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MELORHEOSTOSIS, ISOLATED; MEL

MELORHEOSTOSIS, ISOLATED; MEL

▼ DescriptionMelorheostosis (MEL) is characterized by 'flowing' hyperostosis of the cortex of tubular bones. The lesions are usually asymmetric and involve only ...

▼ 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.

Kang et al. (2018) studied 8 patients with MEL and mosaicism for MAP2K1 mutations in affected bone. Radiographs showed the classic 'candle wax' appearance of melorheostosis. A consistent intraoperative finding while obtaining bone biopsies in these patients was extremely dense, rigid affected bone that often dulled the osteotomes and drill bits. Histomorphometric analysis of melorheostotic bone tissue revealed distinctive parallel layers of primary lamellar bone in the outer regions, an organization that underlay the surgical hardness of the bone. This newly formed compact tissue was intensely remodeled into highly porous osteonal-like bone at greater depth from the surface. Compared to unaffected bone, affected bone showed increased active bone-resorbing osteoclasts, elevated eroded surfaces, and a higher number of bone-forming osteoblasts. There was an approximately 6-fold increase in the thickness of unmineralized bone matrix (osteoid) and a greater than 50-fold increase in osteoid surface/bone surface in the affected bone samples compared to their respective unaffected counterparts.

▼ Molecular Genetics
In samples of affected bone from 8 of 15 patients with isolated melorheostosis, who were negative for somatic or germline mutations in the LEMD3 gene (607844), Kang et al. (2018) identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, 176872.0006; K57N, 176872.0007; and K57E, 176872.0008) that were not present in unaffected bone or peripheral blood leukocytes, or in the ExAC database. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants are located in a MEK1 alpha-helix that negatively regulates kinase function, and that the 3 variants previously had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia, and shown to cause gain-of-function effects. Mosaicism for the respective MAP2K1 mutations was confirmed in skin tissue overlying affected bone in 4 patients but was not detected in 1 patient with a lower disease burden. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, the variants also resulted in reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone. The authors suggested that the marked variability in pattern of bone lesions observed between patients is likely due to mutations arising during different points during development, with earlier mutations resulting in an increased burden of disease.

Associations Pending Confirmation

In a 14-year-old boy with osteopoikilosis (see 166700) and melorheostosis, who was heterozygous for a 24-bp deletion in the LEMD3 gene (607844.0010), Whyte et al. (2017) performed somatic event analysis of DNA from 5 patient tissue samples and detected a Q61H missense mutation in the KRAS gene (190070) that was present in a large linear epidermal nevus and in scleroderma-like dermatosis over the area of melorheostosis, but was not present in 2 samples of normal skin or in blood leukocytes. The variant showed a 30 to 60% allele frequency, indicating that the variant was present within most cells of the tissue samples. Bone biopsy was not performed. The authors suggested a role for postzygotic mosaicism of the KRAS mutation, perhaps facilitated by LEMD3 haploinsufficiency, in the etiology of the proband's melorheostosis.

In a patient with isolated melorheostosis, who was negative for somatic mutation in the MAP2K1 gene and negative for somatic or germline mutation in the LEMD3 gene, Kang et al. (2018) detected a KRAS missense mutation (Q61R) in both affected and unaffected bone. The patient exhibited skin lesions consistent with RASopathy, and the authors suggested that the melorheostosis represented part of a more complex early embryonic mosaic RASopathy.

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).

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