemble some features of accelerated aging. Children with HGPS usually appear normal at birth. Profound failure to thrive occurs during the first year. Characteristic facial features include head that is disproportionately large for the face, narrow nasal ridge, narrow nasal tip, thin vermilion of the upper and lower lips, small mouth, and retro- and micrognathia. Common features include loss of subcutaneous fat, delayed eruption and loss of primary teeth, abnormal skin with small outpouchings over the abdomen and upper thighs, alopecia, nail dystrophy, coxa valga, and progressive joint contractures. Later findings include low-frequency conductive hearing loss, dental crowding, and partial lack of secondary tooth eruption. Motor and mental development is normal. Death occurs as a result of complications of severe atherosclerosis, either cardiac disease (myocardial infarction or heart failure) or cerebrovascular disease (stroke), generally between ages six and 20 years. Average life span is approximately 14.5 years.

Diagnosis/testing: The diagnosis of classic or nonclassic genotype HGPS is established in a proband with characteristic clinical features, along with identification of a heterozygous pathogenic variant in LMNA that results in production of the abnormal lamin A protein, progerin. Individuals with classic genotype HGPS are heterozygous for pathogenic variant c.1824C>T (~90% of individuals with HGPS). Individuals with nonclassic genotype HGPS have the characteristic clinical features of HGPS and are heterozygous for another LMNA pathogenic variant in exon 11 or intron 11 that results in production of progerin (~10% of individuals with HGPS).

Management: Treatment of manifestations: A regular diet with frequent small meals is recommended. Primary tooth extractions after the secondary tooth has erupted and/or fully descended may be required to avoid dental crowding. Use of sunscreen on all exposed areas of skin, including the head, is recommended for outdoor activities. Hip dislocation is best managed with physical therapy and body bracing; reconstructive hip surgery is possible, but comorbidities of surgery in this high-risk population should be considered. Shoe pads are recommended, as lack of body fat leads to foot discomfort. Routine physical and occupational therapy, active stretching and strengthening exercises, and hydrotherapy are recommended. Maintain optimal hydration, while encouraging physical activity, to minimize stroke risk. Anticoagulation as needed for cardiovascular and neurovascular complications. Medication dosages are based on body weight or body surface area, not age. Nitroglycerin can be beneficial for angina; anticongestive therapy is routine for the treatment of congestive heart failure. General anesthesia and intubation should be performed with extreme caution, ideally with fiberoptic intubation, if possible. Exposure keratopathy can be treated with ocular lubrication. Hearing aids can be used when clinically necessary. Age-appropriate schooling with adaptations for physical needs is usually recommended. Prevention of secondary complications: Low-dose aspirin (2-3 mg/kg body weight) is recommended for prevention of cardiovascular and stroke complications. Because the stiffened peripheral vasculature may be less tolerant to dehydration, maintaining optimal hydration orally is recommended. Surveillance: Annual or semiannual electrocardiogram (ECG), annual echocardiogram, carotid duplex ultrasound examination, neurologic examination, MRI/MRA of the head and neck, lipid profile, dental examination, hip x-ray to evaluate for avascular necrosis and progressing coxa valga, dual x-ray absorptiometry and/or peripheral cutaneous computed tomography to measure bone density, physical therapy assessment for joint contractures, ophthalmology examination, audiometry, and assessment of activities of daily living. Agents/circumstances to avoid: Dehydration; large crowds with taller/larger peers because of the risk of injury, trampolines and bouncy houses due to risk of hip dislocation. Physical activity should be self-limited.

Genetic counseling: Almost all individuals with HGPS have the disorder as the result of a de novo autosomal dominant pathogenic variant. Recurrence risk to the sibs of a proband is small (as HGPS is typically caused by a de novo pathogenic variant) but greater than that of the general population because of the possibility of parental germline mosaicism. Once the LMNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

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