Coinheritance of naevoid basal cell carcinoma syndrome and neurofibromatosis type 1 associated with an exceptional spectrum of tumours
Authors: S.J. Ghadiri, P. Brennan, E. Calonje, A.J. Carmichael, N. Rajan
Journal: British Journal of Dermatology (2020)

Dear Editor, The tumours arising in naevoid basal cell carcinoma syndrome (NBCCS) and neurofibromatosis type 1 (NF1) are distinct, and are exemplars of the specific consequences of mutations arising in different tumour suppressor genes. While each syndrome has recognized pathognomonic tumours, an exceptional spectrum of tumours presenting in an individual with either syndrome may represent the interaction of an additional tumour suppressor gene. Here we report two related cases with coinheritance of both syndromes, where the proband is clinically presumed to have inherited NF1 from her mother and NBCCS from her father, with digenic transmission to one of her sons. The previously reported proband presented aged 10 years with multiple jaw cysts.1 She was clinically diagnosed with NBCCS, based on her coexistent macrocephaly with frontal bossing (Figure 1a) and her paternal family history of early-onset multiple basal cell carcinomas (BCCs) and jaw cysts. Subsequently, she has developed over 40 BCCs. Aged 27 years, she presented with a spinal dumbbell neurofibroma. This was ascribed to NF1, based on her multiple cutaneous neurofibromas, café au lait patches and her maternal family history. Aged 57 years, she presented with a tender subcutaneous papule in the right loin. The lesion was excised and histology showed features of a glomus tumour. Aged 58 years, she developed several skin-coloured, shiny, firm, 2–5-mm-diameter papules on her lower legs (Figure 1b). These were distinct from her soft fleshy neurofibromas and prompted a biopsy. Histology showed a polypoid dermal lesion, composed of spindle-shaped tumour cells, with no atypia, set in a myxoid stroma. Immunohistochemical staining of the tumour cells was positive for claudin-1, epithelial membrane antigen and CD34, and negative for S100 and actin. The findings were consistent with a diagnosis of an extraneural perineurioma. Aged 59 years, she presented with recurrent epigastric pain. Laparoscopy revealed three jejunal tumours (Figure 1c), which were excised and shown histologically to be multicentric gastrointestinal stromal tumours (GISTs). Four years following the resection of the GISTs no recurrence has been detected. Genetic testing confirmed both a germline PTCH1 (NBCCS) pathogenic missense variant (NM_000264.5, c.1514G>A, p.G509D) and a germline nonsense NF1 (NF1) pathogenic variant (NM_001042492.3, c.334C>T, p.Q112*). The proband has two sons (Figure 1d). Her elder son, aged 34 years, has inherited both PTCH1 and NF1 pathogenic variants and has exhibited jaw cysts, BCCs, neurofibromas and café au lait patches to date. Her younger son, who inherited the NF1 pathogenic variant alone, has developed neurofibromas, café au lait patches and a plexiform neurofibroma of the neck. At age 32 years he also developed an aggressive grade 3 brain stem glioma, resistant to radical radiotherapy. NBCCS and NF1 are each associated with pathognomonic tumours. In NBCCS,2 BCCs and jaw cysts are typical, and, more rarely, ovarian fibromas, meningiomas, medulloblastomas and cardiac fibromas are reported. In NF1,3 cutaneous and plexiform neurofibromas are typical and astrocytomas, pheochromocytomas, gastric carcinoid tumours, glomus tumours,4 GISTs5 and perineuriomas6 may infrequently occur. Perineuriomas are rare, benign, peripheral nerve sheath tumours showing perineurial cell differentiation.7 In NF1, just two cases of isolated, large, subcutaneous soft tissue perineuriomas have been reported.6 Our proband was exceptional in developing a spectrum of rare tumours including a glomus tumour that was not at a typical subungual site,4 cutaneous perineuriomas and multiple jejunal GISTs, which may relate to the digenic inheritance of heterozygous pathogenic variants in PTCH1 and NF1. We hypothesize that biallelic loss of either or both genes may be present in the various tumour cell types seen in the proband. We report this case to highlight the utility of genetic testing when patients with NBCCS or NF1 present with unusual symptoms or signs. We thank the patient for granting permission to publish this information.