Vulval Intraepithelial Neoplasia And Early Squamous Cell Carcinoma Development In A Patient With Netherton Syndrome

Heterozygous frameshift mutation in glomulin causing autosomal dominant familial glomuvenous malformation with associated intracranial cavernoma K. Farquhar, A. Iqbal, N. Fullerton, C. Thum, P. Beattie, D. Koppell, K. Asakura, D. Baty, A. Jamison, P. Cauchi, C. Jury, M. Zamiri and S. Joss Departments of Dermatology, Neuroradiology, Pathology, Maxillofacial Surgery, Ophthalmology and Clinical Genetics, Queen Elizabeth Hospital, Glasgow, UK; Department of Dermatology, Royal Children’s Hospital, Glasgow, UK; and East of Scotland Regional Genetics Unit, Ninewells Hospital, Dundee, UK Glomuvenous malformations (GVMs; OMIM 13800) are hamartomas most commonly presenting in childhood as multiple bluish soft papules and nodules with a cobblestone appearance. Histologically, they are characterized by abnormal smooth muscle-like ‘glomus cells’ and are inherited in 64% of cases in an autosomal dominant pattern owing to mutations in GLMN, which is located on chromosome 1p21-22. Previously, it was thought that GVMs were a solely cutaneous presentation, but recent reports confirm systemic associations. We report a multigeneration pedigree with autosomal dominant GVM due to a recurrent mutation in GLMN with associated deep intracranial cavernoma and developmental venous anomaly (DVA). A 38-year-old woman attended for assessment of the possible inheritance of an extensive facial vascular malformation, noted from birth, with her 57-year-old mother being similarly affected. Her deceased grandmother, who had a cerebrovascular event at a young age, was reported to have a similar facial lesion. The proband had previously received bleomycin sclerotherapy, but lower lid ectropion and subsequent epiphora occurred. Bony facial asymmetry was present on computed tomography with invasion of fat by the malformation, and surgery was successfully performed with malar osteotomy and debulking of the vascular lesion. Histology from an eyelid biopsy confirmed positive glomus cells (smooth muscle actin + calponin positive), consistent with GVM. Mutation screening of both affected family members confirmed a previously reported pathogenic heterozygous variant in GLMN designated c.743dup, p.(Leu248Phefs*14) resulting in a frameshift and subsequent premature termination of the GLMN encoded protein. Given the grandmother’s history and the extent of the visible malformation, magnetic resonance imaging (MRI) of the head for assessment of the internal vasculature was requested for both patients. The proband had evidence of a mixed vascular malformation (DVA and cavernoma) and associated white matter changes in the left frontal and parietal region. Her mother had a posterior fossa mixed vascular malformation, with old microhaemorrhages noted. The national neurovascular multidisciplinary team suggested clinical observation but no active treatment. The proband’s 10-year-old twins have been invited to attend for assessment and consideration of genetic screening. There are increasing reports of many systemic associations of GVMs, but there is a paucity of information on intracranial vascular anomalies. Mixed malformations have been reported to be associated with epilepsy or present with stroke-like symptoms due to haemorrhage but are considered benign in > 90% of cases. This pedigree highlights the benefit of a multidisciplinary management approach and the role of intracranial MRI in cases of facial GVM.