Melorheostosis, Isolated

Description

Melorheostosis (MEL) is characterized by 'flowing' hyperostosis of the cortex of tubular bones. The lesions are usually asymmetric and involve only 1 limb or correspond to a particular sclerotome. They may be accompanied by abnormalities of adjacent soft tissue, including joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangiomas (review by Hellemans et al., 2004). The designation combines root words meaning 'limb,' 'flow,' and 'bone.'

Melorheostosis may sometimes be a feature of Buschke-Ollendorff syndrome (BOS; 166700), a benign disorder which is caused by mutation in the LEMD3 gene (607844). Although germline or somatic LEMD3 mutations had been postulated to cause isolated melorheostosis (Butkus et al., 1997; Debeer et al., 2003; Happle, 2004; Hellemans et al., 2004), several studies have not been able to prove this (Hellemans et al., 2004; Mumm et al., 2007; Zhang et al., 2009).

Clinical Features

Fryns et al. (1980) reported a 3-year-old girl with clinical and radiologic findings of melorheostosis involving the left lower limb and associated with scleroderma of the overlying soft tissue. Subsequently, at age 17 years, she was admitted to hospital for an Ilizarov operation for lengthening and axis correction of the left tibia. Arterial hypertension (220/130 mm Hg) was noted, and biochemical studies documented high plasma renin activity and high aldosterone concentrations. Renal studies showed a small left kidney, and angiography showed several intrarenal high-grade stenoses of the left renal artery with poor opacification. Partial nephrectomy with removal of the upper and middle portions of the left kidney was performed. Pathologic examination of the small and large blood vessels showed marked intimal proliferation and splitting of the elastica.

Roger et al. (1994) reported that vascular anomalies, such as capillary hemangiomata, lymphangiectasis, vascular nevi, glomus tumors, and arteriovenous aneurysms occur in at least 5% of reported patients. This and the fact that soft tissues overlying the skeletal changes show abnormalities suggested to Fryns (1995) that 'melorheostosis, like Proteus syndrome (176920), may be another example of an early postzygotic mutation of the mesenchyme resulting in asymmetric involvement of skeletal structures, with concomitant vascular and hamartomatous changes in the overlying soft tissues.'

Mumm et al. (2007) reported 4 unrelated patients with sporadic melorheostosis. One girl was affected in the left hand, with lesions in the radial carpal bones and overlying tight skin. Another girl developed ulnar deviation of her right wrist and middle finger and her left thumb. She had significant flexion contractures of some fingers and her right elbow. An 8-year-old boy had congenital deformity of his left leg and foot caused by progressive MEL; skin atrophy affected the foot.

Zhang et al. (2009) reported a 39-year-old man from the U.K. with sporadic melorheostosis. He had a painful flexion deformity of the right elbow. Radiographs showed extensive flowing endosteal hyperostosis that affected the humeral and radial shaft as well as the distal epiphyses with ectopic calcifications in the antecubital fossa. He had no relevant family history of a similar disorder.

Molecular Genetics

Exclusion Studies

Mumm et al. (2007) did not identify germline mutations in the LEMD3 gene (607844) in any of 4 unrelated patients with sporadic isolated melorheostosis. Zhang et al. (2009) did not identify germline or somatic mutations in the LEMD3 gene in a U.K. man with sporadic melorheostosis. Both Mumm et al. (2007) and Zhang et al. (2009) concluded that mutation in the LEMD3 gene does not cause isolated melorheostosis.

History

Happle (1996) presented a concept of type 2 segmental disorders in conditions such as melorheostosis, which is nonhereditary and always shows a segmental arrangement. Type 1 segmental involvement reflects, it was suggested, heterozygosity resulting from a de novo mutation in an otherwise healthy embryo; a type 2 segmental manifestation may be best explained by loss of heterozygosity occurring in a heterozygous embryo at an early developmental stage. Happle (2004) suggested that melorheostosis originates from an early mutation event with loss of the corresponding wildtype allele at the gene locus of osteopoikilosis (166700).