Hypertrophic Osteoarthropathy, Primary, Autosomal Recessive, 2

A number sign (#) is used with this entry because of evidence that autosomal recessive primary hypertrophic osteoarthropathy-2 is caused by homozygous or compound heterozygous mutation in the SLC2A1 gene (601460) on chromosome 3q22.1-q22.2.

Description

Primary hypertrophic osteoarthropathy (PHO), which is also known as pachydermoperiostosis, is a rare genetic disease that affects the skin and bones. PHO is characterized by digital clubbing, periostosis, acroosteolysis, painful joint enlargement, and skin manifestations that include thickened facial skin, a thickened scalp, and coarse facial features (summary by Zhang et al., 2012).

For a discussion of genetic heterogeneity of PHO, see PHOAR1 (259100).

Clinical Features

Castori et al. (2005) reported a 37-year-old Italian man with pachydermoperiostosis (PDP), born of unaffected consanguineous parents. At puberty, the patient noted progressive enlargement of the hands, feet, and knees, as well as facial furrowing. He had redundant skin on the scalp, cheeks, forehead, eyelids, palms, and soles. Seborrhea, folliculitis, and hyperhidrosis were also present. There was terminal broadening of the fingers and toes, and cylindrical enlargement of the legs and forearms. Skeletal radiographs of the long bones showed soft tissue swelling and dense, shaggy, periosteal ossification with cortical thickening. Endosteal and periosteal hyperostosis caused loss of the normal tubulation of the long bones, especially in the hands and feet. The calvarium was moderately thickened. Disease progression ceased at the age of 25 years.

Harifi et al. (2011) described a consanguineous Moroccan family in which a 14-year-old boy had primary hypertrophic osteoarthropathy. The proband developed intermittent arthralgia and profuse sweating of palms and soles at 12 years of age, associated with enlargement of the fingertips. Examination revealed large hands and feet with marked digital clubbing, and enlarged and swollen ankles and knees. He had no facial dysmorphism or thickening or furrowing of facial features, and pachydermia and cutis verticis gyrata were not observed. X-rays documented soft tissue swelling and periosteal reaction at the radial, ulnar, tibial, metacarpal, metatarsal, and proximal phalangeal diaphyses in the absence of acroosteolysis. Laboratory tests revealed an elevated erythrocyte sedimentation rate and a marked increase in C-reactive protein (123260) and bone-modeling markers. Examination of other family members revealed variable manifestations in 3: the father and 19-year-old brother of the proband displayed digital clubbing, and periosteal ossification on the distal ends of the long bones was evident. His 10-year-old sister had no bone or joint complaints, but inconspicuous clubbing of the digits was observed, in the absence of periosteal new bone formation on x-ray. Harifi et al. (2011) concluded that this family had an incomplete form of PHO, with isolated bone involvement and limited skin changes.

Zhang et al. (2012) reported 3 Han Chinese male probands with PHO from 3 unrelated families, 1 of which was consanguineous. Disease onset in the 3 probands occurred at 12 to 15 years of age and manifested as digital clubbing, swelling of the knees, periostosis, and a progressive thickening and furrowing of facial skin. Echocardiography revealed no patent ductus arteriosus or other cardiac defects in the 3 affected individuals. No other family members were affected. Urinary prostaglandin E2 levels were 16 times higher in the 3 patients than in unaffected family members, and urinary PGE-M concentrations were 6 times higher.

Molecular Genetics

In a consanguineous Moroccan family with primary hypertrophic osteoarthropathy, Harifi et al. (2011) sequenced the 7 exons of the HPGD gene (601688) but detected no mutation or polymorphic variants.

In a Han Chinese male proband with primary hypertrophic osteoarthropathy, who was born of first-cousin parents and was negative for mutation in HPGD, Zhang et al. (2012) performed exome sequencing and identified 28 genes that contained homozygous missense, nonsense, or splicing variants. Sanger sequencing of the only functional candidate, SLCO2A1 (601460), revealed a splice site mutation (601460.0001) that was present in homozygosity in the proband and in heterozygosity in his unaffected parents. Analysis of SLCO2A1 in 2 additional Han Chinese probands with primary hypertrophic osteoarthropathy revealed compound heterozygosity for 4 different mutations in SLCO2A1 (601460.0002-601460.0005), which were found in heterozygosity in the unaffected parents and in other unaffected family members, but were not detected in 250 ethnically matched controls.

In patients with primary hypertrophic osteoarthropathy who were negative for mutation in the HPGD gene (601688), Seifert et al. (2012) screened for genetic alterations in genes directly involved in the PGE2 biosynthesis and signaling pathway, and identified 2 unrelated families with 2 different homozygous mutations in the SLCO2A1 gene (see, e.g., 601460.0006). In a third family, the proband had only digital clubbing and he and his unaffected father were both heterozygous for a nonsense mutation in the SLCO2A1 gene (601460.0007).

In 4 unrelated probands of diverse ethnicities who had typical and highly distinctive pachydermoperiostosis, with onset after puberty and severe digital clubbing, skin thickening, and skeletal features, who were negative for mutation in the HPGD gene, Diggle et al. (2012) performed exome sequencing and identified homozygous or compound heterozygous mutations in the SLCO2A1 gene in 3 of the 4 patients (see, e.g., 601460.0008). Conventional Sanger sequencing of SLCO2A1 in 9 additional PDP probands revealed homozygosity or compound heterozygosity for 11 more SLCO2A1 mutations (see, e.g., 601460.0004 and 601460.0009), including the Italian patient previously reported by Castori et al. (2005) (601460.0010). Diggle et al. (2012) noted that mild features, usually digital clubbing, were sometimes apparent in older heterozygous mutation carriers.

Genotype/Phenotype Correlations

Seifert et al. (2012) observed that in patients with homozygous mutations in the SLCO2A1 gene, manifestations of PHO emerged later than in patients with HPGD mutations, beginning with clubbing of distal phalanges during puberty and pachydermia shortly after puberty. However, the degree of arthritis, joint involvement, and pachydermia in patients with homozygous SLCO2A1 mutations seemed to be more pronounced than in individuals with homozygous or compound heterozygous HPGD mutations.

Diggle et al. (2012) stated that certain clinical features appear characteristic of patients with mutations in HPGD or in SLCO2A1: HPGD-deficient individuals generally present with digital clubbing and other symptoms in early childhood, whereas SLCO2A1-deficient patients are diagnosed later, after puberty or in early adulthood; pachydermia occurs in both groups, but severe cutis gyrata is observed only in the SLCO1A1 group; although periosteal bone deposition is seen in both groups, acroosteolysis is much more prominent in the HPGD-deficient group; and myelofibrosis is associated with biallelic mutations in SLCO2A1 but not HPGD. In regard to the observed excess of males with PHO, Diggle et al. (2012) noted that this had been attributed to higher prostaglandin levels in males, resulting in milder manifestations in females with homozygous mutations in HPGD, and suggested that PHO due to SLCO2A1 mutations might also be a difficult diagnosis to make in females.