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.

Suggestive Findings

HGPS should be suspected in probands with the following clinical and radiographic findings in the setting of normal intellectual development (see Figure 1 and Figure 2).

Figure 1.

Female age 11 years and male age six years with Hutchinson-Gilford progeria syndrome displaying characteristic facial features, with total alopecia, lipodystrophy, long, narrow nose with narrow nasal ridge and narrow nasal tip, small mouth, and retrognathia (more...)

Figure 2.

Clinical, imaging, and growth features of Hutchinson-Gilford progeria syndrome (HGPS) A. Girl age three months

Growth deficiency

• Typically postnatal onset during first two years of life
• Short stature (<3rd centile)
• Poor weight gain (<3rd centile); weight distinctly low for height
• Diminished subcutaneous body fat globally, along with low serum leptin levels

Facial features that develop in childhood (See Figure 1.)

• Head disproportionately large for face
• Long, narrow nose (narrow nasal ridge and narrow nasal tip)
• Thin vermilion of the upper and lower lips
• Small mouth, retrognathia, and micrognathia

Ectodermal findings

• Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, tooth misalignment
• Skin. Taut, variably pigmented, sclerodermatous skin outpouchings over lower abdomen and/or proximal thighs, any of which can be the first signs of disease in infancy
• Hair. Total alopecia that develops in the first two years of life, sometimes with very sparse, downy, immature hair remaining; loss of eyebrows
• Dystrophic nails develop at variable ages in childhood.

Musculoskeletal clinical and radiographic findings

• Coxa valga develops within the first three years, with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head.
• Osteolysis of the distal phalanges
• Short clavicles with distal resorption/tapering (distal clavicular osteolysis)
• Pear-shaped thorax
• Normal or mildly low bone density z scores when normalized for height and age
• Joint contractures are present in all individuals; can be present at birth or present later in childhood; locations vary

Other findings

• Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping) is an almost uniform finding and can occur from birth.
• Normal intellectual development
• High-pitched voice
• Low-frequency conductive hearing loss
• Secondary sexual characteristics do not fully develop. Menstruation is variable in females.

Establishing the Diagnosis

Clinical Description

Classic and nonclassic genotype Hutchinson-Gilford progeria syndrome (HGPS) are characterized by growth deficiency, characteristic facial features, dental anomalies, sclerodermatous skin findings, alopecia, lipodystrophy, dystrophic nails, musculoskeletal manifestations, infertility, severe early-onset atherosclerosis, hearing loss, and nocturnal lagophthalmos. Children with progeria usually appear normal at birth and in early infancy.

Growth deficiency. Most infants display normal weight at birth. Profoundly poor weight gain and growth deficiency usually occurs during the first year. Poor weight gain and loss of subcutaneous fat results in weight less than the 3rd centile for age, and weight that is distinctly low for height. Stature also decreases to below the 3rd centile for age. Lack of body fat can contribute to foot discomfort over time.

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 develops in the first year of life and 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. Coxa valga causes a horse-riding stance and wide-based, shuffling gait. Individuals with HGPS are particularly susceptible to hip dislocation because of progressive coxa valga malformation, which can be accompanied by avascular necrosis of the hip. Avascular necrosis can cause hip pain and is evident on radiographs. 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 individuals, 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 instances 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, low-density lipoprotein (LDL), and triglyceride concentrations are not elevated, and high-density lipoprotein (HDL) concentrations may decrease with age. Diastolic dysfunction and cardiac strain are early cardiac abnormalities, usually detected beyond age five years by tissue Doppler echocardiography [Prakash et al 2018, Olsen et al 2023]. 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. Aortic gradient increases exponentially with time at later stages of disease, portending critical aortic stenosis [Gordon et al 2024].

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. The risk of cerebral infarction is around 32% by age 13.5 years, 20% of which are silent strokes.

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

Without lonafarnib treatment, 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]. Average life span is extended to approximately 19 years with lonafarnib therapy, with similar causes of death.

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

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 keratopathy [Mantagos et al 2017].

Other

• Liver, kidney, gastrointestinal, neurologic, strength-for-size, and cognitive functions are normal.
• Tumor rate is not increased over that of the general population.
• 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.

Genotype-Phenotype Correlations

Penetrance

Penetrance is complete.

Nomenclature

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

Prevalence

HGPS is an ultra-rare disease. The prevalence of children with HGPS per total population is one in 20 million living individuals, with an estimated 400 affected individuals worldwide [Gordon et al 2014].

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HGPS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

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.

Avoid anemia and high fever, particularly in individuals with advanced cardiovascular disease.

Avoid calcium supplementation, due to the potential for aggravating extraskeletal calcification formation and hypothetically aggravating vascular plaque status.

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.

A clinical treatment trial administering lonafarnib monotherapy (see Targeted Therapy) is ongoing as an extension of NCT02579044.

A clinical treatment trial administering progerinin, an oral small molecule inhibitor of progerin / lamin A binding, is currently being conducted [Kang et al 2021, Kang et al 2023] (NCT06775041).

A clinical treatment trial administering lonafarnib (see Targeted Therapy) plus everolimus combination therapy has been completed and results are pending (NCT02579044). Everolimus is a rapalog (rapamycin-like drug) mTOR inhibitor that 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.

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]. Extraskeletal calcifications of unknown significance increased with treatment [Gordon et al 2019]. Since rate of bone fracture is normal in individuals with HGPS, this combination therapy was not recommended.

Mode of Inheritance

Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Ninety-eight percent of individuals reported to date with HGPS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant.
  • The parental origin of the de novo LMNA pathogenic variant was paternal in four of the four families included in one study [Eriksson et al 2003].
  • A study of paternal age effect found that on average the father's age was significantly increased by about five years [Brown et al 1985].
• Approximately 2% of currently living individuals with the classic genotype HGPS identified through the Progeria Research Foundation Diagnostic Testing Program have HGPS as the result of an LMNA pathogenic variant inherited from an unaffected parent with presumed gonadal (or somatic and gonadal) mosaicism. Maternal somatic and gonadal mosaicism was demonstrated in one family [Wuyts et al 2005].
• Parents of individuals with HGPS are not affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents. Because HGPS is typically caused by a de novo pathogenic variant (i.e., neither parent of the proband has the LMNA pathogenic variant), the recurrence risk to the sibs of a proband is low but not zero due to the possibility of parental gonadal mosaicism.
• Of the 214 known individuals with classic genotype HGPS in the Progeria Research Foundation International Progeria Patient Registry, four (2%) instances of non-twin sib recurrence have been reported to date. The number of unaffected sibs among the 214 total individuals is unknown. Thus, the recurrence risk for subsequent pregnancies after one individual has been genetically diagnosed with HGPS is low but significantly higher than the one in four million incidence for the general population.

Offspring of a proband. Individuals with classic genotype HGPS are not known to reproduce; there is one individual with nonclassic genotype HGPS and a mild phenotype who is known to have reproduced [Hisama et al 2011].

Prenatal Testing and Preimplantation Genetic Testing

Once the LMNA pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk (because of the rare possibility of gonadal mosaicism in a parent) and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The nuclear lamina is a protein-containing layer attached to the inner nuclear membrane. It is composed of a family of polypeptides, with the major components being the lamins A, B1, B2, and C. Lamins A and C are formed by alternative splicing of the LMNA/C gene transcript. Splicing within exon 10 gives rise to lamin C, whereas transcription of all 12 exons gives rise to lamin A. Lamins B1 and B2 are encoded by separate genes, and there are no known progeroid pathogenic variants within lamins B1 and B2.

Lamin A is normally synthesized as a precursor molecule (prelamin A) and undergoes four major post-translational processing steps. First, because prelamin A contains a CAAX (cysteine / aliphatic / aliphatic / any amino acid) box at its carboxyl terminus, it is modified by farnesylation. Following farnesylation, cleavage of the last three amino acids, methylation of the C terminus, and internal proteolytic cleavage by the ZMPSTE24 protease occurs. Removal of the last 15 coding amino acids along with the CAAX box and farnesyl group generates mature lamin A with 646 amino acids.

The classic LMNA pathogenic variant c.1824C>T activates a cryptic splice site in exon 11, resulting in a protein with a 50-amino acid deletion near its C-terminal end. The deletion removes the recognition site that normally leads to ZMPSTE24 proteolytic cleavage of the terminal 18 amino acids of prelamin A, along with the phosphorylation site(s) involved in the dissociation and reassociation of the nuclear membrane at each cell division. The resulting protein, progerin, is shortened and permanently farnesylated. The lipophilic farnesyl moiety is utilized to zip code prelamin (and hence progerin) into the inner nuclear membrane, but the hydrophobic tail is then normally removed, allowing mature lamin A to move freely in the nuclear scaffold. The lack of farnesyl cleavage for progerin likely results in long-term association with the inner nuclear membrane, where it exerts progressively more damage to cells as they go through repeated mitoses. That the failure to remove the farnesyl group is at least in part responsible for the phenotypes observed in HGPS is strongly supported by studies on both cell and mouse models that have either been engineered to produce a non-farnesylated progerin product or treated with a drug that inhibits farnesylation, rendering a non-farnesylated progerin product.

Other LMNA pathogenic variants that do not result in the production of progerin result in lamin A with abnormal structure and/or function (including abnormal interactions with the nuclear membrane lamin-associated proteins).

Mechanism of disease causation. Gain of abnormal function

LMNA-specific laboratory technical considerations. LMNA pathogenic variants c.1821G>A, c.1822G>A, c.1824C>T, c.1968G>A, and c.1968G>T cause disease by affecting LMNA splicing. Pathogenic variants c.1822G>A and c.1968G>T also result in an amino acid change for the fraction of the RNA that does not use the cryptic splice site (see Table 2).

Author Notes

Dr Gordon is an investigator for progeria clinical treatment trials being conducted at Boston Children's Hospital. She leads the Progeria Research Foundation's International Progeria Patient Registry and Diagnostic Testing Program. She is interested in hearing from patients, patient families, and clinicians with questions about progeria or patients with suspected progeria. She is also interested in hearing from families or clinicians who are considering treatment with lonafarnib. For more information, contact Dr Gordon at gro.hcraeserairegorp@nodrogl.

Sentynl Therapeutics
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Acknowledgments

We are grateful to all those with progeria and their families who have contributed to the medical and research progress on progeria. We thank the Progeria Research Foundation and the Boston Children's Hospital progeria clinical trial team members for advancing progeria natural history studies, treatments, and clinical care.

Revision History

• 13 March 2025 (sw) Comprehensive update posted live
• 17 January 2019 (sw) Comprehensive update posted live
• 8 January 2015 (me) Comprehensive update posted live
• 6 January 2011 (me) Comprehensive update posted live
• 10 August 2006 (me) Comprehensive update posted live
• 12 December 2003 (me) Review posted live
• 31 July 2003 (wtb) Original submission

Published Guidelines / Consensus Statements

• Progeria Research Foundation. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. Includes genetic testing guidelines. Available online (pdf). Accessed 2-12-25.

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