Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature

Summary Background:  Multiple miliary osteoma cutis (MMOC) is a rare nodular skin disease characterized by tiny bone nodules which usually form on the facial skin, typically in middle age. The aetiology of this phenomenon is poorly understood. Objectives:  To search for possible bone formation progenitors and to look for a possible association with mutations in the GNAS gene (encoding the G‐protein α‐stimulatory subunit) and related hormonal parameters in patients with MMOC. We also reviewed the literature and discuss the aetiology and pathogenesis of adult‐onset primary osteomas. Methods:  We report four cases of MMOC. Histological samples were analysed for bone morphogenetic protein (BMP)‐2, BMP‐4 and oestrogen receptor‐α known to be involved in bone formation. Endocrinological laboratory investigations and hand X‐rays were performed to exclude a systemic disease. The GNAS gene was sequenced from DNA extracted from peripheral blood in all four patients and from a skin sample in one patient to exclude somatic mutations. Results:  Histological analyses revealed intramembranous cutaneous bone formation resembling the findings seen in GNAS gene‐based osteoma cutis disorders. However, we did not find any germline or somatic GNAS gene mutations in our patients and all laboratory investigations gave normal results. BMP‐2 and ‐4 were expressed normally in MMOC samples, but oestrogen receptor‐α was not expressed. Altogether 47 MMOC cases, 41 female and six male, have been published between 1928 and 2009. Of these cases, 55% had a history of pre‐existing acne and only 15% had extrafacial osteomas. Conclusions:  MMOC is a rare but distinct disease entity of unknown aetiology. Histologically, the tiny nodular osteomas show intramembranous superficial ossification but the aetiology appears to be different from GNAS ‐related disorders. The osteomas seem to increase slowly in number after appearing in middle age.