4.6 Article

Melorheostosis: Exome sequencing of an associated dermatosis implicates postzygotic mosaicism of mutated KRAS

期刊

BONE
卷 101, 期 -, 页码 145-155

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2017.04.010

关键词

Dysostosis; Hyperostosis; LEMD3; Linear epidermal nevus; Malignancy; Nevus sebaceous; Osteopoikilosis; Osteosclerosis; Scleroderma; TGF beta

资金

  1. Shriners Hospitals for Children
  2. Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund
  3. Hypophosphatasia Research Fund at the Barnes Jewish Hospital Foundation
  4. National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) [DK067145]
  5. National Human Genome Research Institute [NIH NHGRI K99HG007940]
  6. National Cancer Institute [NIH NCI K22CA188163]

向作者/读者索取更多资源

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3. Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to-100 x average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3. Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous ICRAS Q61H (NM_0333603:c.183A>C, NP_203524.1:p.G1n61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS, perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL (C) 2017 Elsevier Inc. All rights reserved.

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