Hutchinson-Gilford progeria syndrome

INTRODUCTION — The LMNA gene on chromosome 1q encodes prelamin A. Prelamin A is ultimately converted to lamin A, a critically important structural protein component of the nuclear lamina that stabilizes the nuclear membrane [1]. Pathogenic variants of LMNA cause a group of degenerative disorders known as laminopathies, which include Hutchinson-Gilford progeria syndrome (HGPS; MIM #176670) and at least 12 known diseases. (See 'Other laminopathies' below.)

Classic HGPS, frequently referred to as "progeria," is an exceedingly rare, fatal, autosomal dominant disorder characterized by accelerated aging that starts early in childhood with severe failure to thrive and progressive development of a characteristic facial appearance, alopecia, lipoatrophy, skeletal dysplasia, and atherosclerosis that results in myocardial infarction, stroke, and ultimately death in the second decade of life [2]. Atypical progeria syndromes have been reported in the literature. While there is considerable overlap in the phenotype, variability remains in the severity, onset, and lifespan as compared with HGPS. Causative variants for atypical progeria have been reported in LMNA but are not the same as the classic G608G pathogenic variant in HGPS [2]. The term "progeroid syndrome" is also more broadly used to refer to various rare disorders with features of premature aging, such as Werner syndrome, Cockayne syndrome, and Bloom syndrome.

The pathogenesis, genetics, clinical characteristics, diagnosis, and management of classic HGPS are discussed here. Other laminopathies are presented separately.

●(See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

●(See "Emery-Dreifuss muscular dystrophy".)

●(See "Limb-girdle muscular dystrophy".)

●(See "Lipodystrophic syndromes", section on 'Familial partial lipodystrophy' and "Lipodystrophic syndromes", section on 'Mandibuloacral dysplasia'.)

EPIDEMIOLOGY — Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare panethnic disorder, with an estimated incidence of one in four to eight million births [3]. The Progeria Research Foundation estimates the prevalence of HGPS at 1 in 20 million [4].

GENETICS AND PATHOGENESIS

Classic Hutchinson-Gilford progeria syndrome — Hutchinson-Gilford progeria syndrome (HGPS) is caused by a single nucleotide substitution in the lamin A/C gene LMNA (c.1824C>T [p.Gly608Gly]), encoding two different types of protein isoforms (lamin A and lamin C) [5,6]. Although the pathogenic variant of LMNA does not change the encoded amino acid glycine, this single de novo C to T pathogenic variant at position 1824 of codon 608 of the LMNA gene activates a cryptic splice donor site. The splice donor site creates a messenger RNA with a 150-nucleotide internal deletion near the C-terminus.

The mutation in HGPS causes production of a unique mutant lamin A protein called progerin, which has a 50-amino acid internal deletion. A missing cleavage site within this deletion leads to permanent farnesylation causing the progerin to remain anchored to the nuclear envelope. This permanently farnesylated state of progerin disrupts the normal organization of the nuclear lamina and is hypothesized to cause nuclear blebbing, disorganized heterochromatin, and dysregulated gene transcription. This genomic instability is thought to cause the premature aging and disease in HGPS. Telomere shortening in HGPS is an area of investigation. Average telomere length is decreased in HGPS fibroblasts [7,8].

Atypical progeria syndromes — Atypical progeria syndromes with similar clinical characteristics to classic HGPS are caused by a variety of pathogenic variants in intron 11 of the LMNA gene, rather than the classic (c.1824C>T [p.Gly608Gly]) pathogenic variant in HGPS [2,9].

Other laminopathies — In addition to HGPS, a broad range of diseases caused by LMNA gene mutations have been identified. These disorders are allelic:

●Mandibuloacral dysplasia (see "Lipodystrophic syndromes", section on 'Mandibuloacral dysplasia')

●Restrictive dermopathy, a rare, lethal neonatal laminopathy [10]

●Familial partial lipodystrophy type 2 (see "Lipodystrophic syndromes", section on 'FPLD type 2')

●Limb-girdle muscular dystrophy with atrioventricular conduction defects (LGMD1B) (see "Limb-girdle muscular dystrophy")

●Autosomal dominant dilated cardiomyopathy with conduction defects (CMD1A or DCM-CD) [11] (see "Genetics of dilated cardiomyopathy", section on 'Autosomal dominant DCM with or without conduction system disease')

●Emery-Dreifuss muscular dystrophy (EDMD2 and EDMD3) (see "Emery-Dreifuss muscular dystrophy")

●Dilated cardiomyopathy and hypergonadotropic hypogonadism (atypical Werner syndrome) [12]

●A relatively severe form of congenital muscular dystrophy classified as LMNA-related congenital muscular dystrophy [13]

●Charcot-Marie-Tooth type 2B1 [14] (see "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis")

●Heart-hand syndrome, Slovenian type [15]

●Malouf syndrome with hypergonadotropic hypogonadism and cardiomyopathy [16]

●Autosomal dominant dilated cardiomyopathy with apical left ventricular aneurysm [17] (see "Genetics of dilated cardiomyopathy")

●Autosomal dominant quadriceps myopathy with dilated cardiomyopathy and associated conduction defects [18]

CLINICAL MANIFESTATIONS — Children affected with Hutchinson-Gilford progeria syndrome (HGPS) appear normal at birth, but the clinical manifestations become apparent in the first few years of life. These include failure to thrive; dermatologic, musculoskeletal, and neurologic abnormalities; and eventually life-limiting cardiovascular disease. Children with HGPS also have audiologic, dental, and ophthalmologic issues that impact their lives.

●Failure to thrive – Despite adequate caloric intake, young children with HGPS have growth impairment, resulting in poor weight gain, short stature, and loss of subcutaneous fat [19]. Sexual maturation is absent in most patients.

●Facial features – Children with HGPS develop a characteristic facial appearance that includes circumoral cyanosis; prominent eyes; thin, beaked nose; micrognathia; retrognathia; thin lips; loss of eyebrows; and prominent scalp veins (picture 1) [2,20,21].

●Skin changes – The skin changes include atrophy and dryness, with areas that appear taut and sclerotic and areas of laxity and outpouching; reticulated hyperpigmentation interspersed with hypopigmentation; and dimpling and mottling, especially over the abdomen and thighs (picture 2) [22]. Young children with HGPS develop alopecia and dystrophic fingernails and toenails [2,20].

●Musculoskeletal abnormalities – Musculoskeletal findings include progressive joint contractures, decreased joint range of motion, fingertip tufting, osteoarthritis, coxa valga, and a wide-based stance and shuffling gait [2,20]. Endocrinologic abnormalities include decreased bone mineral density, lipodystrophy, and insulin resistance [2].

●Neurologic abnormalities – Neurologic findings include intracranial and superior cervical arteriopathy, with evidence of early and clinically silent strokes seen in children as early as 5 to 10 years of age [23]. Cognitive development and intellectual function are normal, and there is no evidence of dementia from limited autopsy studies [24].

●Cardiovascular abnormalities – Cardiovascular findings include progressive reduced vascular function with age and progressive atherosclerosis, resulting in premature death from myocardial infarction or, less frequently, stroke, despite a lack of typical cardiovascular risk factors (eg, elevated cholesterol and C-reactive protein) [25-27].

●Dental abnormalities – Dental findings in children with HGPS include hypodontia (most often missing the second premolars), ogival arch, steep mandibular angles, ankyloglossia, dysmorphic teeth, delayed tooth eruption, and double rows of teeth (picture 3) [20,21].

●Otologic abnormalities – Otologic abnormalities include small or absent ear lobules, stiff auricular cartilages, and hypoplasia of the external ear canal soft tissue (leading to shortened canals) [28]. Audiologically, patients with HGPS have low-frequency conductive hearing loss [28].

●Ocular abnormalities – Ophthalmologic issues include hyperopia, nocturnal lagophthalmos, and corneal dryness [20].

LABORATORY AND IMAGING FINDINGS — Hutchinson-Gilford progeria syndrome (HGPS) is associated with several laboratory and imaging abnormalities, including [2,20,29,30]:

●Decreased serum leptin levels.

●Insulin resistance in up to one-half of patients.

●Decreased bone density.

●Radiographic findings of acro-osteolysis, clavicular resorption, and coxa valga.

●Other routine laboratory studies are generally unremarkable. Mild elevations in platelet and prolonged prothrombin time have been reported [20].

DIAGNOSIS — The clinical diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is suspected in a child presenting with the following features:

●Failure to thrive in the first year of life

●Characteristic facial appearance with micrognathia, prominent eyes, and circumoral cyanosis

●Alopecia and prominent scalp veins

●Sclerotic skin changes with outpouching and dimpling/mottling, especially on the abdomen

●Decreased joint range of motion and joint contractures

The diagnosis of HGPS is established based upon the presence of the clinical features listed above and the identification by genetic testing of the known causative pathogenic variant in the LMNA gene (c.1824C>T[p.Gly608Gly]).

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of classic Hutchinson-Gilford progeria syndrome (HGPS) includes:

●Atypical progeria syndromes – Atypical progeria syndromes, which have clinical features similar to classic HGPS, can be more or less severe and are caused by pathogenic variants in LMNA other than the classic G608G pathogenic variant [2,31].

●Restrictive dermopathy – Restrictive dermopathy (MIM #275210) is a genetic disease, typically lethal in the neonatal period, characterized by abnormally tight skin from birth caused by pathogenic variants in the genes encoding lamin A (LMNA) and a zinc metalloproteinase (ZMPSTE24) that processes lamin A [32]. Affected newborns are usually premature and present with diffusely hard skin that may shear or tear at areas of skin folding, such as the neck, inguinal folds, and lower abdomen (picture 4A-B) [33].

●Familial partial lipodystrophy type 2 – Familial partial lipodystrophy (FPLD) is a group of rare and genetically heterogeneous syndromes characterized by variable loss of adipose tissue that occurs during childhood, puberty, or young adulthood; metabolic abnormalities; and cardiomyopathy [34]. FPLD type 2 (Dunnigan lipodystrophy, MIM #151660) is allelic to HGPS, as it is caused by pathogenic variants in the LMNA gene. (See "Lipodystrophic syndromes", section on 'Familial partial lipodystrophy'.)

Other rare progeroid syndromes with features of premature aging that should be differentiated by HGPS include:

●Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) [35]

●Congenital generalized lipodystrophy (see "Lipodystrophic syndromes", section on 'Congenital generalized lipodystrophy')

●Cockayne syndrome (see "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome')

●Mandibuloacral dysplasia [36]

●Petty-Laxova-Wiedemann progeroid syndrome [37]

MANAGEMENT — Management of Hutchinson-Gilford progeria syndrome (HGPS) is supportive and involves ensuring optimal nutrition, monitoring of disease progression, and treatment of complications as they present [2]. Lonafarnib, the only specific treatment for HGPS, was approved in 2020 by the US Food and Drug Administration for patients 12 months of age and older [38].

Lonafarnib — In November 2020, lonafarnib, an oral farnesyltransferase inhibitor (FTI), was approved by the US Food and Drug Administration (orphan drug designation) for the treatment of HGPS in patients 12 months of age and older [39]. Lonafarnib is administered orally twice daily with meals at a starting dose of 115 mg/m². Adverse effects include vomiting, diarrhea, abdominal pain, infection, and fatigue.

It is hypothesized that lonafarnib may inhibit the formation of the aberrant lamin A protein progerin and prevent its anchoring to the inner nuclear membrane, thus potentially improving disease status in HGPS [40]. Studies supporting the use of lonafarnib for HGPS are summarized here:

●A nonrandomized, clinical trial of lonafarnib in 25 children with HGPS provided some evidence of efficacy in reducing the carotid artery echodensity and improving the bone structure in these patients [41]. In another study using lonafarnib as part of a triple-drug regimen with zoledronic acid and pravastatin in 37 children, 26 (71 percent) achieved at least one of the primary composite outcomes (increase in per-patient rate of weight gain and/or decrease in carotid artery echodensity) [42]. However, a cardiovascular benefit was not observed in this study.

●A subsequent, nonrandomized study evaluated the effect of oral lonafarnib on all-cause mortality in a cohort of 27 patients (median age 8.4 years) with HGPS compared with 27 matched, untreated patients [43]. The median treatment duration was 2.2 years. During this period, the observed mortality rate was 3.7 percent among patients receiving lonafarnib versus 33.3 percent in the untreated group.

●A study using a single molecule counting immunoassay developed to detect the progerin protein in plasma from patients with HGPS showed that treatment with lonafarnib was associated with decreased plasma progerin levels and improved survival [44].

Although these data are encouraging, the results of additional, ongoing studies are awaited before lonafarnib can be recommended for all children with HGPS. (See 'Experimental therapies' below.)

Growth issues — A nutritional assessment, plotting of weight/height on growth charts, and frequent small meals to increase/maximize calorie intake are recommended [2]. Attention to adequate oral hydration is important.

Cardiac and neurologic issues — The primary concern in patients with HGPS is accelerated progressive atherosclerosis leading to myocardial infarction, transient ischemic attack (TIA), and stroke. The cardiac and neurologic status of the patient should be investigated, even in asymptomatic patients, at least once a year. Cardiovascular assessment should include electrocardiogram (ECG), blood pressure measurement, lipid profile testing, and echocardiography.

Neurologic evaluation should include brain and neck magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) and carotid duplex scans to assess vascular status [2,24]. Although aspirin has not been specifically studied in patients with HGPS, antiplatelet therapy may offer benefits to patients with cardiovascular and cerebrovascular disease similar to its use in adults [24]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

Musculoskeletal issues — Skeletal radiographs are recommended after initial diagnosis. Dual-energy x-ray absorptiometry (DEXA) for assessment of bone mineral density (with values normalized for height) is recommended annually.

Given the joint contractures associated with HGPS, standard goniometry for assessment of joint mobility is recommended, as is routine physical and occupational therapy. Patients with HGPS may benefit from orthotics, including shoe pads/inserts and hip braces in the setting of hip dysplasia [2].

Dental issues — Routine dental evaluation (every six months) is recommended, with attention to the possible need for extraction of primary teeth to prevent overcrowding.

Ophthalmologic issues — Ophthalmology evaluation is recommended annually to assess for possible exposure keratopathy. Patients with HGPS may benefit from the use of eye drops for corneal dryness and nighttime use of moisturizing ointment for nocturnal lagophthalmos [2].

Hearing issues — Audiology evaluation is recommended annually to assess for possible low-frequency conductive hearing loss and consideration of hearing aids if needed.

Genetic counseling — In the overwhelming majority of cases, HGPS occurs due to a de novo pathogenic variant (c.1824C>T [p.Gly608Gly]). However, in extremely rare cases, somatic and germline mosaicism has been reported [45]. For assessment of reproductive risk, genetics referral of affected families is recommended.

Medication dosing issues and anesthesia — Medication doses should be based on body weight or body surface area rather than age. General anesthesia and intubation can be difficult in patients with HGPS due to narrow airways, necessitating the use of fiberoptic intubation [2].

EXPERIMENTAL THERAPIES

Lonafarnib plus everolimus — An ongoing clinical trial (NCT02579044) is investigating lonafarnib in combination with everolimus, an mTOR inhibitor. It is hypothesized that while lonafarnib inhibits the progerin formation, everolimus may help clear progerin from cells [46].

PROGNOSIS — Patients with classic Hutchinson-Gilford progeria syndrome (HGPS) develop progressive atherosclerosis, generally leading to death from myocardial infarction or stroke at the age of approximately 15 years [47].

SUMMARY AND RECOMMENDATIONS

●Definition – Hutchinson-Gilford progeria syndrome (HGPS) is an exceedingly rare, autosomal dominant, premature aging disease. It is caused by a single nucleotide substitution in the LMNA gene, c.1824C>T(p.Gly608Gly). (See 'Introduction' above and 'Genetics and pathogenesis' above.)

●Clinical manifestations – The onset of symptoms of HGPS usually occur in the first few years of life. The cardinal features include failure to thrive, loss of subcutaneous fat, poor weight gain, short stature, joint contractures, and accelerated progressive atherosclerosis leading to myocardial infarction, transient ischemic attacks, and stroke. Additional clinical features include atrophic skin changes with hyper/hypopigmentation, alopecia, and a characteristic facial appearance with circumoral cyanosis; prominent eyes; thin, beaked nose; micrognathia; retrognathia; and prominent scalp veins. (See 'Clinical manifestations' above.)

●Laboratory and imaging findings – These include decreased bone mineral density, decreased serum leptin levels, insulin resistance, coxa valga, clavicular resorption, and acro-osteolysis. (See 'Laboratory and imaging findings' above.)

●Diagnosis – The diagnosis of HGPS is established based upon the presence of characteristic clinical features and the identification by genetic testing of the known causative pathogenic variant in the LMNA gene. (See 'Diagnosis' above.)

●Management – Management is supportive and involves ensuring optimal nutrition, monitoring of disease progression, and treatment of complications as they present. Lonafarnib, an oral farnesyltransferase inhibitor (FTI) that appears to inhibit the formation of the aberrant lamin A protein progerin, may improve disease status and survival in patients with HGPS. (See 'Management' above and 'Lonafarnib' above.)

●Prognosis – Patients with HGPS develop progressive atherosclerosis that eventually leads to death from myocardial infarction or stroke in the second decade of life. (See 'Prognosis' above.)