Hyaline Fibromatosis Syndrome

A number sign (#) is used with this entry because hyaline fibromatosis syndrome (HFS) is caused by homozygous or compound heterozygous mutation in the gene encoding capillary morphogenesis protein-2 (CMG2, or ANTXR2; 608041) on chromosome 4q21.

Description

Hyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (summary by Denadai et al., 2012).

Clinical Features

Puretic et al. (1962) described what they considered to be a novel connective tissue disorder. In addition to the proband, a brother and sister were probably affected, having died in infancy with painful flexural contractures of the elbows, shoulder joints and knees, which developed at about 3 months of age. The proband also showed deformity of the face and skull, stunted growth, osteolysis of terminal phalanges, multiple large subcutaneous nodes, some calcified, dysseborrheic, sclerodermiform and atrophic changes of the skin, recurrent suppurative infections of the skin, eyes, nose and ears, and gingival fibromatosis. Ishikawa and Hori (1964) described a 2.5-year-old Japanese infant whose sib had died at 8 months, probably of the same condition. 'Systemic hyalinosis' was suggested as a designation.

Kitano et al. (1972) reported the disorder in 2 sibs, and observed that cells from affected areas contained a metachromatic substance.

Kitano (1976) reported an affected boy who was born of consanguineous parents. He had large tumors on the scalp and whitish nodules on the nape and sides of the neck. Hypertrophic gingivae and tumors at both commissures of the lips were illustrated. Histopathologic studies showed that the tumor cells were embedded in an amorphous eosinophilic ground substance. X-ray films showed numerous osteolytic and osteoclastic lesions of the skeleton.

Aldred and Crawford (1987) gave a comprehensive review of 23 cases of juvenile hyaline fibromatosis from 17 families.

Landing and Nadorra (1986) described a condition, which they called infantile systemic hyalinosis, in 4 female Mexican-American infants, including 2 sibs. The main features were early thickening and focal nodularity of the skin leading to reduced movement and joint contractures, gum hypertrophy, and osteoporosis. The infants failed to thrive and had diarrhea and recurrent infections. All had onset in the first week of life and died before age 20 months. Pathologic examination showed widespread deposits of hyaline material in skin, skeletal muscle, gastrointestinal tract, endocrine glands, and other locations. The condition was probably first described by Nezelof et al. (1978). Landing and Nadorra (1986) suggested that this infantile systemic disorder was distinct from juvenile systemic hyalinosis, which they considered to be the same as juvenile hyaline fibromatosis.

Aldred and Crawford (1987) gave a comprehensive review of 23 cases from 17 families.

Gorlin et al. (1990) emphasized the occurrence of flexion contractures and gingival fibromatosis.

Bedford et al. (1991) described 2 severely affected unrelated children with painful flexion contractures of all the large joints, perianal granulomas, and recurrent infections from which both died at 19 months and 2 years. The parents of 1 of the children were consanguineous.

Stucki et al. (2001) described a brother and sister who presented with infantile systemic hyalinosis at ages 3.5 and 2 months, respectively. Both patients had skin lesions and painful joint contractures. Electron microscopic studies showed increased amorphous mucoid or hyaline material in the skin, with a striking perivascular deposition suggestive of an intravascular origin. The authors concluded that their findings supported the hypothesis of autosomal recessive inheritance of this condition.

Rahman et al. (2002) reported 2 Indian families in which 4 individuals had hyaline fibromatosis. The families were presumably unrelated, but originated from the same small village. The patients presented in early childhood with progressive development of multiple subcutaneous swellings and nodules on the scalp, face, extremities, and trunk. Large nodules on the hands and feet coincided with underlying articular cartilage. Other features included gingival fibromatosis and progressive severe joint contractures. Radiographs showed osteopenia or osteolysis, and skin biopsy showed excessive hyaline deposition.

El-Kamah et al. (2010) reported 3 Egyptian sibs, born of consanguineous parents, with severe infantile-onset hyaline fibromatosis. The first child died of respiratory distress at age 3 days. The second child had multiple cutaneous swellings, painful joint contractures, gingival hypertrophy, repeated chest infections, and intractable diarrhea. He died at age 4 years of cardiac arrest. The third child had painful joint contractures and died at age 2 years from diarrhea. Genetic analysis identified a homozygous truncating mutation in the ANTXR2 gene (1074delT; 608041.0008).

Denadai et al. (2012) reported a pair of sibs and 3 other unrelated patients, all of Brazilian origin, with hyaline fibromatosis syndrome. The sibs developed pearly skin papules on the face and neck and cutaneous nodules on the ears, scalp, and fingers at ages 3 and 8 months, respectively. The girl had recurrent diarrhea and failure to thrive in the first 2 years of life. Her brother developed numerous skin lesions all over the body, including some that coalesced to form plaques in the neck and gluteal regions. Both also had gingival hyperplasia and joint contractures. Two of the other patients also had severe failure to thrive, diarrhea, joint contractures followed by skin lesions, and gingival hyperplasia. The last patient was a 20-year-old man who was wheelchair-bound due to postural deformity and severe contractures of multiple joints. He had a history of pearly and nodular skin lesions, gingival hyperplasia, and joint contractures from the first months of life. Radiographs of the patients showed osteolytic bone lesions. Duodenal biopsy of 1 patient with diarrhea showed deposition of hyalinized material. Histologic analysis of the skin lesions showed proliferation of spindle cells without atypical features forming strands in a homogeneous and hyaline eosinophilic material within the dermis. The material was PAS-positive and diastase-resistant. Some of the lesions had ulcerated. Denadai et al. (2012) concluded that it is difficult to classify patients with this disorder into an infantile or juvenile form, and suggested using the term hyaline fibromatosis syndrome (HFS), which reflects variable severity. Denadai et al. (2012) proposed a 4-grade grading system of the disorder to reflect increasing severity, with grade 4 resulting in early death due to severe clinical decompensation. The authors emphasized that adequate healthcare in the newborn period is critical for survival.

Biochemical Features

Breier et al. (1997) described a 14-month-old girl with this disorder. Compared with controls, synthesis and degradation of type I collagen (120150, 120160) was found to be increased in fibroblasts derived from the patient; in contrast, overall metabolism of type III collagen was reduced by 36%.

Inheritance

Both males and females are affected, and affected sibs have been reported, consistent with autosomal recessive inheritance (Drescher et al., 1967; Enjoji et al., 1968).

Kitano (1976) reported an affected boy who was born of consanguineous parents, suggesting autosomal recessive inheritance.

Landing and Nadorra (1986) suggested autosomal recessive inheritance of infantile systemic hyalinosis since 2 sisters were affected.

Fayad et al. (1987) reviewed 15 previously reported cases; the great majority of these had a positive family history and several had parental consanguinity, suggesting autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of 2 unrelated Indian families with hyaline fibromatosis, Rahman et al. (2002) found linkage to a locus on chromosome 4q21. Fine mapping of this region in these families and in 3 additional affected families (Keser et al., 1999) delineated a 7-cM region on chromosome 4q21 between D4S2393 and D4S395 (maximum 2-point lod score of 4.22 at D4S395, maximum multipoint lod score of 5.5).

Molecular Genetics

Hanks et al. (2003) and Dowling et al. (2003) identified mutations in the CMG2 gene as the cause of both infantile-onset and juvenile-onset hyaline fibromatosis (608041.0001-608041.0007), indicating that these disorders are allelic and part of the same phenotypic spectrum.

History

Murray (1873) and Whitfield and Robinson (1903) reported 3 affected sibs whose unaffected parents were first cousins. These authors described the disorder as molluscum fibrosum.

Suschke and Kunze (1971) considered the condition to be a mucopolysaccharidosis.