Progeria Syndrome

A sporadic syndrome of premature aging with characteristic facies, severe cardiac lesions (including myocardial infarction), and various orthopedic and otorhinolaryngologic lesions.

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Hutchinson-Gilford Progeria Syndrome; Gilford Syndrome; Premature Senility Syndrome.

Rare genetic disease characterized by premature aging. First described by Jonathan Hutchinson in 1886.

Sporadic cases. Fewer than 100 cases reported in the literature. Progeria affects between 1:4 million (estimated actual) and 1:8 million (reported) live births.

In most patients, the syndrome is caused by random genetic changes occurring for unknown reasons. Because it occurs sporadically, it is believed to be an autosomal recessive disorder. However, these mutations might be transmitted as an autosomal dominant trait. Male:female ratio is 1.5:1. Whites account for 97% of all reported cases.

A reduction in the amount of cell DNA repair activity has been demonstrated and postulated as a cause of the premature aging. The genes controlling cell division and DNA or RNA synthesis and processing commonly are downregulated in elderly people and in progeria (15 genes involved). This suggests that abnormal regulation of the separation of the chromosomes during cell division occurs. There are characteristic changes in expression of actin-binding proteins (caldesmons), which are involved in cell cycle-dependent reorganization of the cytoskeleton, desmoplakin I, which plays a role in intercellular adhesive junctions, and autotaxins, which are involved in cellular chemotaxis. On the other hand, transforming growth factor-β (TGF-β) is highly upregulated in patients with progeria, thus yielding tissue fibrosis.

No firm diagnostic criteria have been described in patients with premature aging of postnatal onset, including characteristic facies, musculoskeletal abnormalities, and early death caused by atherosclerosis and/or myocardial ischemia.

Clinical manifestations are evident by the first or second year of life. The appearance includes facial hypoplasia with micrognathia, thin skin, alopecia, dental late eruption, ophthalmic abnormality (microphthalmia, exophthalmia, cataract), ear abnormality (hypoplastic lobe, conductive hearing loss), and a high-pitched voice. Cardiovascular lesions are severe and frequent, characterized by a progressive atherosclerosis (coronary, aortic, and cerebral artery). Hypertension, myocardial infarction, or congenital heart failure often cause premature death. There is no mental retardation. Orthopedic modifications are numerous: hip dislocation, early osteoporosis, dwarfism, restricted joint mobility, clavicle anomalies, and large fontanel. Hypoplastic toe nails are frequent. Hypogonadism and diabetes can be observed.

Obtain full personal history to find existence of symptomatic vascular or CNS disorders. Cardiovascular evaluation is needed (ECG, chest radiograph, echography, coronarography, and even radionuclide imaging to eliminate the possibility of advanced ischemic disease). Evaluate tracheal intubation conditions by cautious clinical examination and radiography. Evaluate the extent of osteoporosis and diabetes.

Cautious patient positioning is imperative to avoid pathological fractures. Direct laryngoscopy and tracheal intubation could be difficult because of facial abnormalities and micrognathia. Loss of teeth occurs more often. Spontaneous ventilation must be maintained, and gentle manipulations are necessary to avoid neck injury during a difficult intubation. Fiberoptic intubation can be proposed in this case. Central venous access by the subclavian vein must be avoided in case of clavicle malformation. Cardiovascular status would influence anesthetic management; avoid hypotension and tachycardia. Hypothermia is frequent because of the thin skin and subcutaneous fat.

Avoid cardiovascular depressive drugs; avoid succinylcholine (fasciculation can cause pathological fracture in patient with severe osteoporosis).

Ruvalcaba Churesigaew Myhre Syndrome (Progeria Variant Syndrome Ruvalcaba Type): A progeria variant that includes kyphosis, mental retardation, and amyotrophy.

Mulvihill Smith Syndrome (Progeria Short Stature Pigmented Nevi): A progeria variant that includes multiple pigmented nevi and mental retardation.

Pseudoprogeria Syndrome (Halberg Rudolph Syndrome): Autosomal recessive transmission with mental retardation, seizure, progressive spastic quadriplegia, and glaucoma.

Werner Syndrome: Autosomal recessive, located on 8p12. The disorder first begins during adolescence. It is rare in Europe, more frequent in northern Japan (1:500,000 live births). Characteristic features include scleroderma-like skin changes, especially in the extremities, prematurely aged facies, cataract, subcutaneous calcification, premature atherosclerosis, diabetes mellitus, an increase in malignancies (10% of patients), and retinal degeneration.

Wiedemann-Rautenstrauch Syndrome: Autosomal recessive transmission. Characteristic features of this disorder include prognathism, general absence of subcutaneous fat but paradoxical, fat accumulation at flanks, buttocks, and anogenital area, psychomotor development deficiency, pseudohydrocephalus, macrocephaly, dysphagia, congenital heart defect, and sudanophilic leukodystrophies.

Cockayne Syndrome: An autosomal recessive disease caused by mutations in the excision-repair cross-complementing group 6 gene with premature aging, poikiloderma, dwarfism, mental retardation, pigmentary retinopathy, blindness, and conduction hearing loss. Photoprotection of eyes and skin is crucial because of an important deficiency in DNA repair after exposure to the sun.

Progeroid Syndrome Petty Type (Petty Laxová Wiedemann Syndrome): Prematurely aged face, prognathism, brittle hair, increased body hair, and loose skin.

Souques-Charcot-Geroderma (Geroderma Infantilis): Features loose, shiny, dry skin, subcutaneous atrophy, eunuchoid habitus, and intellectual deficiency.

Geroderma Osteodysplastica Syndrome: Connective-tissue disease resulting in early aging processes of the skin and generalized osteopenia with predisposition to fractures. Other features include joint hyperlaxity, muscle hypotonia, hip dislocation, sunken eyes, microcorneas, and failure to thrive. Inheritance is X-linked recessive with occasional manifestations in females. Less severe in female heterozygotes.

Pangeria: Premature generalized aging appearance beginning between 15 and 30 years of age. Clinical features include hypogonadism, beak-shaped nose, high-pitched voice, sclerodermous skin and ulcers, severe arteriosclerosis.