Hutchinson-Gilford Progeria Syndrome

Excerpt

Clinical characteristics: Hutchinson-Gilford progeria syndrome (HGPS) is characterized in the first year of life by growth deficiency, lagophthalmos, hair loss, delayed and incomplete primary tooth eruption, subcutaneous fat loss, and areas of abnormal skin (tightness, stippling, and/or small outpouchings over the abdomen and upper thighs). Motor and mental development is normal. Children have profound growth failure, subcutaneous lipodystrophy, total alopecia, high-pitched voice, nail dystrophy, horse-riding stance, coxa valga with possible hip dislocations, narrowed upper thorax, and progressive joint contractures. Characteristic facial features include disproportionately large head for the face, narrow nasal ridge, narrow nasal tip, thin vermilion of the lips, small mouth, retro- and micrognathia, delayed loss of primary teeth, and partial secondary tooth eruption. Additional features include low-frequency conductive hearing loss, dry eye with risk of exposure keratitis, and premature and accelerated atherosclerosis with cerebrovascular and cardiovascular disease. Without lonafarnib treatment death occurs at an average age of 14.5 years (range: 6-20 years). With lonafarnib treatment average life span is extended to approximately 18.7 years.

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

Management: Targeted therapy: Lonafarnib results in increase in life span presumably due to slowed cardiovascular disease progression that includes improved arterial wall stiffness and carotid-femoral pulse wave velocity. The therapy also improves low-tone hearing and may decrease headache frequency. Side effects are primarily gastrointestinal and vary in severity and duration.

Supportive care: Frequent small meals to maximize caloric intake; daily multivitamin; medication dosages are based on body weight or body surface area, not age; shoe pads for foot discomfort; school adaptations for short stature. General anesthesia and intubation should be performed with extreme caution, with fiberoptic intubation if possible. Fluoride supplementation as needed; if secondary teeth erupt palatally displaced, primary tooth extractions after the secondary teeth have erupted and/or fully descended may be required to avoid dental crowding. Sunscreen on exposed areas of skin, including the head, during outdoor activities; encourage sun-protective clothing including hat. 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. Routine treatment for bone fractures; physical and occupational therapy to maintain joint mobility, active stretching and strengthening exercises, and hydrotherapy. Though menstruation is highly variable, in females with excessive pubertal vaginal bleeding, short-term low-dose oral contraceptives can be used to decrease blood loss. Healthy diet with regular physical activity as tolerated; maintain optimal hydration, especially during hot weather and airplane travel. Low-dose aspirin to prevent cardiovascular and neurovascular complications. Nitroglycerin can be beneficial for angina; anti-congestive therapy is routine for the treatment of congestive heart failure. Modified transcatheter aortic valve replacement or modified apico-aortic valve replacement are high-risk interventions to treat critical aortic stenosis. Exercise, diet modification, and statin therapy as needed for hyperlipidemia. Hearing aids can be used when clinically necessary. Exposure keratopathy can be treated with ocular lubrication. Social work and family support.

Surveillance: Assess growth, caloric intake, skin manifestations, and family needs at each visit. Blood pressure, EKG, echocardiogram, and carotid scan every six to 12 months. Dental examination with radiographs, orthopedic evaluation, occupational and physical therapy assessment, lipid profile, neurologic assessment with head and neck MRI/MRA, and ophthalmology and audiology evaluation annually.

Agents/circumstances to avoid: Large crowds with taller and/or larger peers because of the risk of injury; trampolines and bouncy houses due to risk of hip dislocation; dehydration, anemia, and high fever because of cardiac and stroke risks; calcium supplementation because of extraskeletal calcium deposits.

Genetic counseling: HGPS is an autosomal dominant disorder. Ninety-eight percent of individuals with HGPS have the disorder as the result of a de novo LMNA pathogenic variant. Approximately 2% of individuals have the disorder as the result of a pathogenic variant inherited from an unaffected parent with gonadal mosaicism. Because HGPS is typically caused by a de novo pathogenic variant, the recurrence risk to the sibs of a proband is low but not zero because of the possibility of parental gonadal mosaicism. Once the LMNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.