Hutchinson-Gilford Progeria Syndrome

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.

Suggestive Findings

Hutchinson-Gilford progeria syndrome (HGPS) should be suspected in individuals with severe growth failure, areas of sclerodermatous skin, partial alopecia that progresses to total alopecia by age two years, generalized lipodystrophy, retrognathia, x-ray findings including distal clavicular and terminal phalangeal resorption as well as coxa valga, and delayed/incomplete primary tooth eruption, all in the setting of normal intellectual development.

Growth deficiency

• Short stature (<3rd percentile)
• Poor weight gain (<3rd percentile), weight distinctly low for height
• Diminished subcutaneous body fat globally

Facial features (see Figure 1)

Figure 1.

Female age 11 years and male age six years with HGPS displaying classic features Photo courtesy of the Progeria Research Foundation

• Head disproportionately large for face
• Long narrow nose
• Thin vermilion of the upper and lower lips
• Retrognathia and micrognathia

Ectodermal

• Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, dental crowding
• Skin. Taut, variably pigmented, sclerodermatous, skin outpouchings over lower abdomen and/or proximal thighs
• Hair. Total alopecia, sometimes with very sparse downy immature hair remaining; loss of eyebrows
• Dystrophic nails

Musculoskeletal

• Coxa valga with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head
• Osteolysis of the distal phalanges
• Short clavicles with distal resorption
• Pear-shaped thorax

Other

• Thin, high-pitched voice
• Low-frequency conductive hearing loss
• Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping)

Establishing the Diagnosis

Five major categories help to define LMNA-related disorders. Categories 1 and 2 define HGPS; categories 3-5 are not considered HGPS:

1.

Progerin-producing classic genotype HGPS

2.

Progerin-producing nonclassic genotype HGPS

3.

Non-progerin-producing progeroid laminopathies (see Differential Diagnosis)

• Due to heterozygous LMNA pathogenic variant that does not result in progerin production
• Due to pathogenic variants in other genes (e.g., ZMPSTE24)

4.

Non-progeroid laminopathies (see Differential Diagnosis)

5.

Non-laminopathy progeroid syndromes (see Differential Diagnosis)

The diagnosis of classic genotype HGPS is established in a proband with the above Suggestive Findings and a heterozygous c.1824C>T pathogenic variant in LMNA identified on molecular genetic testing (see Table 1).

The diagnosis of nonclassic genotype HGPS is established in a proband with Suggestive Findings similar to classic genotype HGPS and an autosomal dominant progerin-producing pathogenic variant in either the exon 11 splice junction or intron 11 of LMNA identified on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing).

Single-gene testing

• Targeted analysis for LMNA pathogenic variants c.1824C>T (identified in 90% of individuals with HGPS), can be performed first in individuals with Suggestive Findings of HGPS.
• Sequence analysis of LMNA can be performed if no pathogenic variant is found on targeted analysis. Sequence analysis of intron 11 should be included if this was not already completed with targeted analysis.
  Note: LMNA deletions and/or duplications have not been reported in individuals with HGPS.

A multigene panel that includes LMNA, ZMPSTE24, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing. When the phenotype is indistinguishable from many other inherited disorders characterized by progeroid phenotype, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Classic and nonclassic genotype Hutchinson-Gilford progeria syndrome (HGPS) are characterized by clinical features that develop in childhood and resemble some features of accelerated aging. Children with progeria usually appear normal at birth and in early infancy.

Growth deficiency. Profound failure to thrive usually occurs during the first year. Poor weight gain and loss of subcutaneous fat results in weight less than the third percentile for age, and weight that is distinctly low for height. Stature also decreases to below the third percentile for age.

Characteristic facial features (see Figure 1) include a head that appears disproportionately large for face, narrow nasal ridge with a narrow nasal tip, thin vermilion of the upper and lower lips, small mouth, retrognathia, and micrognathia. Ogival (steeple-shaped) palatal vault occurs in 60%-70% of affected individuals. A short, thick lingual frenulum that limits tongue mobility is seen in about 50% of affected individuals. Narrow airway and rigid laryngeal structures cause a high-pitched voice.

Dental. Delayed eruption and delayed loss of primary teeth are common. Dental crowding occurs as a result of a small mouth, lack of primary tooth loss, and secondary tooth eruption behind the primary teeth. Secondary tooth eruption is often partial.

Skin. Skin findings may be evident at birth and are present in all individuals by age two years. "Sclerodermatous" skin changes variably include areas that are described as taut, thickened, fibrotic, indurated, or rippled. In addition, dimpling or irregular small outpouchings can occur over the lower abdomen and proximal thighs. Skin also displays abnormal pigmentation consisting of light or dark macules and patches along with some papules and skin mottling.

Hair. Partial alopecia progresses to total alopecia. Sparse downy hairs may be present on the occiput. Loss of eyebrows is common, and loss of eyelashes occurs in some individuals.

Nails. Fingernails and toenails become dystrophic.

Musculoskeletal. Individuals with HGPS are particularly susceptible to hip dislocation because of the progressive coxa valga malformation, which can be accompanied by avascular necrosis of the hip (osteonecrosis). Avascular necrosis can cause hip pain and is evident on x-ray. The coxa valga causes a wide-based shuffling gait. Additional bone changes include osteolysis of the distal phalanges, short clavicles with distal resorption, a pear-shaped thorax, and mildly low bone density for age. Fractures are not more commonly reported in individuals with HGPS. Extraskeletal calcifications are present in 40% of cases, with unknown clinical significance. Progressive stiffness of the joints due to tightened joint ligaments and osteoarthritis occurs with variable severity.

Endocrine. Affected individuals do not become sexually mature. Females reach Tanner Stage 1 (78%) or 2 (22%) during pubertal years, and approximately 60% of females experience menarche [Greer et al 2018]. No cases of fertility have been described. Serum leptin concentrations are below the limit of detection. Insulin resistance occurs in about 50% of individuals, without the overt development of diabetes mellitus.

Cardiovascular/cerebrovascular. Individuals with HGPS develop severe atherosclerosis, usually without obvious abnormalities in lipid profiles [Gordon et al 2005]. In general, serum cholesterol, LDL, and triglyceride concentrations are not elevated and HDL concentrations may decrease with age. Diastolic dysfunction is an early cardiac abnormality, usually detected beyond age five years by tissue Doppler echocardiography [Prakash et al 2018]. Sequential manifestations of cardiovascular decline include impaired relaxation of the heart muscle, followed by ventricular hypertrophy. This may occur in the setting of heart valve thickening or stenosis, or with hypertension that is often labile. Mitral and aortic valve abnormalities, including calcification, stenosis, and regurgitation, usually develop in the second decade of life.

Systolic dysfunction is usually present in the setting of advanced disease, with or without identified coronary vascular insufficiency. Clinical symptoms of angina, dyspnea on exertion, or overt heart failure appear as late findings in the course of disease.

Transient ischemic attacks, silent strokes, or symptomatic strokes have occurred as early as age four years [Silvera et al 2013]. Strokes can occur at any brain site and, therefore can lead to a variety of physical limitations and/or cognitive decline. Partial and complete carotid artery blockages can occur from plaque formation. Despite underlying vascular disease, most children do not have clinically identified strokes.

Raynaud phenomenon in fingers occurs in a minority of affected individuals.

Death typically occurs as a result of complications of cardiac or cerebrovascular disease. More than 80% of deaths are due to heart failure and/or myocardial infarction, most often between ages six and 20 years, with an average life span of approximately 14.5 years [Gordon et al 2014, Gordon et al 2018a].

Ophthalmologic. Nocturnal lagophthalmos (the inability to fully close the eyes during sleep) is common. As a result, corneal dryness and clouding can occur. In a minority of individuals, corneal ulceration occurs due to exposure keratitis [Mantagos et al 2017].

Hearing. Conductive hearing loss is highly prevalent at all ages, with low-frequency hearing loss more prevalent than high-frequency [Guardiani et al 2011, Gordon et al 2012].

Other

• Motor and mental development are normal.
• Tumor rate is not increased over that of the general population. One individual died of a chondrosarcoma of the chest wall at age 13 years [King et al 1978].
• Other changes associated with normal aging such as nearsightedness or farsightedness, arcus senilis, senile personality changes, or Alzheimer disease have not been documented.
• Children with HGPS appear to have a normal immune system; they respond as well as the general population when subjected to various infections. Wound healing is normal.
• Liver, kidney, gastrointestinal, neurologic, and cognitive functions are normal.

Genotype-Phenotype Correlations

Penetrance

Penetrance is complete.

Nomenclature

HGPS is also referred to as the Hutchinson-Gilford syndrome or progeria.

Prevalence

The prevalence of children with HGPS per total population is one in 20 million [Gordon et al 2014].

The estimated birth incidence for HGPS is one in four million births with no observed differences based on ethnic background [Hennekam 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Hutchinson-Gilford progeria syndrome (HGPS), the following evaluations are recommended if they have not already been completed:

• Weight and height plotted on standard growth charts to evaluate growth over time
• Electrocardiogram (ECG) and echocardiogram
• Carotid artery duplex scans to evaluate size of the lumen and intimal thickness in order to establish baseline vascular status
• MRI/MRA of the brain and neck
• Skeletal x-rays to evaluate for characteristic findings: acroosteolysis, clavicular resorption, coxa valga, and extraskeletal soft tissue calcifications [Cleveland et al 2012]
• Orthopedic evaluation for progressive coxa valga and/or avascular necrosis
• Dual-energy x-ray absorptiometry (DXA) to assess bone mineral density. Note: This must be normalized for height-age [Gordon et al 2011].
• Occupational and physical therapy assessments, including six-minute walk test, goniometry to assess joint mobility, and assessment of activities of daily living
• Nutritional assessment, although dietary intake is generally not compromised in these patients
• Audiologic, ophthalmologic, and dental examinations
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A complete, system-based management guide is available from the Progeria Research Foundation.

Growth deficiency. Frequent small meals tend to maximize caloric intake.

Dental. Extraction of primary teeth may be required to avoid crowding and development of two rows of teeth. Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or almost fully descended. Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position with time.

Skin. Use of sunscreen on all exposed areas of skin, including the head, is recommended for outdoor activities.

Orthopedic. Conservative management of hip dislocation with physical therapy and body bracing when possible; surgical correction if essential, with special attention to intubation and anesthesia guidelines. Surgery should be treated as substantial risk for stroke and/or cardiac events. Podiatric evaluation is indicated to determine if shoe inserts are needed as lack of body fat leads to foot discomfort. Fracture rate is equivalent to the general pediatric population. When children do fracture, treatment and healing are routine.

Routine physical and occupational therapy is recommended to help maintain range of motion in large and small joints; see Physical Therapy and Occupational Therapy in Progeria (pdf). Active stretching and strengthening, along with hydrotherapy, are recommended.

In cases of dysfunctional vaginal bleeding or spotting, short-term (i.e., 3-6 months) provision of low-dose combined oral contraceptive pills can be helpful to stabilize the endometrium.

Cardiovascular. A regular healthy diet is indicated unless the lipid profile becomes abnormal, at which point appropriate treatment includes exercise, diet modification, and medication as warranted. Avoiding anemia, dehydration, and high fever can be important, particularly in individuals with more advanced CV disease. Maintaining optimal hydration orally is recommended.

Prior to decline in cardiovascular or neurologic status (resulting from strokes, angina, or heart attacks), children should be encouraged to be physically active as tolerated, taking into account possible limitations related to restricted range of motion of joints and hip problems including osteoarthritis and hip dislocation.

Anticoagulants other than the routinely recommended aspirin (see Prevention of Secondary Complications) may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.

Although lipid profiles are usually normal, dietary therapy ± statin therapy can be implemented if abnormalities occur.

Medications. Dosages should be based on body weight or body surface area and not on age. Anesthetics should be used with particular caution.

• Nitroglycerin is frequently of benefit if angina develops.
• Routine anticongestive therapy is appropriate if congestive heart failure is present.

General anesthesia and intubation should be performed with extreme caution, ideally with fiberoptic intubation. Individuals with HGPS have retrognathia, stiffened laryngeal structures, and a narrow and unusually shaped airway; additionally, they may exhibit an extreme sensitivity to alterations in blood pressure due to vascular stiffness.

Ophthalmologic. Corneal dryness, clouding, or ulceration should be fully evaluated by an ophthalmologist. Exposure keratitis can be treated during daytime with ocular lubrication and during sleep with moisturizing ointment or by closing eyelids with skin tape.

Hearing loss. Low-frequency conductive hearing loss often does not interfere with activities of daily living. Sitting at the front of the classroom can be helpful. Hearing aids can be used, when clinically necessary.

Education. Because intellect and maturity are normal, age-appropriate schooling is usually indicated.

Infections are generally handled as for unaffected children.

Prevention of Secondary Complications

Aspirin. Based on the evidence from adult studies that low doses of aspirin help delay heart attacks and strokes, it is probably appropriate to give children with HGPS low-dose aspirin treatment, at doses of 2-3 mg/kg body weight per day. Note: If chicken pox or influenza is prevalent in the community, it may be advisable to discontinue the aspirin during that time because of the increased risk of Reye syndrome.

Adequate oral hydration is recommended, as the vasculature becomes generally less pliable and the risks of stroke and cardiac complications increase over time due to decreased vascular compensation. This is especially important during hot weather or airplane travel.

Vitamin supplementation. Standard amounts of over-the-counter daily multivitamin tablets are appropriate. Calcium supplementation is not recommended, due to the potential for aggravating extraskeletal calcification formation and hypothetically aggravating vascular plaque status. Maintenance of normal calcium levels from dietary sources is encouraged.

Fluoride supplements are recommended in areas where needed.

Immunizations. The routine doses and administration schedule for all immunizations are recommended. Immunizations are generally handled as for unaffected children.

Surveillance

A complete, system-based management guide is available from the Progeria Research Foundation.

Annually or semiannually. Consistent measurement of blood pressure with the appropriately sized cuff, ECG, echocardiogram, and carotid duplex scans to monitor for cardiovascular disease. Note: Children may experience severe carotid artery atherosclerotic blockage prior to any significant ECG changes.

Annually

• Neurologic assessment for signs and symptoms of headaches and stroke
• MRI/MRA of head and neck to assess for presence of vascular changes and silent strokes and to allow for the assessment of changes (increases) in risk over time
• Lipid profile
• Dental examination, x-ray, and cleaning
• Orthopedic evaluation for avascular necrosis (osteonecrosis) of the hip and progressing coxa valga that result in horse-riding stance and potential hip dislocation
• Occupational and physical therapy assessments including six-minute walk test, goniometry to assess joint mobility, and assessment of activities of daily living
• Ophthalmologic examination with special attention to possible exposure keratopathy
• Audiology evaluation with special attention to possible low-frequency conductive hearing loss

Agents/Circumstances to Avoid

Children should avoid being in the midst of large crowds with much taller and larger peers because of the increased risk of injury. Physical activity should be self-limited. Avoid uneven surfaces that could aggravate hip dysplasia, such as trampolines and bouncy houses. Avoid being carried by underage peers. Avoid dehydration due to increased risk of stroke.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search HGPS or progeria within ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical trials for HGPS.

The two therapies currently under human clinical trial investigation for HGPS are lonafarnib and everolimus (see Figure 2). Two clinical trials currently exist, with one administering lonafarnib monotherapy and one administering lonafarnib plus everolimus combination therapy.

Figure 2.

Post-translational processing and medications currently under investigation in clinical treatment trials for HGPS. Items in green promote the pathways. Items in red inhibit the pathways. * denotes medications tested in clinical trials. Everolimus is a (more...)

• Lonafarnib is an investigational farnesyltransferase inhibitor. For HGPS, its target action is inhibition of post-translational farnesylation of progerin, the active disease-causing protein in HGPS. Lonafarnib is an oral medication administered twice daily. Clinical trial results for lonafarnib have revealed improvement in the rate of weight gain, vascular distensibility as measured via pulse wave velocity and vascular echodensity, bone rigidity, neurosensory hearing [Gordon et al 2012], headaches [Ullrich et al 2013], and life span [Gordon et al 2014, Gordon et al 2018b].
• Everolimus is a rapalog (rapamycin-like drug) mTOR inhibitor that additionally increases cellular autophagy. It is an oral medication administered once daily. Everolimus is approved as a medication to treat non-HGPS conditions. Rapamycin improved cellular phenotypes in HGPS fibroblasts via increased autophagy [Cao et al 2011, Cenni et al 2011] and extends life span in a lamin A-deficient mouse model. Clinical trial results are not yet known.

Other

• A clinical treatment trial administering lonafarnib in combination with pravastatin and zoledronate demonstrated evidence of increased bone mineral density but no other improvements over that of lonafarnib monotherapy [Gordon et al 2016].
• A clinical treatment trial administering pravastatin and zoledronate as combination therapy has been conducted.

The following proposed treatments have not been tested in humans (see Table 3). For a comprehensive review of evidence for these potential treatments, see Strandgren et al [2017].