The Buschke–Ollendorff syndrome: a case report of simultaneous osteo-cutaneous malformations in the hand

Abstract

BackgroundWe describe a male with functionally impairing radial deviation of the thumb who presented to us at 24 years of age. Two sclerotic skin lesions had been excised 7 years before because of consecutive skin contracture. Latest radiological examination showed a spotted pattern consistent with osteopoikilosis.Case presentationA corrective osteotomy of the thumb was carried out due to the patients discomfort. Facing the simultaneous osteo-cutaneous malformation we postulated a Buschke–Ollendorff syndrome. Buschke–Ollendorff syndrome is a rare autosomal-dominant hereditary disorder of connective tissue with typical osteo-cutaneous manifestations. To explore our hypothesis, biopsies were taken from the affected bone lesions and surrounding skin and soft tissue for histological investigation and genetic testing of the LEMD3 gene was performed on blood of the patient. The histology showed typical changes of the bone architecture and a fibrotic collagenous nodule of the skin. The genetic testing on DNA extracted from peripheral blood leucocytes confirmed a heterozygous loss of function mutation in the LEM domain-containing protein 3 (LEMD3) gene coding for the inner nuclear membrane protein MAN1, which causes osteopoikilosis by antagonizing transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signalling.ConclusionsIn atypical cases of simultaneous occurrence of fibrotic skin lesions and a spotted pattern in the X-ray we recommend the genetic screening of the LEMD3 gene. A correct diagnosis of Buschke–Ollendorff syndrome is necessary to spare patients from expensive investigations and to provide reassurance about the benign nature of the disease.

Modeling-based bone formation transforms trabeculae to cortical bone in the sclerotic areas in Buschke-Ollendorff syndrome. A case study of two females with LEMD3 variants

“…Therefore, the findings of formation of lamellar bone structures with layer upon layer build-up and a secondary osteonal remodeling process provide evidence that BOSassociated sclerotic noduli are dynamic and reflect transformation of trabeculae to cortical bone, a process that may to extent resemble the physiological corticalization during growth. In contrast to the histological findings in a distal phalanx of a BOS patient [13], we found no evidence of formation of an increased rate of intracortical bone remodelling, but clear evidence of a local thickened cortical bone, as reported in the distal phalanx. Studies of bone histology from further BOS subjects are required to substantiate whether this is a consistent finding in individuals with impaired LEMD3.…”

“…Abbrevations: aBMD, Areal bone mineral density, BASP, alkaline phosphatase, BOS, Buschke-Ollendorff syndrome, BSU, bone structural unit, BV/TV, trabecular bone volume, LEMD3, LEM domain-containing protein, BMP, MAN1 antagonizes bone morphogentic protein, MBF, modeling-based bone formation, NaF, 18F-sodium-fluoride, Ob, osteoblast, OCN, osteocalcin, oRBF overflow remodeling-based P1NP, pro-collagen type 1 amino terminal peptide PTH, parathyroid hormone, RANKL, Receptor activator of nuclear factor kappa-Β ligand, RBF, remodeling-based bone formation, Smad, mothers against decapentaplegic, drosophila homolog, TGF-β, transforming growth factor beta, VOS, volume of interest Journal Pre-proof J o u r n a l P r e -p r o o f 6 Previous clinical reports on the bone phenotype in patients with BOS include radiological and histological investigations of bone tissue from two BOS patients known to carry a pathogenic LEMD3 variant. While nodular sclerotic areas in the femoral head were described as "silent" [1], bone remodeling and a network of thick bone trabeculae, enlarged Haversian canals and fibrotic tissue were observed in a proximal phalanx [13]. However, TGF-β signalling and histomorphometric details including the remodeling process within the sclerotic areas have not been reported in BOS patients.…”

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

“…The association of skin lesions, even atypical, and a spotted bone pattern on the X-rays may lead to a genetic screening of the LEMD3 gene (Fig. 4a ) [ 31 , 32 ].…”