Hutchinson–Gilford progeria syndrome: Review of the phenotype

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide‐spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra‐abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non‐classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non‐classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant‐negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A. © 2006 Wiley‐Liss, Inc.

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

“…Skeletal muscle abnormalities, including muscle atrophy, first proximally (scapulae, buttocks) then distally in the limbs, are classical symptoms described in HGPS. 38 As the diminished joint mobility observed in HGPS patients does not appear to be due to tightening of the skin, one may hypothesize that it may be due to muscle sclerosis and tightness similar to what is observed in myopathies. The emergence of LMNA gene mutations in HGPS patients prompted the examination of skeletal muscle, leading to the description of the first cases with progeroid syndrome and confirmed earlyonset myopathy due to p.Ser143Phe LMNA substitution 39,40 or type A MAD due to p.Arg471Cys homozygous 41 or p.Arg527His/Val440Met compound heterozygous 42 LMNA mutation.…”

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…Clinically, HGPS is characterized by segmental features of premature aging including alopecia, loss of subcutaneous fat and early death (usually in the second decade), mostly due to myocardial infarction. 10 After the identification of the main genetic cause of HGPS as a de novo LMNA mutation (c.1824C4T, Gly608Gly) affecting splicing and prelamin A maturation, 11,12 mutations in ZMPSTE24 were then identified in patients affected by severe Mandibulo-acral dysplasia associated with B-type lipodystrophy (MAD-B), 13 and later in RD. 1,3,14 Clinically, MAD is characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis of distal phalanges, cutaneous atrophy and lipodystrophy.…”

Infection susceptibility and immune senescence with advancing age replicated in accelerated aging LmnaDhe mice

“…Reciprocally, aberrant accumulation of lamin A variants occurs in natural aging as well as accelerated aging progeria disorders (Gonzalez et al ., 2011). In Hutchinson–Gilford syndrome, rapidly progressive loss of subcutaneous fat, joint contractures, and arteriosclerosis beginning in early childhood occurs in association with spontaneous mutations in the LMNA gene encoding lamin A (Hennekam, 2006; Merideth et al ., 2008). Mice with spontaneous Lmna defects have similar accelerated aging phenotypes (Mounkes et al ., 2003; Varela et al ., 2005).…”