Hutchinson–Gilford Progeria Syndrome

Hutchinson-Gilford progeria of classic and non-classic genotype (LMNA, progerin production), with the atypical progeroid laminopathies and the forms due to biallelic ZMPSTE24 (mandibuloacral dysplasia type B and restrictive dermopathy) in the differential diagnosis. The non-progeroid laminopathies (dilated cardiomyopathy, progressive conduction disease, left ventricular non-compaction, Emery-Dreifuss muscular dystrophy and partial lipodystrophies) are included only as allelic disorders.

Literature and regulatory information update: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical descriptions

The first record attributed to progeria is a note in the St. James Gazette of 1754 on Hopkins Hopkins, "the little Welshman", who died in Glamorganshire aged 17 years and 2 months "of mere old age", never having weighed more than 17 pounds and, in the previous three years, no more than 12 [30]. In 1886, Jonathan Hutchinson described a boy with congenital absence of hair and skin atrophy, accompanying the description with a photograph at 15.5 years in which the disproportionately large head, the "pinched" facial features, lipodystrophy, incomplete extension of knees and elbows and the senile appearance can be recognised [2, 30]. Hastings Gilford studied that patient and a second one, and in 1904 proposed the term "progeria", noting that only two well-documented cases were then known and that one of them had died of angina pectoris at 18 years of age [2, 30]. DeBusk reviewed 60 cases in 1972, used the designation "Hutchinson-Gilford syndrome" for the first time and gathered the arguments in favour of a sporadic dominant disease: rare parental consanguinity (3 of 19 families in which it was sought), a paternal age effect and exceptional recurrence in siblings, which he attributed to germline mosaicism [2, 30].

During the second half of the twentieth century, reports accumulated of consanguineous families with more than one affected child, such as an Egyptian family, a consanguineous Brazilian family with two branches of affected cousins and a Libyan family, which for years supported the hypothesis of a recessive form [2]. OMIM records that, in the Brazilian family described by Maciel in 1988, recessive inheritance was unequivocal, but the diagnosis of HGPS was not demonstrated [2]. In the light of the current classification, these reports correspond mainly to recessive progeroid laminopathies and mandibuloacral dysplasias, and familial recurrence with unaffected parents in true HGPS is explained by parental mosaicism [2, 3, 10].

1.2. Molecular discovery of 2003

The molecular cause was identified in April 2003, in simultaneous publications by two groups. The PRF genetics consortium, with the National Human Genome Research Institute and Francis Collins, located the gene on the long arm of chromosome 1 on the basis of two cases of uniparental isodisomy of 1q and a monozygotic twin with a paternal interstitial deletion of about 6 Mb, which defined an interval of 4.82 Mb with about 80 genes [31]. Sequencing of LMNA, a gene in that interval already linked to six diseases (Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, Dunnigan familial partial lipodystrophy, limb-girdle muscular dystrophy 1B, Charcot-Marie-Tooth 2B1 and mandibuloacral dysplasia), showed in 18 of 20 classic cases the same heterozygous de novo substitution G608G (GGC>GGT) in exon 11, and in one additional case the substitution G608S (GGC>AGC) in the same codon [31]. In the eight families in which DNA from both parents was available, the variant was absent in the parents, and in the four informative families the mutant allele was of paternal origin [3, 31]. RT-PCR revealed an abnormal product due to activation of a cryptic splice donor in exon 11, with loss of 50 amino acids near the carboxyl terminus, and immunofluorescence of fibroblasts showed visible anomalies of the nuclear envelope [31]. The Marseille group (De Sandre-Giovannoli and colleagues) described at the same time activation of the same cryptic site in two patients, with marked changes in the shape and size of lymphocyte nuclei, lamin A detectable in only 10% to 20% of these cells and about 25% of normal lamin A levels on Western blot [2, 32].

The identification of progerin gave rise to a clinical research programme conducted mainly in Boston: the National Institutes of Health (NIH) natural history cohort of 2005–2006, with 15 children [17]; the first trial of a farnesyltransferase inhibitor, started in 2007 with 28 children from 16 countries, about 75% of the cases then known [33, 34]; and the approval of lonafarnib (Zokinvy®) by the US Food and Drug Administration (FDA) on 20 November 2020, as the first authorised treatment for the disease [20, 35].

1.3. Nomenclature and classification

The historical classification of the skeletal dysplasia books distinguished classic, "childhood-onset" and congenital forms, allowing for the latter two homozygosity or compound heterozygosity for LMNA [8]. The classification used by GeneReviews and the PRF clinical handbook is molecular and organises the LMNA-associated diseases into five groups: (1) HGPS of classic genotype, progerin-producing; (2) HGPS of non-classic genotype, also progerin-producing; (3) non-progerin-producing progeroid laminopathies, due to mono- or biallelic LMNA variants or to variants in other prelamin A processing genes, such as ZMPSTE24; (4) non-progeroid laminopathies; and (5) non-laminopathic progeroid syndromes [3, 4]. Only the first two groups are HGPS. Orphanet associates with ORPHA:740 the genes LMNA and ZMPSTE24 and dominant and recessive inheritance, which reflects the inclusion of HGPS-like phenotypes caused by ZMPSTE24; GeneReviews classifies these phenotypes as non-progerin-producing progeroid laminopathies [1, 3]. A second proposal, based on transcript analysis, separates the syndromes with impaired processing and accumulation of truncated prelamin A isoforms (progerin or Δ50, Δ35 and Δ90) from the atypical progeroid syndromes due to missense variants that alter lamins A and C without prelamin A accumulation [36].

The distinction has therapeutic consequences. The lonafarnib label in the USA and the EU uses the expression "processing-deficient progeroid laminopathies" for the forms with a heterozygous LMNA variant and accumulation of progerin-like protein or with biallelic ZMPSTE24 variants, and excludes processing-proficient progeroid laminopathies and the other progeroid syndromes [19, 21].

1.4. Entities within scope

HGPS of classic genotype is defined by the characteristic clinical findings and the heterozygous variant NM_170707.4:c.1824C>T p.(Gly608=) [3]. HGPS of non-classic genotype is defined by similar findings and another heterozygous variant of exon 11 or intron 11 of LMNA that produces progerin; the phenotype ranges from severe neonatal progeria to mild adult-onset forms [3, 25]. Mandibuloacral dysplasia (MAD) is autosomal recessive and is divided into type A, due to LMNA, with partial lipodystrophy, and type B, due to ZMPSTE24, with generalised lipodystrophy and a more severe course [26, 27, 37]. Restrictive dermopathy is the neonatal lethal form of the processing defect, almost always due to complete loss of ZMPSTE24 in homozygosity or compound heterozygosity and, less frequently, to dominant de novo LMNA variants that eliminate exon 11 [28, 38]. Atypical progeroid laminopathies without progerin include neonatal progeria due to p.(Glu55Lys) or p.(Glu55Gly), the phenotypes intermediate between HGPS and MAD-A due to homozygous p.(Arg527Cys), atypical Werner syndrome, cardiocutaneous progeroid syndrome and non-syndromic cardiac progeria [13, 14, 39–41].

The non-progeroid laminopathies are included here only as allelic disorders: dilated cardiomyopathy, conduction disease and atrioventricular block, left ventricular non-compaction, Emery-Dreifuss and limb-girdle 1B muscular dystrophy and Dunnigan familial partial lipodystrophy type 2.

2. Molecular Genetics and Pathophysiology

2.1. The LMNA gene and the nuclear lamina

The nuclear lamina is a protein network attached to the inner face of the inner nuclear membrane, formed by lamins A, C, B1 and B2 [3]. Lamins A and C are products of the same gene, LMNA, by alternative splicing: lamin C uses a splice site in exon 10, upstream of its stop codon, and lamin A is encoded by the 12 exons, joining exons 11 and 12 [3, 31]. The gene spans about 25 kb of genomic DNA [31]. Lamins B1 and B2 are encoded by other genes and have no known progeroid variants [3]. The current reference is the MANE Select transcript NM_170707.4 (protein NP_733821.1; LRG_254t2), at 1q22; GeneReviews still uses version NM_170707.2, without change in the numbering of the variants discussed [3, 5].

2.2. Prelamin A processing and the role of ZMPSTE24

Lamin A is synthesised as a precursor, prelamin A, with a CAAX box at the carboxyl terminus, and undergoes four post-translational steps: farnesylation of the cysteine of the CAAX box; removal of the last three amino acids; methylation of the new terminus; and internal proteolytic cleavage by ZMPSTE24, which removes the last 15 amino acids with the farnesyl group and generates mature lamin A of 646 amino acids [3]. ZMPSTE24 (also called FACE-1) is a transmembrane zinc metalloprotease of the endoplasmic reticulum and inner nuclear membrane, encoded at 1p34.2 [42]. The lipophilic farnesyl group targets prelamin A to the inner nuclear membrane; its removal in mature lamin A allows the protein to move within the nuclear skeleton and to dissociate and reassociate at each mitosis [3]. Retention of farnesylated prelamin A is toxic, and the amount of residual ZMPSTE24 activity explains the clinical spectrum: complete loss in restrictive dermopathy, partial activity in MAD-B [27, 28, 37].

2.3. The classic variant and progerin

The variant NM_170707.4:c.1824C>T (NC_000001.11:g.156138613C>T on GRCh38) is synonymous at codon level, GGC>GGT, and is therefore written p.(Gly608=); "G608G" and "p.G608G" are the historical form, and OMIM also records the designation "2036C>T" used in 2003 by one of the groups [2, 5]. The substitution increases spliceosome binding to a cryptic donor sequence at c.1818–1824, which competes with the normal intron 11 donor; the resulting transcript loses 150 bp in the 3' part of exon 11 and the protein loses 50 amino acids near the carboxyl terminus [3, 4]. The deletion removes the ZMPSTE24 cleavage recognition site, located within the terminal 18 amino acids, and the phosphorylation sites involved in dissociation from the nuclear membrane at each division; the protein retains the CAAX box and remains farnesylated [2, 3]. This protein, called progerin or lamin A Δ50, remains permanently associated with the inner nuclear membrane and accumulates with successive divisions; in fibroblasts, accumulation is accompanied by lobulation of the nuclear envelope, thickening of the lamina, loss of peripheral heterochromatin and clustering of nuclear pores, changes that worsen with ageing of the cultures [2, 3].

The mechanism is an abnormal gain of function, with a dominant negative effect on the lamina [3, 43]. Activation of the cryptic donor is not complete, so the c.1824C>T allele also produces normal transcripts [25]. The role of persistent farnesylation is supported by cellular and murine models with non-farnesylated progerin or treated with farnesyltransferase inhibitors, and as early as 2005 exposure to one of these inhibitors corrected the nuclear morphology of cells expressing progerin [2, 3]. Everyone produces small amounts of progerin, which links the disease to physiological ageing; plasma progerin in people without HGPS is about 95 times lower than in affected children [4, 44].

In the tissues, the central finding is loss of smooth muscle cells from the arterial media, with increased collagen deposition and secondary alteration of elastin, which make the arteries rigid [15, 30]. The most affected tissues (bone and cartilage, vascular smooth muscle and dermis) are of mesodermal and neural crest origin, and a 2025 review proposes that high levels of lamin B1 in the neonatal period explain why manifestations appear only from the second month of life; this is a hypothesis without new clinical data [45]. Liver, kidney, central nervous system, immune system and wound healing function normally, which may be due to low progerin expression in some cell types or to greater resistance of some organs [3, 4].

2.4. Non-classic genotypes and genotype-phenotype correlation

Non-classic variants act through the same mechanism: they increase use of the exon 11 cryptic donor or weaken the normal intron 11 donor [3, 25]. Severity correlates with the amount of progerin: c.1968+1G>A and c.1821G>A produce progerin/lamin A ratios (in mRNA and protein) higher than those of the classic variant and cause severe neonatal progeria, whereas c.1968G>A and c.1968+5G>A produce little progerin and cause adult-onset forms with coronary disease [2, 25]. Variants c.1822G>A and c.1968G>T also change the amino acid in the fraction of transcripts that follows normal splicing [3]. Variants at the exon 11 boundary also produce a transcript lacking the whole of exon 11 (prelamin A Δ90, sometimes called "dermopathin", p.Gly567_Gln656del), which confirms that c.1968 is the last nucleotide of exon 11 and corresponds to codon 656, which encodes glutamine [2, 36].

GeneReviews Table 2 assigns to c.1968G>A and c.1968G>T the notations "p.Gly656Gly" and "p.Gly656His", and Table 9 assigns "p.Gly656His" to c.1968G>A. Normalisation in VariantValidator on NM_170707.4 gives p.(Gln656=) and p.(Gln656His), consistent with the p.Q656Q notation of the PRF handbook; the notations with glycine should not be reproduced [3–5].

Sources: phenotypes and numbers of patients from GeneReviews (comparisons with the middle of the classic HGPS spectrum; the same variant may give variable severity); coordinates and protein notation from VariantValidator; the 2019 PRF handbook gives smaller counts (113 patients with the classic variant), as it is older [3–5].

Somatic mosaicism may modify the phenotype. A girl diagnosed at 10 months, without total alopecia, with less marked retrognathia and contractures and with normal growth, blood pressure and electrocardiogram at 5.9 years, had c.1968+2T>A in blood (41.3%) and c.1968+2T>C in fibroblasts (4.7%), with about 50% normal sequence; the authors proposed a partial somatic rescue event on the initial germline variant, by comparison with a child with c.1968+2T>A who died at 3.5 years and another with c.1968+2T>C alive at 11.5 years with a moderate phenotype [2, 3].

2.5. Progeroid laminopathies without progerin and ZMPSTE24 forms

LMNA variants that do not produce progerin alter the structure of lamin A and its interactions with the nuclear membrane and lamina-associated proteins, and give phenotypes that partially overlap with HGPS [3, 4]. The heterozygous de novo variants NM_170707.4:c.163G>A p.(Glu55Lys) and c.164A>G p.(Glu55Gly), in exon 1, cause an aggressive neonatal progeria, intermediate between HGPS and MAD, with severe upper airway obstruction, without progerin accumulation and with efficient prelamin A processing [5, 39]. The variant c.1579C>T p.(Arg527Cys) in homozygosity, in exon 9, described earlier in seven families and later in two Syrian siblings of consanguineous parents with late onset and intrafamilial variability, gives a phenotype intermediate between HGPS and MAD-A, with generalised lipodystrophy, severe micrognathia and acro-osteolysis; it was the most frequent progeroid laminopathy in a Chinese series [40, 46]. Homozygous c.1580G>A p.(Arg527His), in the same codon, is the most frequent cause of MAD-A [5, 27, 37]. The variant c.898G>A p.(Asp300Asn), in exon 5, has been associated both with a familial non-syndromic cardiac progeria, with early valvular and coronary disease and presumed gonadal mosaicism, and with syndromic progeroid phenotypes with metabolic and skeletal changes [41]; another substitution at the same residue, c.899A>G p.(Asp300Gly), was described in cardiocutaneous progeroid syndrome, with normal lamin A processing and improvement of nuclear morphology under farnesyltransferase inhibitors in vitro [2]. Compound heterozygosity for LMNA may also give a progeroid phenotype without prelamin A accumulation, as in a 2-year-old Dutch boy with features of HGPS and MAD whose parents and sister were asymptomatic carriers [2, 8].

ZMPSTE24 was associated with MAD-B in 2003, in a patient with a severe form, progeroid appearance and generalised lipodystrophy, compound heterozygous for Phe361fsX379 (published designation) and Trp340Arg (= NM_005857.5:c.1018T>C p.(Trp340Arg)); in a yeast complementation assay, the first allele was inactive and the second partially active [37]. In 2004 and 2005, restrictive dermopathy was defined as a lethal neonatal laminopathy: in a series of 9 fetuses and newborns, 2 had heterozygous LMNA splicing variants with loss of exon 11 and 7 had the same insertion in ZMPSTE24 with a premature stop codon [38]; in a series of 10 patients, all were homozygous or compound heterozygous for ZMPSTE24, mostly null, with a hotspot in exon 9 due to recurrent insertion of a thymine in a homopolymeric tract, absence of ZMPSTE24 and of mature lamin A and accumulation of prelamin A [28, 42]. Inheritance of the ZMPSTE24 form is therefore autosomal recessive [28]. In fibroblasts from patients with MAD-B and ZMPSTE24 variants P248L or L425P (historical numbering, = NM_005857.5:c.743C>T p.(Pro248Leu) and c.1274T>C p.(Leu425Pro)), lonafarnib corrected nuclear morphology, which did not happen in processing-proficient laminopathies; two lines with LMNA R644C (historical numbering, = NM_170707.4:c.1930C>T p.(Arg644Cys)), despite proximity to the cleavage site, had no processing defect [47]. These laboratory data support the regulatory indication of lonafarnib in processing-deficient forms and its exclusion in the others [19, 21, 47].

2.6. Inheritance, penetrance and mosaicism

HGPS is autosomal dominant, with complete penetrance, and almost always sporadic [3]. In 98% of patients whose parents were tested the variant is de novo; in the four informative families of the 2003 study it was of paternal origin, and the father is on average about 5 years older than in the population, an effect described since the 1970s (mean paternal age of 35.6 years in 20 cases) [2, 3, 31]. Parental mosaicism was demonstrated in 2005 in a mother without signs of disease, with somatic and germline mosaicism for c.1824C>T [10]. GeneReviews estimates that about 2% of living patients with classic genotype identified by the PRF inherited the variant from an unaffected parent with mosaicism, and the PRF handbook reports 3 of 110 (3%) [3, 4]. Expressivity varies more in non-classic genotypes and somatic mosaicism than in the classic genotype [2, 3]. The ZMPSTE24 forms and MAD-A are autosomal recessive, and restrictive dermopathy due to LMNA is dominant de novo [27, 28, 42].

2.7. Allelic disorders of LMNA

LMNA causes more than 20 phenotypes, with unclear genotype-phenotype correlations outside the progerin axis [48]. Farnesyltransferase inhibitors act on persistent farnesylation and have no role in non-progeroid laminopathies [6].

Sources: GeneReviews Table 3, GeneGuidance and OMIM [2, 3, 6].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history data sources

Knowledge of the natural history rests on a few series, almost all linked to the PRF and the Boston hospitals. Hennekam's 2006 review brought together 10 own cases and 132 from the literature [15]. The NIH study prospectively assessed 15 children aged 1 to 17 years between February 2005 and May 2006, about half of the patients then known worldwide [17, 49]. The 2018 survival analysis included 258 patients from 6 continents, with known genotype in 141 and the classic variant in 125 of them (88.7%) [50]. The most recent data come from the Boston trial cohorts, who received lonafarnib, and from Chinese series of 2024–2026 [44, 46, 51, 52]. Descriptions prior to 2007 correspond to natural history; from 2007 a growing proportion of the patients followed receive lonafarnib, and the findings of the late phases, such as critical aortic stenosis, have come to be seen more often in treated patients who live longer [23, 53].

3.2. Initial presentation and growth

Most children have normal weight and length at birth; the mean birth weight of 17 patients in a historical series was 2.7 kg [3, 30]. The first manifestations appear between birth and 2 years: in Hennekam's review, the first symptom was growth retardation in 55%, hair loss in 40%, skin changes in 28% and lipodystrophy in 20% [15]. The PRF handbook highlights that tight or bulging skin of the abdomen and thighs is often the first sign, and in a Chinese series skin sclerosis in the first month of life was the typical onset in patients of classic genotype [4, 46].

Growth failure sets in during the first year: weight falls below the 3rd centile and becomes low for height, height falls below the 3rd centile, and growth velocity then stabilises at about one third to one half of normal [3, 30]. Mean height above 13 years of age was 109.0 cm and mean weight 14.5 kg [15]. In a Hangzhou series with 8 patients aged at least 3 years and 18 controls, the delay in height and weight was already significant at 2 months; mean energy intake was 91% ± 39% of estimated basal metabolic rate, sufficient in 4 of the 8 patients [51]. Growth failure is not explained by insufficient intake, lack of insulin response or growth hormone deficiency, and increasing caloric intake, including by nasogastric tube or gastrostomy, does not change growth [3, 4, 17]. Serum leptin is below the detection limit [3].

The lipodystrophy is generalised, with preservation of intra-abdominal depots; the last areas to lose fat are the cheeks and the pubic region [15, 30]. On densitometry in the Hangzhou series, visceral fat was increased, subcutaneous fat decreased and total and limb muscle mass below −2 standard deviations (SD) [51]. On peripheral quantitative computed tomography (pQCT) of the radius, the shape of the radius was abnormal in 70% of patients at all ages, and forearm muscle area and bone area grew more slowly than in controls (muscle 0.3 versus 1.4 cm²/year; radius 0.5 versus 5.8 mm²/year); muscle area normalised for size was similar to that of controls at younger ages and diverged with age [54].

3.3. Face, mouth and airway

The face becomes characteristic during childhood: head disproportionately large in relation to the face (Smith refers to postnatal microcephaly, GeneReviews to craniofacial disproportion), wide fontanelles with late closure, prominent scalp veins, prominent eyes, long narrow nose with a beaked tip, thin vermilion, small mouth, retrognathia and micrognathia, ears with rigid cartilage and small or absent lobule, and perioral cyanosis [3, 8, 30]. A high-arched palate is present in 60% to 70% and a short, thick lingual frenulum, which limits the tongue, in about 50% [3]. The primary dentition erupts and is shed late; permanent teeth often erupt behind the primary teeth or fail to erupt, with severe crowding, class II malocclusion, permanent molars in the mandibular ramus, agenesis (mainly of the second premolars), gingivitis, periodontal disease and a high caries rate [3, 4, 30]. The airway is narrow and unusually shaped, with a rigid larynx and limited mouth opening, which explains the high-pitched voice, the risk of obstructive sleep apnoea and difficult intubation [3, 4]. The NIH study documented functional oral deficits [17].

3.4. Skin, hair and nails

All children have skin changes by 2 years of age, sometimes from birth: tight, thickened, fibrotic or rippled skin, soft bulges of 1–2 cm on the lower abdomen and thighs, light or dark macules, mottled skin and pigmentary changes in sun-exposed areas [3, 4, 30]. In some children the tight skin restricts chest wall movement and gastric capacity [4]. Calcinosis cutis, composed of hydroxyapatite, has been observed in about 5% to 10% of children, on the fingertips, heel, trunk, limbs and abdomen, and may ulcerate or become infected [4]. Hair is lost from the periphery of the scalp during the first year, with total alopecia by 2 years and residual fine down; the eyebrows are lost in the first years and the eyelashes become sparse [3, 4]. The nails become dystrophic, slow-growing, sometimes yellowish and curved [3, 30].

3.5. Musculoskeletal system

Joint contractures are present in all patients, with onset at birth or later, and result from disease of tendons and ligaments, bone and skin [3, 4]. Characteristic patterns include limited hip flexion, rotation and abduction, limited knee flexion and extension, a subtalar joint fixed in eversion from early on and a crouched gait with calcaneovalgus and midfoot pronation [4]. Coxa valga appears in the first 3 years and, with acetabular dysplasia, coxa breva and coxa magna, causes the "horse-riding" stance, the wide-based gait and susceptibility to hip subluxation and dislocation; avascular necrosis of the femoral head manifests as pain [3, 4]. Almost all eventually have radiographic signs of hip osteoarthritis, but only a minority have persistent pain; a minority have shoulder dislocation due to shortening of the clavicles [4]. Foot pain is related to calcaneovalgus and the absence of plantar fat and may prevent barefoot walking [4].

Bones are smaller and narrower, but mineral density, once corrected for size, is normal or slightly low, and the fracture rate and healing are similar to those of children without the disease [3, 4]. In the Hangzhou series, without correction for height, the bone mineral density Z-score was −2.82 ± 1.46 [51]. Extraskeletal calcifications are visible on radiographs in about 40%, of unknown clinical significance [3].

3.6. Cardiovascular system

Cardiovascular disease determines the prognosis. Atherosclerosis is generalised and progressive, without the usual lipid changes: total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides generally normal, high-density lipoprotein (HDL) cholesterol and adiponectin decreased with age and C-reactive protein not raised [3, 4]. Vascular function declines with age, with raised blood pressure, lower compliance, reduced ankle-brachial index and adventitial thickening [17]; carotid-femoral pulse wave velocity and ankle-brachial index are abnormal from 3 years of age [30]. Blood pressure is more labile than frankly raised, and an arterial occlusion causes pressure to fall downstream, so it is measured in all four limbs [4].

The early cardiac changes are diastolic dysfunction and altered myocardial deformation (strain), usually detected after 5 years of age by tissue Doppler; these are followed by ventricular hypertrophy, thickening and stenosis of the mitral and aortic valves in the second decade and, in advanced disease, systolic dysfunction with or without identified coronary insufficiency [3, 4]. In a case-control study of 35 children with untreated classic HGPS (median age 6.2 years, 2.1 to 17.5) and 35 matched controls, seen between 2014 and 2019, ejection fraction was similar (66% ± 6% versus 65% ± 3%), but left ventricular longitudinal strain was reduced in all three layers (mean difference of −4.7 to −4.8 percentage points), as was that of the right ventricle (−5.8) and left atrial reservoir strain (−11.5), without association with age [55]. The authors interpret these findings as myocardial dysfunction earlier and more extensive than previously thought, possibly due to diffuse fibrosis and microvascular dysfunction [55]. Longitudinal data from the same Boston and Copenhagen team were published in 2023 and 2025 and were not consulted in full text [56, 57].

Calcific aortic stenosis develops in the second decade and the gradient increases exponentially in the late phases; with the prolongation of survival by lonafarnib it has become a frequent and emerging cause of cardiac death [3, 23, 58]. The Boston surgical team observed that, when the peak gradient reaches 50–60 mm Hg, it tends to progress to 80–100 mm Hg with marked hypertrophy [58]. Angina, exertional dyspnoea and heart failure are late findings [3]. In the 2018 analysis, heart failure was the primary cause of death in 79.4% of the 73 deaths with an identified cause [50], and GeneReviews and the PRF handbook attribute more than 80% of deaths to heart failure and/or myocardial infarction, mainly between 6 and 20 years of age [3, 4]. Coronary disease should enter the differential diagnosis of chest pain at any age [59].

3.7. Central nervous system and cerebrovascular disease

Cognition is normal [3, 15]. Cerebrovascular disease is the main cause of morbidity: transient ischaemic attacks (TIA) and strokes, silent or symptomatic, occur from 4 years of age, mainly due to thrombosis on stenoses [3, 4]. In a series of 25 children with neuroimaging, the intracranial and cervical arteriopathy was distinct from moyamoya disease and from the atherosclerosis of ageing, with intracranial steno-occlusive lesions, collaterals in the basal cisterns, slow collateral flow over the convexities, distal vertebral artery stenosis and stenosis and calcification of the internal and common carotid arteries; there was radiographic infarction in 60%, half probably silent, with territorial, white matter, lacunar and watershed infarcts [60]. GeneReviews estimates a risk of cerebral infarction of about 32% at 13.5 years, 20% of which are silent [3]. In the review of Chinese cases, hemiplegia and weakness were the most frequent symptoms, followed by headache, epilepsy, dysarthria and, rarely, presenting psychosis, with predominance of the internal carotid and middle cerebral territories [61]. Collateral vessels are fragile and sensitive to variations in blood pressure and hydration, and hyperventilation, hypotension and dehydration precipitate neurological symptoms [4]. Headaches are frequent and seizures may be the presentation of a stroke [4]. Extensive scalp haematomas and, less frequently, intracranial haematomas after minor trauma have been described, especially in children on aspirin [4, 62].

3.8. Hearing and vision

Low- and mid-frequency conductive hearing loss is present in almost all children, at all ages, usually mild and sometimes moderate, without otitis media with effusion; high-frequency otoacoustic emissions are preserved, without a presbycusis pattern, and stapedial reflexes are raised or absent, which suggests middle ear stiffness [3, 4, 17]. The rigid auricular cartilage makes headphones and tympanometry probes painful, and dry wax plugs are frequent [4]. Nocturnal lagophthalmos is almost constant, sometimes from birth, and causes dryness, exposure keratopathy, opacification and, in a minority, corneal ulcer; photophobia, madarosis, mild to moderate hypermetropia with accommodative insufficiency and pterygium are frequent [3, 4]. Sources differ on refraction: GeneReviews states that the myopia and hypermetropia of ageing have not been documented, whereas the PRF handbook and Smith describe frequent hypermetropia [3, 4, 30]. Glaucoma, cataract and retinal degeneration associated with ageing have not been observed [4].

3.9. Endocrine system and puberty

Sexual maturation is incomplete. GeneReviews, citing a 2018 study, states that girls reach Tanner stage 1 (78%) or 2 (22%) at pubertal age, whereas the PRF handbook reports about 40% at stage 1 and the rest at stage 2, without reaching stage 3 [3, 4]. About 60% of girls have menarche, at a mean age similar to that of the population (about 14.5 years), with irregular cycles and bleeding ranging from scanty to heavy with anaemia; menarche occurs independently of size, body fat and leptin [3, 4]. Insulin resistance is present in about 50%, without overt diabetes [3]. No cases of fertility or pregnancy have been described in the classic genotype [3, 4].

3.10. Preserved systems and laboratory findings

Hepatic, renal, gastrointestinal, immune and neurological functions are normal, as are wound healing and strength for size; the tumour rate is not increased, and Alzheimer disease, arcus senilis and senile personality changes have not been documented [3, 4]. Smith describes, in adolescents who survived, subcortical renal scars, diffuse glomerulosclerosis and interstitial nephritis in pathological studies, which contrasts with the normal renal function described in GeneReviews and probably corresponds to late autopsy findings [3, 30]. The NIH study documented prolonged prothrombin time and raised platelets and serum phosphorus [17]. Lung capacity may be restricted by a small chest and tight skin [4].

3.11. Non-classic, late-onset and atypical forms

Non-classic genotypes cover a broader spectrum than the classic genotype. Variants c.1821G>A and c.1968+1G>A give severe neonatal progeria; the three French cases of "neonatal HGPS" from the 1980s, who died on the first day or at 20 months without signs of coronary occlusion, illustrate this extreme, although without known genotype [2, 25]. At the other extreme, c.1968G>A and c.1968+5G>A cause adult-onset forms: a mother and two children with coronary disease, short stature, loss of fat and hair and a beaked nose, two of whom underwent revascularisation surgery, and a 48-year-old woman who died after revascularisation surgery [2]. A man seen at 30 years of age with late-onset HGPS, diffuse atherosclerosis and aortic stenosis died at 35 years after cardiac surgery [2]. In the non-classic phenotypes described by Hennekam, growth is less affected, hair is retained longer, lipodystrophy progresses more slowly and osteolysis is more marked, with survival into adulthood [15].

There are exceptional survivals: a Japanese patient described in 1986, clinically typical but without known genotype, died of infarction at 45 years, and a 21-year-old Chinese woman with c.1824C>T, weighing 13 kg and measuring 85 cm, was admitted with 3 years of progressive exertional dyspnoea and an ejection fraction of 30.8% [2, 59].

3.12. Treated and untreated disease

Without specific treatment, mean life expectancy is 14.5 years, with deaths between 6 and 20 years of age [3, 16]; the 2014 untreated cohort gave 14.6 years and Hennekam's review a mean age at death of 12.6 years, and the books cite a median of 13.4 years (7 to 27.5) [2, 8, 15, 63]. Lonafarnib increases survival, with estimates that depend on the method (section 7.7), but does not eliminate progression: the causes of death are the same, aortic stenosis has become more frequent in older patients and, in a pQCT series, lonafarnib did not normalise the muscle-bone unit at 24 months, with partial normalisation of the shape of the radius in 25% [3, 23, 54]. The PRF summarises that treated children continue to die of heart disease, on average in late adolescence [64].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion arises at different ages depending on which sign appears first. In the first months of life, a child born with normal weight and length who develops areas of tight, hardened skin or skin with small soft bulges on the lower abdomen and thighs, or skin with irregular pigmentation, should be assessed for HGPS, because these changes may be the first sign [3, 4]. Between 6 and 24 months, the most frequent sign is a fall of the weight curve and then of the length curve below the 3rd centile, without a nutritional cause, accompanied by progressive hair loss from the periphery of the scalp and loss of subcutaneous fat [3, 15, 30]. In the young child, the combination of total alopecia, generalised lipodystrophy, retrognathia, prominent scalp veins, late tooth eruption, joint stiffness with a wide-based gait and normal intellectual development is suggestive [3, 4]. On radiographs requested for another reason, acro-osteolysis of the distal phalanges and resorption of the distal ends of the clavicles are the earliest findings [4, 8]. The mean age at diagnosis was 2.9 years in Hennekam's review, and the PRF diagnostic programme was also created because, before molecular testing, misdiagnosis was frequent [15, 18].

In the adolescent or adult, a progeroid phenotype with early coronary or calcific valvular disease, lipodystrophy, alopecia and short stature suggests late-onset non-classic HGPS or an atypical progeroid laminopathy, and LMNA is not excluded because the child grew almost normally [2, 41]. In the prenatal and neonatal period, fetal akinesia with rigid, translucent skin, a mouth fixed in an "O" shape, contractures and polyhydramnios suggests restrictive dermopathy [29, 65].

4.2. Warning signs in a child with a known diagnosis

The PRF handbook gives guidance for distinguishing urgent symptoms. Chest pain or pressure in a child with HGPS should be considered ischaemic until proven otherwise, especially if there is a cardiovascular history, recurrent pain with breathing difficulty, altered consciousness, sweating or dizziness; any symptom that worsens with exertion and disappears with rest is concerning [4]. Weakness of a limb or one side of the body, difficulty speaking, loss of vision, confusion, seizure or severe headache without known cause require urgent assessment for stroke or TIA, and many children with a first clinical stroke already have silent infarcts on magnetic resonance imaging (MRI) [4, 60]. Persistent hip pain should be investigated for dislocation and avascular necrosis [4]. Increasing fatigue, exertional dyspnoea and loss of capacity for usual activities may be the first signs of aortic stenosis or heart failure [3, 4]. Minor head injury with vomiting or altered state of consciousness requires urgent imaging, because epidural and subdural haematomas have been described after trivial falls [4, 62]. Dehydration, high fever, anaemia (including from menorrhagia) and long journeys increase the risk of ischaemic events [3, 4].

During lonafarnib treatment, repeated vomiting or diarrhoea with dehydration or weight loss, new visual changes and palpitations or syncope justify contacting the team, because of the possibility of dehydration, retinal toxicity and prolongation of the corrected QT interval (QTc) [19, 21].

4.3. Newborn screening

There is no newborn screening for HGPS. The disease almost always results from de novo variants, with no founder population described in the sources consulted, and has no routine biochemical marker; the plasma progerin immunoassay is a research tool [3, 6, 44].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated scoring criteria. GeneReviews considers that the clinical diagnosis is established when the pathognomonic features appear in the first two years with normal intellectual development: at least one of the characteristic skin findings, severe growth failure, alopecia, global lipodystrophy and small clavicles [3]. The PRF handbook frames suspicion around severe growth failure, areas of scleroderma-like skin, partial alopecia progressing to total by 2 years, generalised lipodystrophy, retrognathia, resorption of the distal clavicles and terminal phalanges, coxa valga and late or incomplete primary eruption [4]. The absence or delay of these findings does not exclude the disease, because the classic and non-classic genotypes vary in age at onset, and molecular testing should always accompany the clinical diagnosis [3].

Sources: GeneReviews, "Suggestive Findings", and the PRF handbook [3, 4].

5.2. Molecular tests and algorithm

The diagnosis of HGPS of classic genotype is established with the suggestive findings and the heterozygous variant c.1824C>T; that of non-classic genotype with similar findings and another heterozygous progerin-producing variant at the exon 11 boundary or in intron 11 [3, 4]. GeneReviews proposes two approaches. When the phenotype is typical, targeted sequencing of exon 11 and of at least the first 7 bases of intron 11 is performed first, which should be the standard of any request for exon 11 sequencing; without a variant, the whole of LMNA is sequenced, including intron 11 if not already included; without a variant in LMNA, sequencing of ZMPSTE24 is considered [3]. A multigene panel with LMNA, ZMPSTE24 and the genes of the non-laminopathic progeroid syndromes may be the most cost-effective option, with the caveat that the genes included, coverage and detection of deletions and duplications vary between laboratories [3, 4]. When the phenotype cannot be distinguished from other progeroid syndromes, the exome is the most used option, and the genome is possible [3].

Testing is performed on blood (1 to 2 teaspoons) or, less often, on saliva, and the PRF diagnostic programme, carried out in a CLIA-certified (Clinical Laboratory Improvement Amendments) laboratory, is free for families and physicians in any country, after review of the clinical history by the foundation's medical director, with results in 2 to 4 weeks delivered through the attending physician [4, 18].

Source: GeneReviews Table 1; about 90% of patients with a typical phenotype have the classic genotype and about 10% non-classic genotypes [3].

The proportion of variants detected by a method is not the clinical sensitivity of the test. A child with an HGPS-like phenotype and negative exon 11 sequencing may have a progeroid laminopathy without progerin, a ZMPSTE24 form or a non-laminopathic progeroid syndrome, and targeted sequencing only excludes progerin-producing variants [3, 4].

5.3. Limits of the tests

Exon sequencing with short intronic boundaries may miss intron 11 variants if it does not cover at least up to c.1968+7, and panels and exomes should explicitly cover this region [3]. Low-fraction somatic mosaicism may not be detected by Sanger sequencing in blood; the case with c.1968+2T>A in blood and c.1968+2T>C in fibroblasts shows that the variant and its proportion may differ between tissues, and that deep sequencing and study of fibroblasts may be necessary when the phenotype is milder than expected [2, 3]. Low-level parental mosaicism may go unnoticed when the parents' blood is studied, as in the mother with a weak signal of the mutant allele described in 2005 [2, 10]. LMNA deletions and duplications do not cause HGPS, but uniparental isodisomy of 1q and a large interstitial deletion were the findings that allowed the gene to be located in 2003, in patients with no point variant identified in the original study [3, 31]. A negative test for LMNA and ZMPSTE24 does not exclude a progeroid syndrome, and interpretation of LMNA missense variants outside exon 11 requires care, because the gene has many variants associated with cardiac and muscular phenotypes unrelated to progeria [3, 9].

5.4. Report content and interpretation

The report should state the gene, the transcript with version (NM_170707.4), the HGVS notation of the variant at DNA and protein level, with the synonymous form p.(Gly608=) for the classic variant and p.? for intronic variants, the zygosity, the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), the method and the region covered (exon 11 and intron 11) [3, 5]. The variant c.1824C>T is classified as pathogenic in ClinVar, with criteria provided by several submitters without conflicts, last evaluated in April 2025; the same record also lists dilated cardiomyopathy and Charcot-Marie-Tooth 2 as conditions, from panel submissions, which does not mean that the classic variant causes those diseases [9]. The EU indication for lonafarnib requires a genetically confirmed diagnosis, and the molecular category (progerin production, processing defect due to LMNA or ZMPSTE24, or efficient processing) determines eligibility [19, 21]. A variant of uncertain significance (VUS) in LMNA in a child with a progeroid phenotype may be reclassified by study of the parents (to demonstrate de novo occurrence), by transcript analysis in fibroblasts and by demonstration of accumulation of prelamin A or progerin-like protein [36, 42].

5.5. Biomarkers and functional tests

There is no routine biochemical assay [6]. An ultrasensitive plasma progerin immunoassay has been developed, with a detection range of 59 to 30,000 pg/mL and no cross-reactivity with lamin A: in 69 people without HGPS (0.2 to 71.3 years) the value was 351 ± 251 pg/mL and in 74 untreated patients (2.1 to 17.5 years) 33,261 ± 12,346 pg/mL, about 95 times higher, with no difference between sexes [44]. Under lonafarnib, progerin fell 35% to 62% per visit from baseline in the first 4 months and remained low for up to 10 years, and the magnitude of the fall was associated with survival [44]. The assay is a tool for research and for evaluating progerin-targeted therapies, not a routine diagnostic test [6, 44]. In research laboratories, skin fibroblasts allow assessment of nuclear morphology, mature lamin A and prelamin A accumulation, which confirms a processing defect but does not identify the gene [42]. Ultraviolet irradiation of fibroblasts to assess DNA repair applies to the differential diagnosis with Cockayne syndrome, not to HGPS [66].

5.6. Imaging

Radiographs show a thin calvaria with late closure of fontanelles and sutures and wormian bones, small facial bones with an obtuse mandibular angle, clavicles with progressive distal osteolysis, thin tapering ribs with a bell-shaped thorax, coxa valga (neck-shaft angle >125°), coxa breva and magna, acetabular dysplasia, avascular necrosis of the femoral head, gracile diaphyses with widened and relatively demineralised metaphyses, enlarged humeral capitulum, acro-osteolysis and soft tissue and vascular calcifications [4, 8, 30]. Acro-osteolysis and clavicular resorption are the earliest findings and the most useful for diagnosis; bone age, growth plates, sutures and the elbow, wrist, knee and ankle joints are normal in the description of the PRF handbook, which differs from Smith regarding suture closure [4, 30]. Dual-energy X-ray absorptiometry (DXA) gives falsely low Z-scores if not corrected for height-age [3, 4]. GeneReviews Figure 2 documents facial progression between 3 months and 16 years, a 100% occlusion of the left carotid on MR angiography at 4 years, acro-osteolysis, shortening of the clavicles, coxa valga and the growth curves of 10 girls [3].

5.7. Prenatal and preimplantation diagnosis

Once the variant has been identified in the proband, prenatal diagnosis and preimplantation genetic testing are possible in a pregnancy at increased risk because of the possibility of gonadal mosaicism [3, 4]. The sources consulted do not describe fetal ultrasound signs of HGPS; most newborns have normal weight and length, although Hennekam's review describes growth retardation already prenatally in some cases [3, 15]. In restrictive dermopathy, molecular diagnosis of the index case is necessary to distinguish the recessive form due to ZMPSTE24, with a 25% risk, from the dominant de novo form due to LMNA, and to offer prenatal or preimplantation diagnosis [28, 42].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis is made at three levels: separating HGPS from progeroid laminopathies without progerin and from ZMPSTE24 forms, which share features but differ in inheritance, prognosis and eligibility for lonafarnib; separating the laminopathies from the non-laminopathic progeroid syndromes, with other genes and other complications; and recognising non-genetic causes of growth failure and skin sclerosis. Molecular testing is the decisive discriminator, and the lonafarnib label expressly excludes Werner, Bloom, Rothmund-Thomson and Cockayne syndromes, xeroderma pigmentosum, trichothiodystrophy and ataxia-telangiectasia [3, 19, 21].

6.2. Mandibuloacral dysplasia type A

MAD-A shares with HGPS micrognathia, alopecia, acro-osteolysis and clavicular osteolysis, but is not associated with premature atherosclerosis and progresses slowly, without compromising survival; several patients are over 50 years of age [26]. It was described by Cavallazzi as an atypical form of cleidocranial dysostosis [27]. The usual onset is between 3 and 14 years, with proptosis, micrognathia with progressive difficulty opening the mouth, loss of facial fat and bulbous distal phalanges, acro-osteolysis being earliest in the second finger [27]. The lipodystrophy is partial, with loss of fat in the limbs and normal or increased fat in the neck and trunk, and the main complications are metabolic: insulin resistance, glucose intolerance, diabetes, hypertriglyceridaemia, acanthosis nigricans and glomerulopathy [26, 27]. Radiology shows wormian bones, late sutural closure, hypoplasia and osteolysis of the mandibular rami and clavicles, acro-osteolysis with dystrophic calcifications and, in some patients, resorption of the posterior ends of the ribs [26]. An Italian family raised the question of a higher frequency in Italy, without a population estimate [27]. Treatment is supportive, including that of the metabolic complications of lipodystrophy [26].

6.3. Mandibuloacral dysplasia type B and other ZMPSTE24 phenotypes

MAD-B begins before 1 year, with growth retardation, progeroid face, mandibular and clavicular hypoplasia, acro-osteolysis, late closure of sutures, contractures, skin atrophy and generalised lipodystrophy; it has severe glomerulopathy, more extensive skeletal changes and subcutaneous calcifications, and the course is faster [27, 42]. Homozygous missense variants have been associated with congenital myopathy, and biallelic N-terminal frameshift variants with a non-lethal progeroid phenotype, through use of an alternative initiation codon [42]. In the 2024 Chinese series, 3 of the 42 patients with a genetic report were compound heterozygous for ZMPSTE24 [46]. Rare ZMPSTE24 variants associated with hypertriglyceridaemia and metabolic syndrome are risk associations without a ClinGen, GenCC or OMIM assertion, and should not be reported as a diagnosis [42]. Forms due to biallelic ZMPSTE24 are included in the lonafarnib indication in the USA and the EU, on the basis of the mechanism and cellular data, but no patient with ZMPSTE24 was included in the trials that supported approval [19, 21, 42, 47].

6.4. Restrictive dermopathy

Described by Toriello in 1983 in two infants, it has about 60 published patients [29]. The features result mainly from restriction of movement in utero: intrauterine growth restriction, wide fontanelles, hypertelorism, entropion, small nose, mouth fixed in an "O" shape due to temporomandibular ankylosis, micrognathia, dysplastic ears, tight, thin and translucent skin with visible vessels, erosions and fissures, absent eyelashes and eyebrows, multiple contractures, rocker-bottom feet, bipartite clavicles, thin ribbon-like ribs and a poorly mineralised skull [29, 38]. Histology shows hyperkeratosis, a thin dermis with parallel collagen, and absence of elastin and rete ridges [29]. Pregnancy is complicated by polyhydramnios, an enlarged placenta with a short cord, reduced fetal movements from about 6 months, premature rupture of membranes and preterm delivery; most are stillborn due to pulmonary hypoplasia, intubation is very difficult and live-born infants usually die in the first week, with a maximum described survival of 120 days [29, 38]. The ZMPSTE24 form is recessive and the LMNA form is dominant de novo; a clinical diagnosis of restrictive dermopathy does not by itself establish the recurrence risk [28, 42].

6.5. Atypical progeroid laminopathies

Neonatal progeria due to p.(Glu55Lys) or p.(Glu55Gly) was described in three unrelated newborns, with a homogeneous phenotype between HGPS and MAD, earlier onset, more aggressive course and episodes of severe upper airway obstruction, with normal prelamin A processing and profound lamina anomalies reproduced by expression of the mutants in control fibroblasts [39]. Atypical Werner syndrome was defined in an international Werner registry: 26 of 129 probands (20%) had no WRN variants, and 4 of these had heterozygous LMNA variants (A57P, R133L in two and L140R; historical numbering, = NM_170707.4:c.169G>C p.(Ala57Pro), c.398G>T p.(Arg133Leu) and c.419T>G p.(Leu140Arg)), with a phenotype more severe than classic Werner syndrome; it was later proposed that this was late-onset HGPS, and the neighbouring variants L59R (= c.176T>G p.(Leu59Arg)) were reclassified as cardiomyopathy with hypergonadotrophic hypogonadism [2]. LMNA-associated cardiocutaneous progeroid syndrome was described in a family with 5 affected members over three generations, with loss of eyebrows and eyelashes in childhood, progeroid appearance at the end of the third decade, calcific mitral and aortic stenosis with valve replacement, myocardial infarction at 44 years, intracranial haemorrhage at 34 years and basal cell and squamous cell carcinomas, papillary renal carcinoma and carcinoid tumour [2, 14]. Non-syndromic cardiac progeria due to p.(Asp300Asn) presents as severe early-onset valvular and coronary disease without systemic progeroid features [41].

6.6. Non-laminopathic progeroid syndromes and other causes

Werner syndrome has initial symptoms at a mean age of 13 years, but diagnosis at a mean age of 39 years (SD 7.7), with premature greying and thinning of hair, aged appearance, short stature, type 2 diabetes, hypogonadism, osteoporosis, atherosclerosis, hoarse voice and cataracts; Orphanet assigns it a point prevalence of 1–9 per 100,000 in a specific population [6, 67]. Wiedemann-Rautenstrauch syndrome is progeroid from birth, with intellectual disability in most, and in a series of 13 patients 4 died in the first weeks, 2 in the first year, 4 between 5 and 10 years of age and 1 at 17 years, and 2 were alive at 20 years [68]. Cockayne syndrome is distinguished by progressive microcephaly with developmental delay, demyelination with calcifications, photosensitivity, retinopathy and sensorineural deafness, with a prevalence in Western Europe of about 2 per million live births [67]. MDPL may be called a MAD variant, but is distinguished by progressive generalised lipodystrophy with truncal accumulation, absence of acro-osteolysis, clavicular hypoplasia and alopecia, early sensorineural deafness and better survival [27]. HGPS also appears in the differential diagnoses of childhood-onset lipodystrophies, cutis laxa and poikiloderma, and among the inherited causes of restrictive cardiomyopathy [69–72]. Growth failure of nutritional, endocrine or psychosocial cause and localised scleroderma are distinguished by the absence of the combination with alopecia, lipodystrophy, acro-osteolysis and clavicular osteolysis [3].

7. Treatments and Risk Management Strategies

7.1. Sources of the recommendations and principles

There is no scientific society guideline on HGPS. Practical recommendations come from three types of source: GeneReviews, updated in March 2025, whose assessment, treatment and surveillance tables derive from the experience of the Boston trials; the PRF Progeria Clinical Care Handbook, 2nd edition of 2019, written by specialists who have followed more than 100 children from 47 countries, available in nine languages, including Portuguese; and the prescribing information for lonafarnib in the USA and the EU [3, 4, 19, 21]. For critical aortic stenosis there is a consensus document from an international group of experts, without a sponsoring society [23]. The first author of GeneReviews and executive editor of the handbook is principal investigator of the trials and medical director of the PRF, which gives the sources coherence but reduces their independence [3, 4]. The handbook states that its physiotherapy and occupational therapy recommendations are based on clinical observation, without efficacy studies [4].

Management rests on four components: targeted treatment with lonafarnib, started as soon as the diagnosis is confirmed; prevention and treatment of cardiovascular and cerebrovascular disease, with low-dose aspirin, hydration and surveillance; treatment of the dental, ophthalmological, auditory, cutaneous and orthopaedic manifestations; and support for the family, school and social integration, given that intellectual development is normal [3, 4, 21]. All drug doses should be calculated by weight or body surface area, never by age [3, 4].

7.2. Lonafarnib (Zokinvy®): pharmacology and indication

Lonafarnib is a farnesyltransferase inhibitor that prevents farnesylation and the subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane [19]. This is the international non-proprietary name; the trade name is Zokinvy® in the USA and the EU, with ATC code A16AX20 [19, 21]. It is presented as hard capsules of 50 mg (opaque yellow, "LNF 50", size 4) and 75 mg (opaque light orange, "LNF 75", size 3), with less than 1 mmol (23 mg) of sodium per dose [19, 21].

Sources: FDA label §1, §2.1 and §8.4; EU SmPC §4.1, §4.2 and §4.4 [19, 21].

7.3. Lonafarnib: dosage

The starting dose is 115 mg/m² twice daily, with the morning and evening meals, and after 4 months it is increased to the maintenance dose of 150 mg/m² twice daily, which is the highest dose provided for in both labels; no absolute maximum dose is defined in the source, and the dosing tables end at a BSA of 1.00 m², with 300 mg/day [19, 21]. The total daily dose is rounded to the nearest 25 mg and divided into two equal or nearly equal doses, about 12 hours apart [19, 21]. The dosage is the same in children aged 12 months or more and in adults; safety and efficacy below 12 months have not been established, and in adults they were extrapolated from paediatric studies from 2 years of age [19, 21].

Sources: FDA label Tables 1 and 2 (BSA–total dose pairs) and EU SmPC Tables 1 and 2 (distribution by capsule, matching in the common rows) [19, 21].

Capsules are swallowed whole, with water, without chewing. For those who cannot swallow them, the content can be mixed with a vehicle, prepared fresh and consumed within about 10 minutes. Vehicles differ between jurisdictions: in the USA, Ora Blend SF® or Ora-Plus® and, if unavailable or not tolerated, orange juice or apple sauce, with 5–10 mL of liquid or 1–2 teaspoons of purée per capsule; in the EU, since the 2026 variation, orange juice (5 or 10 mL), mashed banana, yoghurt or semolina porridge (1–2 teaspoons), with express exclusion of apple sauce, peanut butter and oat porridge, and with rinsing with 5 mL of water per capsule [19, 21, 73]. Grapefruit and Seville orange (including bitter orange marmalade) should be avoided and, in the EU, also cranberry and pomegranate [19, 21]. A missed dose is taken with food as soon as possible, provided more than 8 hours remain until the next one; otherwise it is skipped [19].

7.4. Lonafarnib: adjustments, contraindications and interactions

Sources: FDA label §2.2, §2.3, §4 and §7; EU SmPC §4.2–4.5 [19, 21].

Lonafarnib is a CYP3A substrate, a strong mechanism-based CYP3A inhibitor, a moderate CYP2C19 inhibitor and a weak P-glycoprotein (P-gp) inhibitor [19]. Sensitive CYP3A substrates and CYP2C19 substrates should be avoided or have their dose reduced according to their respective label [19]. Pharmacokinetics are time-dependent: with repeated doses clearance decreases by 75% (from 48.2 to 12.1 L/h) and half-life increases by 60% (from 3.5 to 5.6 h); tmax is 2 to 4 hours and excretion is mainly faecal (61% in faeces and less than 1% in urine within 24 hours) [21]. The statins lovastatin, simvastatin and atorvastatin are contraindicated; pravastatin was the statin used in the Boston combination trials [19, 21, 74]. Loperamide should not exceed 1 mg once daily when started in combination, with slow increases, and is contraindicated below 2 years of age [19]. Drugs that prolong QT should be avoided; if unavoidable, an ECG is performed at baseline, during treatment and when indicated [19]. The 2026 European variation added warnings about substrates of organic cation transporter 1 (OCT1), antiarrhythmics and other substances that prolong QT [73].

7.5. Lonafarnib: adverse effects and their management

The safety database includes 84 people treated, 8 of them for 10 years or more; the frequencies in the US label come from 63 patients in two open-label phase 2 trials, with 128 patient-years, aged 2 to 17 years, 95% with classic HGPS, 3% non-classic and 2% (one patient) with an LMNA progeroid laminopathy [19]. The EU SmPC presents the reactions considered treatment-related in the same population, so the percentages differ [21].

Sources: FDA label Table 4; EU SmPC §4.8 and Table 3 [19, 21].

Gastrointestinal toxicity is the most frequent and is concentrated at the start: most reactions occur in the first 4 weeks and decrease thereafter [21]. In the first 4 months of the first trial, 68% had vomiting, 36% nausea and 82% diarrhoea; at the end of the trial, 11% still had diarrhoea and 14% needed antiemetics; 43% received loperamide and 4 patients discontinued treatment, mainly because of nausea and vomiting [19, 21]. Vomiting was mild in 53% and moderate in 46% (outpatient intravenous hydration), and diarrhoea severe in 8% [19]. GeneReviews suggests loperamide for diarrhoea, ondansetron for nausea and cyproheptadine for loss of appetite, and the SmPC recommends monitoring weight, caloric and fluid intake and loperamide toxicity, and restoring volume orally or intravenously [3, 21]. Of the 63 patients, 15 (24%) needed dose adjustment: 1 permanent discontinuation, 11 interruptions and 3 reductions, 10 of them because of gastrointestinal disturbance [21].

Lonafarnib prolongs QTc in a concentration-dependent manner. In 64 healthy volunteers, 200 mg twice daily for 10 days produced a maximum mean increase of 19 ms (upper limit of the 90% CI 27 ms), with a maximum concentration similar to the mean observed in patients with HGPS [19]. For this reason, and because QTc prolongation is known in the syndrome itself, treatment is avoided in patients with arrhythmias, long QT, symptomatic bradycardia, hypokalaemia, hypomagnesaemia or heart failure, and an ECG and electrolytes are obtained before and during treatment [19, 21, 73]. Laboratory abnormalities (electrolytes in 43%, myelosuppression in 35%, AST in 35% and ALT in 27%) often improved without discontinuation; severe ALT elevations (>5 to 20 times the upper limit) occurred in 2 of 17 patients with increased ALT, and one patient discontinued because of raised transaminases, hypertriglyceridaemia and hyperglycaemia [19]. Nephrotoxicity in rats and rod-dependent loss of vision in low light in monkeys, at exposures similar to human ones, underpin renal and ophthalmological monitoring; the EU sets annual intervals for liver function, renal function and ophthalmological assessment, and at any time in the presence of new signs [19, 21]. Overdose has no antidote and is treated with supportive measures [21].

7.6. Comparative regulatory status

Sources: Drugs@FDA, FDA label, EPAR page, SmPC and EMA procedural steps, PRF announcement on Japan (not confirmed in a database of the Japanese agency) [19–22, 73].

Outside the USA, the EU and Japan, lonafarnib is obtained through Sentynl's managed access programme, through the attending physician in countries that allow it, and all children who took part in PRF trials continue to receive it free of charge through the monotherapy extension or the managed access programme; the PRF provides information on the programme in Brazilian and European Portuguese [4, 33]. The sources consulted do not describe the marketing status, price or reimbursement of lonafarnib in Portugal (INFARMED) or in Brazil (Agência Nacional de Vigilância Sanitária, ANVISA). A ClinicalTrials.gov record of the access programme of Eiger BioPharmaceuticals, the original developer, has been listed as "approved for marketing" since 2021 [75].

7.7. Clinical trials

Sources: [19, 21, 50, 63].

All these analyses compare patients treated in open-label single-arm trials, at a single centre, with external natural history cohorts; there was no randomised trial, and the estimates depend on the matching algorithm, which explains why, with the same 62 treated patients, the FDA estimates +2.5 years and the EU +4.3 years at the last follow-up [19, 21]. The FDA review considered that the large effect on an objective outcome, mortality, with a well-matched comparator, mitigated the sources of bias [35]. The EU cautions that the result at the last follow-up should be read with caution because patients received additional potentially beneficial treatments, such as the pravastatin and zoledronic acid of the triple trial, and that the gain may be as low as 2.6 years [21]. At 3 years, the absolute differences are weeks to months, and the confidence interval of the FDA estimate includes zero, although the HRs are significant; the relative reduction in the risk of death should be read together with the absolute rate, which in the US label went from 19.4% to 8.1% at 3 years and from 40.3% to 33.9% at the last follow-up [19]. The figure of 4.3 years or 30% that circulates in PRF announcements and in the aortic stenosis consensus corresponds to the European estimate, and the life expectancy "with lonafarnib" of 18.7 to 19 years in GeneReviews coincides with the sum of that estimate and the 14.5 years without treatment, so it is not an observed survival [3, 16, 23]. The figure of 1.6 years, still cited by the PRF and in recent reports, comes from the 2014 analysis [33, 62, 63]. There is no valid comparison between the efficacy of lonafarnib alone and that of the combinations, because the combination trials had no concurrent control group and the plasma progerin analysis showed no additional effect of pravastatin and zoledronic acid [44, 74]. The triple trial was negative in its cardiovascular objectives: it did not improve carotid echodensity or pulse wave velocity compared with monotherapy, it increased plaques and calcifications, and the combination is not recommended [3, 74]. The statin + aminobisphosphonate combination described as "promising" in 2018 books corresponds to laboratory data prior to that trial [8].

The benefit depends on the age at initiation: according to the SmPC, the expected survival gain is smaller when treatment starts at 10 years of age or later, and in these patients it should be weighed against the gastrointestinal toxicity of the first months [21]. The results of 12 Chinese children, with 7 months of follow-up and no comparison group, showed only improvement in LDL, without growth benefit or vascular or skeletal worsening [52].

7.8. Cardiovascular disease

Low-dose aspirin should be considered in all children with HGPS, at any age, regardless of whether there is overt cardiovascular disease or lipid changes, to prevent TIA, stroke and coronary insufficiency through inhibition of platelet aggregation; the recommendation is based on studies of adults and of children at risk of arterial occlusion, not on trials in HGPS [3, 4]. The dose is 2–3 mg/kg/day, once daily or on alternate days, adjusted to the available forms (quarter, half or whole 81 mg tablet, the standard strength in the USA) and reduced in the presence of bruising or bleeding; this is off-label use [3, 4]. The PRF handbook considers the risk of Reye syndrome very small compared with the benefit, but recommends stopping aspirin during varicella, and GeneReviews suggests considering stopping it when varicella or influenza is circulating in the community [3, 4]. Non-steroidal anti-inflammatory drugs add to the antiplatelet effect: short-term combined use is acceptable, prolonged use is not, and paracetamol may be used for pain [4]. Aspirin is usually stopped 1 week before surgery or an invasive dental procedure, after weighing the risk with the surgeon, cardiologist and neurologist [4].

When hypertension, TIA, stroke, seizures, angina, exertional dyspnoea, heart failure or worrying ECG or echocardiographic changes appear, antihypertensives, drugs for heart failure and anticoagulants may be justified, always dosed by weight and adjusted to toxicity [3, 4]. GeneReviews considers glyceryl trinitrate frequently beneficial in angina and recommends routine anticongestive treatment in heart failure, whereas the PRF handbook recommends avoiding, in the acute setting, drugs such as nitrates that lower blood pressure, because of the risk of stroke; the divergence reflects different contexts (chronic angina and emergency) and requires individualisation [3, 4]. Hyperlipidaemia is rare and is treated with exercise, diet and, if necessary, a statin compatible with lonafarnib [3, 4, 19]. Hydration is a central cardiovascular and neurological measure: the minimum requirement is about 1 litre per day, with a target close to 1.5 litres, to be increased in the 24–48 hours before journeys, in hot weather and in intercurrent illness [3, 4].

Critical aortic stenosis has become the main indication for intervention. GeneReviews recommends frequent echocardiography when the peak gradient reaches 20 mm Hg and considers that gradients of 80–90 mm Hg justify intervention [3]. The Boston surgical team, observing that progression is rapid from 50–60 mm Hg and that above 80–100 mm Hg the margin for surviving the intervention is small, now considers intervention with a peak gradient of 60 mm Hg or more [58]. The 2024 international consensus assessed four typical cases and considered modified transcatheter aortic valve replacement (TAVR) and the left ventricular apico-aortic valved conduit feasible, although high-risk; after the meeting, two patients received TAVR and two the conduit, three successfully and one died perioperatively [23]. GeneReviews counts 2 modified TAVRs (1 successful, 1 intra- or perioperative cardiac death) and 4 conduits (2 with more than 2 years of successful follow-up, 1 death before 2 years and 1 death weeks after surgery), including unpublished data [3]. The obstacles are the hypoplastic aortic annulus, the mismatch between patient and device, diffuse peripheral arterial disease, fragile skin and bone and the difficult airway [23, 58]. Surgery with cardiopulmonary bypass has its own anaesthetic requirements [53]. In 1987, surgical coronary revascularisation and percutaneous angioplasty were described in a 14-year-old girl [2].

7.9. Cerebrovascular disease

In stroke with new symptoms, blood pressure management is a priority: a rapid fall, which worsens ischaemia, should be avoided, and in extensive strokes intensive care monitoring is justified until stabilisation; anticoagulation is often considered at that point [4]. Initial treatment of suspected TIA or stroke is supportive, with oxygen and intravenous fluids, and seizures are treated according to the usual paediatric standards [4]. The presence of narrowing or collaterals on MR angiography identifies the children who benefit most from daily aspirin and strict attention to hydration [4]. Headaches may improve with rest in a dark environment, hydration and paracetamol, and lonafarnib was associated with fewer headaches in a 2013 study [3, 4].

7.10. Emergency, anaesthesia and perioperative care

In an emergency, chest pain is ischaemic until proven otherwise; if the child is not taking prophylactic aspirin, they should chew half to one children's aspirin tablet (40.5–81 mg), and treatment is supportive, with oxygen, careful correction of hypovolaemia, analgesia and anxiety control to reduce tachycardia; arrhythmias are treated according to paediatric advanced life support algorithms [4]. Venous access is difficult, because the veins, although prominent, are poorly elastic [4].

The airway is difficult because of mandibular hypoplasia, micrognathia and retrognathia, small mouth opening, abnormal dentition, high-arched palate, stiffness of the temporomandibular and cervical joints, narrow nostrils and a rigid larynx [3, 4]. Equipment should be chosen according to height and not age, with smaller tubes than expected; supraglottic devices and fibreoptic equipment should be available, and fibreoptic intubation is the technique of choice when direct laryngoscopy is not possible [3, 4]. For investigations and minor surgery, mask or supraglottic device ventilation is preferable when safe, and sedation without a protected airway should only be performed by experienced teams [4]. Two general anaesthetics for dental treatment in a girl aged 8 and 10 years were performed with fibreoptic intubation [85]. Vascular rigidity makes patients very sensitive to variations in blood pressure, so hypovolaemia, hypotension and drugs that increase myocardial oxygen consumption should be avoided, and hydration should be maintained before and after the procedure [3, 4]. The risk of hypothermia is increased by alopecia and absence of fat [4]. Exercise tests do not predict intraoperative risk well [4]. Lonafarnib should be stopped 10–14 days (USA) or 14 days (EU) before any administration of midazolam and resumed 2 days later, which requires sedation for elective procedures to be planned in advance [19, 21]. Any surgery, including hip surgery, carries a substantial risk of stroke and cardiac events [3].

7.11. Supportive treatment by system

The calcium, vitamin D and zinc supplementation proposed by the authors of the Hangzhou series, based on 8 patients, contradicts the GeneReviews and PRF recommendation on calcium and has no outcome data [3, 4, 51].

7.12. Agents and circumstances to avoid

Long-term calcium supplementation should be avoided; so should dehydration, high fever and anaemia, especially in advanced cardiovascular disease; trampolines, bouncy castles and uneven surfaces that favour hip dislocation; crowds of much larger peers and being carried by smaller children; imposed physical activity, which should be self-limited; and rapid falls in blood pressure [3, 4]. Under lonafarnib, strong CYP3A inhibitors and inducers, midazolam, lovastatin, simvastatin and atorvastatin, drugs that prolong QT, sensitive CYP3A and CYP2C19 substrates and grapefruit are avoided [19, 21]. Swimming is beneficial for mobility, but requires heated water, a custom-made wetsuit, floats and supervision, because the children lose heat and float poorly [4].

7.13. Pregnancy, breastfeeding, fertility and transition

No cases of pregnancy or fertility have been described in women with the classic genotype, and ovulation has not been studied; one person with a non-classic genotype and mild phenotype had children, in the adult-onset family in which a mother and two children were affected [2–4]. Lonafarnib caused post-implantation loss and lower fetal weight in rats at 1.2 times the human exposure and skeletal malformations in rabbits at exposures below the human one, impaired fertility in rats of both sexes and was toxic to the male reproductive system in monkeys at exposures below the human one; the impact on human puberty and fertility has not been assessed [19]. Women of reproductive potential should use effective contraception during treatment and, according to the SmPC, until at least 1 week after the last dose, with an additional barrier method because the effect on steroid contraceptives has not been studied; men with a partner of reproductive potential should use contraception until 3 months after the last dose [19, 21]. Lonafarnib is not recommended in pregnancy; it is excreted in rat milk (milk/plasma ratio of 1.5 at 12 hours), there are no human data, and the decision is between stopping breastfeeding or treatment [19, 21]. The sources consulted do not describe transition programmes to adult care; the increase in survival into late adolescence and the third decade, with aortic stenosis and coronary disease as the dominant problems, makes the involvement of adult cardiology and cardiac surgery necessary, as in the 2024 consensus [23, 58, 59].

7.14. Mandibuloacral dysplasia and ZMPSTE24 forms

Treatment of MAD-A is supportive, focused on the metabolic complications, and there is no indication for lonafarnib in laminopathies with efficient processing [19, 21, 26]. MAD-B and the other forms due to biallelic ZMPSTE24 are included in the lonafarnib indication in the USA and the EU on the basis of the mechanism and cellular data, with no ZMPSTE24 patients in the underlying trials; restrictive dermopathy, with death usually in the first week, is not in practice treated [19, 42, 47].

7.15. Investigational therapies

Studies in humans. The combination of everolimus, an mTOR (mechanistic target of rapamycin) inhibitor that increases autophagy and progerin degradation, with lonafarnib has been in a phase 1/2 trial since 2015, without published results; the rationale comes from fibroblasts and from a tissue-engineered blood vessel model derived from induced pluripotent stem cells (iPSC) [2, 80, 86]. Progerinin (SLC-D011), an oral small molecule derived from the compound JH4 that inhibits progerin binding to lamin A, prolonged the life of LmnaG609G/G609G mice by about 10 weeks and, orally, that of LmnaG609G/+ mice by about 14 weeks, compared with about 2 weeks with lonafarnib in the same model, and attenuated the murine cardiac anomalies; the 2021 article had corrections published in 2021 and 2026 [87, 88]. After a phase 1 study in 64 healthy volunteers, the phase 2a trial in children on lonafarnib ended on 30 April 2026, with 10 participants; the PRF states that the results are under evaluation and that a phase 2b efficacy trial will be considered afterwards [81–83]. The absence of published results is not equivalent to a negative result. Umbilical cord blood transfusion was tested in 2 patients in South Korea, without results in the registry [84].

Preclinical studies. An adenine base editor targeting c.1824C>T corrected 87% to 91% of the pathogenic allele in patient fibroblasts, without detectable off-target editing; in transgenic mice with the human allele, a single injection of adeno-associated virus serotype 9 (AAV9) corrected 20% to 60% of the variant in several organs, preserved vascular smooth muscle cells and, given on day 14, increased median survival from 215 to 510 days [43]. In bone, correction was about 14%, 22%, 10% and less than 1% when the editor was given at 3 and 14 days and at 1 and 4 months of life, with partial rescue of bone structure only in those treated on day 14, which shows the dependence on the treatment window [89]. A variant-independent editing platform, which disrupts the LMNA farnesylation motif, eliminated perinuclear progerin in human neuromuscular organoids and could serve the atypical laminopathies [90]. Peptide-conjugated morpholino oligomers targeting the pathogenic splicing (SRP-2001) reduced progerin in the murine aorta and increased survival by 61.6%, and a screen of 198 antisense oligonucleotides identified candidates targeting the exon 12 junction that prolonged murine survival [91–93]. Also in the preclinical phase are the first proteolysis-targeting chimeras (PROTAC) that degrade progerin, baricitinib combined with lonafarnib, the NLRP3 inhibitor dapansutrile combined with lonafarnib and dietary nitrites, which prevented vascular stiffness in mice [30, 94–97]. Lonafarnib improved cardiovascular function and survival in a mouse model [98].

PRF gene therapy programme. The PRF is developing a base editor designated SamPro-2, given intravenously in AAV9, with the aim of correcting the classic variant mainly in the cardiovascular system; according to the foundation, a progeria-targeted editor increased the life expectancy of mice by 140% (2.4 times) [64, 99]. The programme is in the preclinical phase: the PRF announced manufacturing partnerships with Forge Biologics and PureSyn in 2026, anticipates interactions with the FDA for an investigational new drug application and a first N-of-1 trial, and there is no trial registered on ClinicalTrials.gov as of 17 October 2026 [64, 82]. A South Korean hospital registered in September 2026 two studies not yet recruiting, one a natural history study in a single patient over 3 years, to support a future RNA-targeting therapy based on AAV-Cas13, and another to create iPSC lines and test candidates in vitro [100, 101].

7.16. Developments in the last 12 months

In the USA no label change has been approved since 21 March 2024, and in the EU there was no extension of indication, negative opinion, suspension or withdrawal in the period; searching official sources does not exclude ongoing unpublished procedures [20, 73].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

8.2. Content of counselling

Counselling begins with molecular confirmation of the category, because the same clinical appearance may correspond to dominant de novo HGPS, with a low recurrence risk, or to a recessive progeroid laminopathy or ZMPSTE24 form, with a 25% risk [3, 8, 42]. Parental consanguinity and recurrence in siblings increase the probability of a recessive form, but do not demonstrate it, because recurrence with unaffected parents is also explained by gonadal mosaicism [2, 10]. Parents should be informed that the variant is a chance occurrence, not contagious, that advanced paternal age is associated with de novo variants and that the risk after an affected child is about 2% to 3% according to PRF counts [3, 4]. Study of the parents' blood may not detect low-level mosaicism, and a negative result does not reduce the risk to zero [2, 10]. In cardiac progeria due to p.(Asp300Asn), the variant was present in unaffected daughters and nieces and absent in both parents of the proband, which suggests gonadal mosaicism and shows that carriers without apparent disease may exist in the family [41].

8.3. Prenatal and preimplantation diagnosis and cascade testing

Once the variant has been identified in the index case, prenatal diagnosis and preimplantation genetic testing are available, and the decision should be made in the context of genetic counselling and respect for the different perspectives of professionals and families [3, 4]. In recessive forms, carrier testing in the extended family and in the partners of consanguineous carriers allows the same options to be offered [42]. In adult-onset non-classic genotypes and in atypical laminopathies with cardiovascular disease, carrier relatives with coronary or valvular disease and carrier relatives still without apparent disease have been identified, which gives testing of at-risk relatives a role in guiding surveillance [2, 41].

8.4. Counselling of minors and of the affected child

Because intellectual development is normal, the child perceives their difference, and the PRF handbook gathers the experience of families: there is no right moment to talk about the disease, children ask what they are ready to hear, and siblings need attention of their own so as not to feel less important [4]. Family planning is part of the repeated counselling visits [3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The figures are not comparable with each other: birth incidences come from historical series of detected cases, prevalences from the ratio between known cases and population, and registry counts depend on the identification capacity of each country [15, 16, 46]. Incidence is the same in both sexes and in all ethnic origins, and patients have been described on all continents [2–4]. The frequency of 0.3 per 100,000 sometimes associated with LMNA in databases refers to Emery-Dreifuss muscular dystrophy from all genes and not to HGPS [6]. Progeroid laminopathies have even scarcer estimates: MAD has about 40 published cases or families, restrictive dermopathy about 30 in Orphanet and about 60 in Smith, and cardiocutaneous progeroid syndrome 5 [11, 12, 14, 29].

9.2. Geography, ancestry and founder populations

Classic HGPS has no founder effect, because the variant arises de novo in each family [3, 31]. The Boston trials included children from 37 countries and six continents, and the PRF registry identifies patients in 52 countries [4, 16]. Recessive forms are concentrated in consanguineous families: homozygous p.(Arg527Cys) was the most frequent progeroid laminopathy in China and was described in a consanguineous Syrian family, homozygous p.(Arg527His) is the most frequent cause of MAD-A, MAD has been described repeatedly in Italian families, and a consanguineous family from northern India with features of MAD-A and HGPS led to the proposal that recessive HGPS and MAD-A are the same disease with different severities [2, 27, 40, 46]. The disease has been described in Japan, where the PRF counted 6 children in January 2024 [22].

The sources consulted contain no specific epidemiological data from Portugal or Brazil, which does not prove that none exist. OMIM records a consanguineous Brazilian family with a presumed HGPS phenotype and recessive inheritance, without confirmation of the diagnosis [2]. The PRF care handbook has a Portuguese translation, and information on the lonafarnib managed access programme exists in Brazilian and European Portuguese [4, 33]. The 2024 cardiology study resulted from a collaboration between Boston and Copenhagen, and the Italian and Spanish patient associations co-funded the 2025 workshop [24, 55].

9.3. Special populations

Children with HGPS are smaller than peers of the same age, and drug doses, airway equipment sizes and densitometry references should be based on weight, body surface area or height [3, 4]. Patients aged 10 years or more at the start of lonafarnib have a smaller expected benefit [21]. Patients who survive to late adolescence and the third decade reach adult services with calcific aortic stenosis, coronary disease and heart failure, and a 19-year-old patient weighing 14.6 kg and a 21-year-old woman weighing 13 kg illustrate the disproportion between age and size that constrains devices and techniques [58, 59]. Adolescent girls with menorrhagia are at risk of anaemia, which increases ischaemic risk [3, 4]. Children on aspirin have extensive haematomas after minor trauma [4]. There are no pregnancy data in patients with classic HGPS [3, 4].

9.4. European reference networks and patient associations

The sources consulted do not assign HGPS to a specific European Reference Network (ERN). Given the nature of the manifestations, the networks of interest for referral include ERN ITHACA (rare congenital anomalies and intellectual disability, which covers dysmorphic syndromes), ERN GUARD-Heart (rare heart diseases), Endo-ERN (lipodystrophies and rare endocrine diseases) and EURO-NMD (neuromuscular laminopathies, for the allelic forms); the sources consulted do not describe which of them includes HGPS within its scope.

The Progeria Research Foundation (Peabody, Massachusetts, USA; https://www.progeriaresearch.org/), founded in 1999 by the family of Sam Berns, maintains the international patient registry, the free genetic diagnosis programme, the medical and research database (224 children), the cell and tissue bank (about 211 to 214 cell lines, including 10 iPSC lines), the Boston clinical trials, 15 international scientific meetings and materials translated into 38 languages [4, 16]. In Europe, the sources consulted identify the Associazione Italiana Progeria Sammy Basso, which funded the Italian and Arabic translations of the PRF handbook, and the Asociación Progeria Alexandra Peraut, in Spain [24, 102]. GeneReviews also lists MedlinePlus and the National Organization for Rare Disorders (NORD) as resources [3].

10. Illustrative Clinical Case

Ozmarasali and colleagues published in 2026 the case of a 15-year-old girl with known HGPS, the daughter of cousins, with several deaths from progeria in the family, a healthy sister and a brother also with progeria [62]. She had a ground-level fall in a playground and, two hours later, had nausea and vomiting. At a secondary trauma centre, computed tomography (CT) showed a right frontoparietal epidural haematoma, with a Glasgow coma scale score of 14, and she was transferred within 1.5 hours with a paediatric cervical collar and normal saline, without airway intervention. On arrival, the Glasgow score was 12 and CT showed an epidural haematoma with a maximum thickness of 22 mm, a 6 mm midline shift to the left and a "swirl sign". The patient had severe cachexia (112 cm, 14 kg, body mass index of 11.16 kg/m²), micrognathia and cervical ankylosis, blood pressure of 105/65 mm Hg, heart rate of 92/min and saturation of 96% on room air, without Cushing's triad; the ECG was normal, as was coagulation (INR 1.14; activated partial thromboplastin time 24.2 s) [62].

The team administered mannitol 0.5 g/kg, raised the head of the bed to 30° and performed mild hyperventilation by mask. Induction was with propofol 2 mg/kg and fentanyl 1 µg/kg, deliberately avoiding neuromuscular blocking agents, because of the cachexia and the anticipated difficult airway, in order to preserve spontaneous ventilation; mask ventilation was confirmed before proceeding and a radial arterial line was placed. Attempts at orotracheal intubation with a Macintosh 2 blade and cuffed tubes of 5.0 and 6.0 mm failed because of glottic sclerosis and anatomical distortion, and the 2.8 mm fibreoptic bronchoscope did not allow the tube to be passed because of hypertrophic arytenoids and a high epiglottis. In view of rapid desaturation, an emergency percutaneous tracheostomy was performed with a 5.0 mm cannula, and anaesthesia was maintained with sevoflurane 2%. Surgery took place within 4 hours of the injury, with silicone gel pads at all pressure points to protect the atrophic skin, the head on a ring pillow and cervical rotation limited to 15° by the ankylosis. The craniotomy had significant bleeding from epidural veins, associated with diastasis of the coronal suture, controlled with coagulation, bone wax and repeated dural tack-up sutures. Postoperative CT showed complete evacuation; the patient stayed 5 days in paediatric intensive care, ventilated through the tracheostomy, and was discharged on day 10 with full neurological recovery; the tracheostomy was kept for planned orthodontic treatments. The authors also described a very low glottis, severe orthodontic anomalies, increased tongue volume and conversion of the ankylosed cervical lordosis into a kyphotic angulation with a Cobb angle of 24.6° [62].

The figures consulted show the axial cranial CT, the mouth opening and dentition, the sagittal cervical CT and the endoscopic images of the airway (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC13047787/figure/Fig1/), and the positioning, craniotomy, the haematoma before and after evacuation, replacement of the bone flap and the postoperative CT (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC13047787/figure/Fig2/) [62]. It is the third published case of epidural haematoma in HGPS, after a 10-year-old boy with temporal and posterior fossa haematomas (2003) and a 7-year-old boy with a parietal haematoma intubated blindly after failed laryngoscopy (2013) [62].

The case illustrates several aspects of the management of HGPS. The minor head injury with vomiting required immediate imaging, and the PRF handbook describes a higher risk of intracranial haematomas after minor trauma [4]. The airway proved more difficult than anticipated even with fibreoptic equipment, and the plan preserved spontaneous ventilation from the outset, in line with the recommendation to prepare difficult airway techniques [3, 4]. Emergency tracheostomy is not routine management and resulted from failure of the recommended techniques. The published data do not include the genotype, the usual medication (lonafarnib or aspirin) or the prior cardiovascular assessment; in a patient on lonafarnib, induction with propofol and fentanyl avoids the contraindicated combination with midazolam [19, 62]. Recurrence in a brother, in a consanguineous family with several deaths, does not by itself distinguish between parental gonadal mosaicism in dominant HGPS and a recessive progeroid laminopathy, and only molecular testing resolves the question for counselling [2, 3]. The authors also cite a life expectancy gain of about 1.6 years with lonafarnib and about 140 living children in the PRF registry, figures that predate the regulatory estimates and the 2026 count [16, 19, 62].

A second report, from Boston, documents the late phase of the disease: a 19-year-old patient weighing 14.6 kg with severe calcific aortic stenosis (peak gradient of 75–100 mm Hg, aortic annulus of 10 mm), mild aortic regurgitation, left ventricular hypertrophy and diastolic dysfunction with preserved function and exertional angina, in whom TAVR was excluded because of annular hypoplasia. With planning on a three-dimensional model, she underwent, through sternotomy and with cardiopulmonary bypass, a valved conduit from the left ventricular apex to the ascending aorta, with an apical cannula made by the surgeon from a reinforced 12 mm polytetrafluoroethylene graft and a 14 mm Hancock valved conduit; the postoperative course was uncomplicated, she was asymptomatic at 6 months and received warfarin for 3 months followed by aspirin indefinitely [58]. The same team had previously treated a 15-year-old child weighing 15.5 kg with critical aortic stenosis by the same procedure [58].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Without specific treatment, mean life expectancy is 14.5 years, with death between 6 and 20 years of age from heart failure and/or myocardial infarction in more than 80% of cases; historical series give means of 12.6 to 14.6 years and a median of 13.4 years (7 to 27.5) [3, 8, 15, 63]. Cerebrovascular disease is rarely the direct cause of death, but it is the main cause of morbidity, with a risk of cerebral infarction of about 32% at 13.5 years and radiographic infarcts in 60% of a neuroimaging series [3, 4, 60]. With lonafarnib, the estimated mean survival gain at the last follow-up is 2.5 years (95% CI 0.8–4.1) according to the FDA and 4.3 years (95% CI 2.6–6.1) according to the EU, with the same causes of death, and calcific aortic stenosis has become a critical risk factor in older patients [3, 19, 21, 23]. The expected benefit is smaller when treatment starts at 10 years of age or later [21]. The fall in plasma progerin under treatment is associated with survival: a fall of 15,000 pg/mL corresponds to a 63.9% reduction in the risk of death, and for the same fall life expectancy increases with the duration of treatment [44].

Non-classic genotypes have a prognosis linked to the amount of progerin, from neonatal death to survival into adulthood with coronary disease [2, 25]. MAD-A progresses slowly without compromising survival, with patients over 50 years of age; MAD-B is more severe because of the glomerulopathy; restrictive dermopathy is lethal in the neonatal period, with a maximum described survival of 120 days; in cardiocutaneous progeroid syndrome, deaths occurred between 29 and 44 years of age from heart disease and intracranial haemorrhage [2, 26, 27, 29].

11.2. Assessments after diagnosis

For the initial assessment, GeneReviews recommends weight and height on standard charts and nutritional assessment; dental examination and radiographs at initial eruption; skin assessment; orthopaedic assessment, DXA normalised for height-age and radiographs (acro-osteolysis, clavicular resorption, coxa valga, extraskeletal calcifications); physiotherapy and occupational therapy assessment with a 6-minute walk test, goniometry and activities of daily living (ADL); ECG, echocardiogram, baseline carotid Doppler ultrasound (lumen and intimal thickness) and brain and neck MRI and MR angiography; audiological and ophthalmological assessment; genetic counselling; and connection with support organisations and social services [3]. The PRF handbook adds the first dental visit by the first year of life and measurement of blood pressure in all four limbs [4]. Before lonafarnib, ECG, electrolytes (including potassium and magnesium), full blood count, liver enzymes and renal function are obtained, and the baseline ophthalmological assessment is recorded [19, 21].

11.3. Surveillance

The cardiovascular intervals differ between GeneReviews (6–12 months) and the PRF handbook (annual), and the intervention threshold for aortic stenosis differs between GeneReviews (80–90 mm Hg) and the Boston surgical team (60 mm Hg). Because children may have severe carotid occlusion before significant ECG changes and the aortic gradient grows exponentially in the late phases, the interval is shortened when there is established disease [3, 4, 58]. The reduction in myocardial strain with normal ejection fraction indicates that echocardiography with strain analysis detects dysfunction earlier, and the authors propose it as an outcome for future trials [55]. The PRF handbook notes that carotid Doppler ultrasound and pulse wave velocity are not available in all paediatric centres [4].

12. Summary and Final Considerations

Hutchinson-Gilford progeria syndrome is an autosomal dominant disease, almost always de novo, with a birth incidence of about 1 in 4 million, caused in about 90% of patients by the synonymous LMNA variant NM_170707.4:c.1824C>T p.(Gly608=) and in the rest by other exon 11 or intron 11 variants that produce the same protein, progerin [3, 5, 15]. Progerin is a prelamin A lacking 50 amino acids, which retains the farnesyl group, remains attached to the inner nuclear membrane and progressively damages vascular smooth muscle, bone, skin and adipose tissue, sparing cognition and most internal organs [3, 31]. Severity correlates with the amount of progerin, and non-classic genotypes range from neonatal progeria to adult-onset forms [25].

The child is born apparently normal and, in the first two years, develops severe growth failure, total alopecia, generalised lipodystrophy, scleroderma-like skin, retrognathia, osteolysis of the clavicles and distal phalanges, coxa valga and contractures [3, 4]. The disease that determines the prognosis is vascular: early diastolic dysfunction and altered myocardial deformation, atherosclerosis without dyslipidaemia, frequently silent strokes from 4 years of age and calcific aortic stenosis in the second decade, with death at a mean age of 14.5 years without treatment [3, 55, 60]. The diagnosis is confirmed by sequencing of exon 11 and intron 11 of LMNA, available free of charge through the PRF programme; if negative, testing proceeds to the whole of LMNA, ZMPSTE24 and panels or exome, because progeroid laminopathies without progerin and the recessive ZMPSTE24 forms, such as mandibuloacral dysplasia and restrictive dermopathy, differ in inheritance, prognosis and therapeutic eligibility [3, 18, 28].

Lonafarnib (Zokinvy®), authorised in the USA in 2020, in the EU in 2022 under exceptional circumstances and in Japan in 2024, is the only targeted treatment; it is started at 115 mg/m² twice daily and increased to 150 mg/m² after 4 months, with mainly gastrointestinal toxicity in the first months and monitoring of QTc, electrolytes, liver, kidney and retina [19, 21, 22]. The estimated survival gain, without a randomised trial, is 2.5 years according to the FDA and 4.3 years according to the EU, greater when treatment starts early, and it does not change the causes of death [19, 21]. The European variation decided in September 2026 added QTc and OCT1 warnings and new soft foods, and the European authorisation changed holder [73]. The combination with pravastatin and zoledronic acid brought no cardiovascular benefit, and everolimus, progerinin and base editing are in trials or in the preclinical phase [43, 74, 80, 81].

Supportive care, defined by GeneReviews and the PRF handbook in the absence of a society guideline, includes low-dose aspirin (2–3 mg/kg/day), strict hydration, calcium from diet only, six-monthly to annual cardiovascular and neurovascular surveillance, intervention for aortic stenosis with modified TAVR or apico-aortic conduit in experienced centres, and anaesthetic care that anticipates the difficult airway and avoids hypotension and midazolam under lonafarnib [3, 4, 19, 23]. The recurrence risk for the parents of a child with HGPS is about 2% to 3% because of the possibility of mosaicism, and prenatal and preimplantation diagnosis are available [3, 4]. The sources consulted provide no data from Portugal or Brazil and do not identify the competent European reference network, and the PRF international registry counted, in March 2026, 216 living patients with HGPS or progeroid laminopathies in 52 countries [16].

13. References

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2. Online Mendelian Inheritance in Man. #176670 Hutchinson-Gilford Progeria Syndrome; HGPS. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/176670
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4. Gordon LB, executive editor. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. 2nd ed. Peabody (MA): The Progeria Research Foundation; 2019 (2020 lonafarnib update). Available from: https://www.progeriaresearch.org/wp-content/uploads/2022/03/English-Progeria-Handbook-Edition-2.pdf (Portuguese version: https://www.progeriaresearch.org/wp-content/uploads/2022/11/Manual-da-Progeria-2-ed.-Potugues-reduced-size-PDF.pdf)
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6. GeneGuidance. LMNA — curation record of the gene and associated conditions (version of 26 September 2026). Primary sources cited: GeneReviews NBK1121; Orphanet; ClinGen.
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