A Report of a Novel Pathogenic Variant in a Family with Buschke–Ollendorf Syndrome

Abstract

Buschke–Ollendorf Syndrome (BOS) is a benign autosomal dominant disorder caused by pathogenic mutations in LEMD3. Here, we describe a family diagnosed to have varied phenotypes associated with BOS. Single gene testing of LEMD3 detected a heterozygous frameshift pathogenic variant in both the affected family members. Besides the phenotypic description, this report highlights the need for a comprehensive evaluation in connective tissue disorders and the importance of genotype–phenotype correlation in BOS.

Keywords

familial Buschke–Ollendorf syndrome - osteopoikilosis - collagenoma - LEMD3

• References

• 1 Hellemans J, Preobrazhenska O, Willaert A. , et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet 2004; 36 (11) 1213-1218
• 2 Zhang Q, Mo ZH, Dong CS, Yang F, Xie YH, Jin P. Identification of a novel LEMD3 Y871X mutation in a three-generation family with osteopoikilosis and review of the literature. J Endocrinol Invest 2016; 39 (06) 679-685
• 3 Lin F, Morrison JM, Wu W, Worman HJ. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet 2005; 14 (03) 437-445
• 4 Giro MG, Duvic M, Smith LT. , et al. Buschke-Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture. J Invest Dermatol 1992; 99 (02) 129-137
• 5 Korman B, Wei J, Laumann A, Ferguson P, Varga J. Mutation in LEMD3 (MAN1) associated with osteopoikilosis and late-onset generalized morphea: a new Buschke-Ollendorf syndrome variant. Case Rep Dermatol Med 2016; 2016: 2483041
• 6 Chambers DM, Moretti L, Zhang JJ. , et al. LEM domain-containing protein 3 antagonizes TGFβ-SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol. J Biol Chem 2018; 293 (41) 15867-15886
• 7 Richards S, Aziz N, Bale S. , et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 8 Barad P, Fernandes J, Shukla P. Eruptive collagenoma: a rarely reported entity in Indian literature. Indian J Dermatol 2015; 60 (01) 104
• 9 Hershkovitz D, Amitai B, Sprecher E. Familial cutaneous collagenomas resulting from a novel mutation in LEMD3. Br J Dermatol 2007; 156 (02) 375-377
• 10 Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X. DOG 1.0: illustrator of protein domain structures. Cell Res 2009; 19 (02) 271-273