Stiff Skin Syndrome

A number sign (#) is used with this entry because of evidence that stiff skin syndrome (SSKS) is caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.

Description

Stiff skin syndrome is characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness (Loeys et al., 2010).

Patients with similar phenotypes involving stiff skin have been described; see, e.g., familial progressive scleroderma (181750), symmetric lipomatosis (151800), and congenital fascial dystrophy (228020).

Clinical Features

Esterly and McKusick (1971) described a disorder characterized by thickened and indurated skin of the entire body and limitation of joint mobility with flexion contractures. One patient they reported was a sporadic case but the other had an affected sister and mother. Syndesmodysplasic dwarfism (272450) and the Parana hard-skin syndrome (260530) bear similarities to this syndrome but are apparently distinct recessive entities. Singer et al. (1977) reported a family with transmission through at least 4 generations and father-son involvement.

Pichler (1968) described a father, daughter and son with flexion deformities of fingers and toes, limited motion of several other joints and the vertebral column, sclerodermatoid changes of the skin, and generalized increase in the consistence of otherwise slightly underdeveloped muscles. Suspected myosclerosis could not be confirmed by biopsy. The appearance of the affected son rather suggested that of pseudo-Hurler polydystrophy (252600) but no corneal changes were described and autosomal dominant inheritance seems likely.

Stevenson et al. (1984) described a kindred in which many members had stiff skin beginning in adulthood. The presence of symmetrical lipomatosis suggested to the authors that this is the disorder described in entry 151800.

Loeys et al. (2010) studied 4 families segregating autosomal dominant stiff skin syndrome with high penetrance, including a family with 10 affected individuals over 5 generations. All affected individuals displayed diffusely thick and hard skin from the time of birth and had developed joint contractures. Additional clinical features not previously described for stiff skin syndrome included cutaneous nodules that predominantly affected the distal interphalangeal joints, relative short stature, and diffuse entrapment neuropathy, with nerve injury and dysfunction due to local compression. None of the patients had skeletal, ocular, or cardiovascular findings of Marfan syndrome (MFS; 154700). However, Loeys et al. (2010) also examined a 14-year-old boy with a 'hybrid' phenotype, who had ocular lens dislocation, which is a cardinal manifestation of Marfan syndrome, glaucoma, retinal detachment, and tight skin with diffuse joint contracture. The boy, who was 1 of fraternal triplets, was considerably shorter than his unaffected brothers and displayed none of the skeletal or cardiovascular manifestations of MFS.

Pathogenesis

Loeys et al. (2010) performed pulse-chase analysis of dermal fibroblasts from patients with stiff skin syndrome and controls and found equivalent secretion of fibrillin-1 (FBN1; 134797); however, confocal immunofluorescence analysis of skin biopsies from the patients revealed increased deposition of both fibrillin-1 and elastin in the dermis relative to age- and gender-matched control samples. Microfibrillar bundles at the dermal-epidermal junction had a stubby appearance in the patients, without the deep projections into the underlying dermis seen in controls. In addition, dermal deposition of elastin was seen immediately adjacent to the epidermis in the patients, a zone that shows relative exclusion of elastin in controls. Trichrome staining of skin biopsies revealed a wide zone of increased collagen deposition in the papillary dermis of the patients relative to control samples. Loeys et al. (2010) suggested that pathogenic events in stiff skin syndrome alter the amount and architecture of microfibrillar deposits and are abnormally permissive for the association of fibrillin-1 and elastin at the dermal-epidermal junction.

Molecular Genetics

Loeys et al. (2010) sequenced the FBN1 gene (134797) in probands from 4 unrelated families with stiff skin syndrome and identified heterozygous missense mutations in each, all within exon 37 of the gene (see 134797.0050-134797.0053, respectively). Another patient who had a 'hybrid' phenotype of stiff skin syndrome with ectopia lentis was found to be heterozygous for a missense mutation in exon 38 of FBN1 (134797.0054). None of the mutations were found in more than 400 ethnically matched controls.

Nomenclature

Loeys et al. (2010) used the symbol SSS for stiff skin symbol; the symbol used here is SSKS because SSS is a well-established symbol for sick sinus syndrome (see 606467).

Animal Model

Gerber et al. (2013) generated 2 Fbn1-targeted mouse models of stiff skin syndrome, one harboring a W1572C mutation, which is equivalent to human W1570C (134797.0050 and 134797.0051), and the other harboring a D1545E mutation, which eliminates the RGD motif needed to mediate cell-matrix interactions by binding to cell surface integrins. Gerber et al. (2013) showed that mouse lines harboring these mutations recapitulated aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the profibrotic cytokine transforming growth factor-beta (TGFB; 190180). Mutant mice showed skin infiltration of proinflammatory immune cells, including plasmacytoid dendritic cells, T helper cells, and plasma cells, as well as autoantibody production. These findings were normalized by integrin-modulating therapies or TGFB antagonism. Gerber et al. (2013) concluded that the results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and profibrotic programs and highlight new therapeutic strategies for systemic sclerosis (181750).