Identification of a Novel Point Mutation in the LEMD3 Gene in an Infant With Buschke-Ollendorff Syndrome

Buschke-Ollendorff syndrome (BOS; OMIM 166700) is a rare autosomal dominant disease characterized by the variable occurrence of skin lesions (connective tissue nevi such as collagenomas or elastomas) and/or bone abnormalities known as osteopoikilosis. The underlying heterozygous loss-of-function mutation in the LEM domain-containing protein 3 gene (LEMD3) was identified in 2004.¹ An integral protein of the inner nuclear membrane, LEMD3 antagonizes transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling.^1,2 Loss of LEMD3 expression leads to increased connective tissue and elastin production by fibroblasts via enhanced TGF-β and BMP signaling, thereby producing the characteristic clinical phenotype.³

A 4-year-old boy presented with multiple asymptomatic skin lesions on his trunk, abdomen, and forearms. The skin lesions first occurred at age 18 months. Physical examination revealed multiple yellowish papules coalescing into larger plaques (Figure 1A). Apart from this, his general health conditions and development were unremarkable. Histological examination of a skin lesion from the trunk showed an accumulation of enlarged and fragmented elastic fibers under elastica van Gieson staining (Figure 1B), while arrangement and structure of collagen fibers appeared normal. At age 2 years and 9 months, radiographic examination of the hands, knees, feet, and pelvis had not shown any skeletal abnormalities. The family history revealed that his father had similar skin lesions at the trunk and hip in childhood, which had been misdiagnosed as scleroderma for many years.

To confirm the diagnosis of BOS, mutation analysis of the LEMD3 gene was performed by polymerase chain reaction amplification and direct sequencing of all coding exons and flanking introns. A heterozygous point mutation was found in exon 1 of the LEMD3 gene (c.1363C>T, p.Q455*) leading to a nucleic acid exchange at position 1363 of the cDNA, which results in a premature stop codon at the translation level (Figure 2). The heterozygous mutation was also detected in DNA from blood of the patient’s father consistent with an autosomal dominant inheritance pattern.

The coexistence of connective tissue nevi and osteopoikilosis was first described by Buschke and Ollendorff in 1928.⁴ BOS is a rare disease with an estimated incidence of 1 in 20 000 worldwide. The cutaneous manifestations consist of connective tissue nevi in which elastic or collagen fibers appear thickened and interlaced. The skeletal lesions, appearing as brighter spots on radiographic examinations, are areas of increased bone density typically located in the substantia spongiosa of the epiphyses and metaphyses of long bones and the pelvis.

The skin and skeletal abnormalities generally follow a benign course, beginning in childhood and persisting throughout life. However, additional associated skeletal abnormalities like otosclerosis, congenital spinal stenosis, and craniosynostosis have been reported.⁵ In spite of these associations, there is no evidence for increased morbidity or mortality in affected individuals.

The skeletal lesions of BOS can be mistaken for metastases and may lead to unnecessary clinical investigations_. With regard to cutaneous lesions in BOS, sporadic and inherited connective tissue nevi such as familial or nonfamilial collagenomas and/or elastomas, Proteus syndrome, and Shagreen patches of tuberous sclerosis should be considered as differential diagnoses.⁶

The LEMD3 gene spans approximately 78 kb and includes 13 coding exons.¹ According to the open access database LOVD (http://databases.lovd.nl/whole_genome/genes/LEMD3), 125 pathogenic mutations of the LEMD3 gene have been detected so far, including 113 point mutations, 9 deletions, 2 insertions, and 1 duplication. To our knowledge, we present a novel point mutation of the LEMD3 gene that results in a mild phenotype of BOS consisting of elastic-tissue nevi in the absence of skeletal lesions.

Corresponding Author: Johanna Kratzsch, MD, Department of Dermatology, Venerology, and Allergology, University of Leipzig, Philipp-Rosenthal-Str 23, 04103 Leipzig, Germany (Johanna.Kratzsch@medizin.uni-leipzig.de).

Published Online: March 23, 2016. doi:10.1001/jamadermatol.2016.0350.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient’s parents for granting permission to publish this information.