Hutchinson-Gilford Progeria syndrome (HGPS)

What is Hutchinson-Gilford Progeria syndrome (HGPS)?

This rare disease is a fatal genetic condition named for the doctors who first identified it, in 1886 and 1897 respectively.

The syndrome triggers accelerated ageing in those affected. Heart disease is also a serious and common complication of the rare disease.

Syndrome Synonyms:
HGPS Hutchinson-Gilford syndrome Progeria Progeria Syndrome, Childhood-onset, With Osteolysis; Pscoo

What gene changes cause Hutchinson-Gilford Progeria syndrome (HGPS)?

Mutations on the LMNA, POLR3A and BANF1 genes are responsible for the syndrome.

These genes produce Lamin A, now known to be what holds the nucleus of a cell together. A mutation in the genes leads to a lack of Lamin A, which creates an unstable nucleus and triggers premature ageing.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Hutchinson-Gilford Progeria syndrome (HGPS)?

Symptoms of premature ageing generally occur in the first two years of an affected individuals life. These symptoms include, slowed growth, a loss of body fat and hair, hip dislocations, an increased stiffness in the joints as well as the more serious medical conditions of heart disease and stroke.

The condition is fatal, and expected life expectancy for someone with the syndrome is just 14 years. Heart disease is the leading cause of death for someone with this condition.

Possible clinical traits/features:
Progressive clavicular acroosteolysis, Sparse eyelashes, Osteolytic defects of the distal phalanges of the hand, Osteoporosis, Autosomal recessive inheritance, Short stature, Lipoatrophy, Joint stiffness, Micrognathia, Spotty hyperpigmentation, Midface retrusion, Proptosis, Sparse and thin eyebrow, Scoliosis, Pulmonary arterial hypertension, Sinus tachycardia, Wide cranial sutures, Atherosclerosis, Abnormality of the ribs, Abnormality of the forearm, Convex nasal ridge, Dental crowding, Malar flattening, Delayed closure of the anterior fontanelle, Flexion contracture, Failure to thrive

How does someone get tested for Hutchinson-Gilford Progeria syndrome (HGPS)?

The initial testing for Hutchinson-Gilford Progeria syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Hutchinson-Gilford Progeria syndrome (HGPS)

Birth-weight may be low, less than 2500 gm, but major problems with growth do not occur until after the first year, when growth may almost cease. An important early sign may be scleroedema of the skin of the lower trunk and upper legs. This can give an oedematous appearance, but the skin is hard to the touch. Later the skin becomes thinned and atrophic. Erdem et al., (1994) report such a case and review other cases in the literature. After the first year progressive signs of apparent ageing appear; loss of scalp hair, eyebrows and eyelashes, prominent scalp veins and a small triangular face with a relatively large cranial vault. The mandible is small with crowded teeth that erupt late. The nose is thin and beaked. The skin becomes dry and thin and the nails are brittle and short (reflecting shortening of the underlying distal phalanges). There is generalised wasting with a cachectic appearance and prominent joints. Hypertension, cardiomegaly and early atheroma can occur. Death is in the second decade in most cases (Fukuchi et al., (2004) reported a mildish case - with mutation - who died at 45 years). The diagnosis in the case reported by Gillar et al., (1991) is uncertain - it could be mandibulo-acral dysplasia. This case had irregular pigmentary changes of the abdominal skin which first appeared as ""burn-like strial markings"". Later the lesions were described as hypopigmented. Likewise the diagnosis in the case reported by Labeille et al., (1987) with scleroderma-like skin changes is uncertain. Hou and Wang (1995) also reported a baby with early onset features of progeria associated with sclerodermatous skin changes. Note that some bona fide cases of early childhood progressive systemic sclerosis can develop a very progeroid appearance (Urano et al., 1981). Ishikawa et al., (1993) also reported a 17 year old girl with severe progeroid features who had a scleroderma-like variant of recessive dystrophic epidermolysis bullosa.
Note the 2 unusual families reported by Hisama et al., (2011) with adult onset coronary artery disease and facial features of premature ageing. Mutations were found at the junction of exon 10 and intron 11 of LMNA. Lipids were abnormal, not a usual finding in progeria.
An osteosarcoma was a complication in the patient reported by Shalev et al., (2007).
Matsuo et al., (1994) reported a 7-year-old boy who was thought to have the condition (although no photographs were published). He had normal mental development, but an MRI scan revealed a previous brain infarction in the right putamen. Fibroblast culture was said to demonstrate 76% unscheduled DNA synthesis. Wang et al., (1991) also reported this phenomenon in four patients. Oshima et al., (1996) reported no detectable mutations in the Werner helicase gene.
Most cases are sporadic, although there have been a few reports of affected sibs. Fatunde et al., (1990) described three affected sibs. Maciel (1988) reported an inbred pedigree with affected individuals in two sibships. Khalifa (1989) reported a similar inbred family with three affected individuals. Radiographs revealed absent clavicles, coxa valga and widened metaphyses. The long bones were generally thin and there was absence of terminal phalanges. A Moroccon patient reported by Doubaj et al., (2012) had normal growth and development aged 11 years. His normal father was a mosic for the LMNA mutation.
Delgado-Luengo et al., (2002) reported a convincing case with a 1q23 deletion. The parents did not consent to their chromosomes being looked at.
De Sandre-Giovannoli et al., (2003) reported a heterozygous Lamin A splicing mutation in two patients (c.1824 C>T/p.G608G). Erikkson et al., (2003) observed two cases with uniparental isodisomy of 1q and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA showed that 18 out of 20 classical cases had an identical de novo G608G(GGC > GGT), mutation within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Most patients with the G608G mutation have classical progeria (Mazereeuw-Hautier et al., (2007). Cao and Hegele (2003) studied seven Hitchinson-Gilford patients. They found four novel LMNA coding sequence variants among the HGPS probands, R471C, R527C, G608S and c.2036C>T. All seven cases had at least one LMNA variant, which were found in none of the genomes of 100 normal controls. There might be a paternal origin for these germ-line mutations (D'Apice et al., (2004). It should be noted thar patients with atypical progeroid syndroms might have LMNA mutations (Csoka et al., 2004). For instance, the patient reported by Kirschner et al., (2005) had features of an early onset myopathy. She had a p.S143F mutation.
Geneticists beware: a family reported by Plasilova et al., (2004) had 4 affected members. The family was Indian and was consanguineous (see above for other recessive families). Molecular analysis revealed a homozygous LMNA mutation in those affected. Heterozygous mutation carriers were normal. In addition, Wuyts et al., (2005) reported an affected boy whose phenotypically normal mother was found to have a somatic mosaicism. Progeria is expertly reviewed by Hennekam (2006). Two sibs, homozygous for a mutation was reported by Liang et al., (2009). The clavicles were absent, the anterior and posterior fontanelles persisted, scoliosis was pronounced (in one). Both had gastro-intestinal symptoms, full cheeks, and joint mobility was severely restricted.
Sewairi et al. (2016) described a male patient from a consanguineous family with Hutchinson–Gilford progeria syndrome with scleroderma-like skin changes due to a homozygous missense LMNA mutation. Clinical characteristics included hypo- and hyperpigmented skin macules around small and large joints, buttocks, and face; thinning of the skin (scleroderma-like) of both hands and feet (mainly the palms and the soles), progressive contractures, small and rounded terminal phalanges, and chronic constipation. X rays showed diffuse osteopenia and resorption of the distal phalanges. Skin biopsy showed hyperkeratosis and hyperpigmentation of the basal layer.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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