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Bone. 2017 Aug;101:145-155. doi: 10.1016/j.bone.2017.04.010. Epub 2017 Apr 21.

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

Author information

1
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mwhyte@shrinenet.org.
2
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mgriffit@wustl.edu.
3
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: ltrani@wustl.edu.
4
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: smumm@wustl.edu.
5
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA. Electronic address: ggottesman@shrinenet.org.
6
Department of Pediatric Radiology, Mallinckrodt Institute of Radiology at St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mcalisterw@wustl.edu.
7
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: kkrysiak@wustl.edu.
8
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: robert.lesurf@oicr.on.ca.
9
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: zskidmor@wustl.edu.
10
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: katiecampbell@wustl.edu.
11
Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: irosman@wustl.edu.
12
Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: sbayliss@wustl.edu.
13
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA. Electronic address: vbijanki@shrinenet.org.
14
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA. Electronic address: anenninger@shrinenet.org.
15
Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: bvantine@wustl.edu.
16
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: obigriffith@wustl.edu.
17
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Genomics and Bioinformatics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: elaine.mardis@nationwidechildrens.org.

Abstract

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× 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 KRAS Q61H (NM_033360.3:c.183A>C, NP_203524.1:p.Gln61His), 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.

KEYWORDS:

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

PMID:
28434888
PMCID:
PMC5518630
DOI:
10.1016/j.bone.2017.04.010
[Indexed for MEDLINE]
Free PMC Article

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