Adrenal cancer in neurofibromatosis type 1: case report and DNA analysis

Abstract

SummaryAdrenal cortical carcinoma (ACC) has previously only been reported in eight patients with type 1 neurofibromatosis (NF1). There has not been any clear evidence of a causal association between NF1 gene mutations and adrenocortical malignancy development. We report the case of a 49-year-old female, with no family history of endocrinopathy, who was diagnosed with ACC on the background of NF1, due to a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene. A left adrenal mass was detected by ultrasound and characterised by contrast computerised tomography (CT) scan. Biochemical tests showed mild hypercortisolism and androgen excess. A 24-h urinary steroid profile and 18flouro deoxy glucose PET suggested ACC. An open adrenalectomy was performed and histology confirmed ACC. This is the first reported case with DNA analysis, which demonstrated the loss of heterozygosity (LOH) at the NF1 locus in the adrenal cancer, supporting the hypothesis of an involvement of the NF1 gene in the pathogenesis of ACC. LOH analysis of the tumour suggests that the loss of neurofibromin in the adrenal cells may lead to tumour formation.Learning points ACC is rare but should be considered in a patient with NF1 and adrenal mass when plasma metanephrines are normal.Urinary steroid metabolites and PET/CT are helpful in supporting evidence for ACC.The LOH at the NF1 region of the adrenal tumour supports the role of loss of neurofibromin in the development of ACC.

Adrenocortical Carcinoma: Updates of Clinical and Pathological Features after Renewed World Health Organisation Classification and Pathology Staging

“…These syndromes could occur in high as 5–10% of patients with ACC [ 29 ]. In adult patients with ACC, these syndromes include multiple endocrine neoplasia type 1 ( MEN1 , approximately 20 cases reported) [ 30 ], Lynch syndrome (mismatch repair genes) (approximately 10 cases) [ 31 ], Li-Fraumeni syndrome ( TP53 , more than 10 cases) [ 32 ] and neurofibromatosis type 1 ( NF1 , approximately 10 cases) [ 33 ]. Rarely, ACC can occur in patients with Carney complex ( protein kinase A regulatory subunit 1A [ PRKARIA ]) [ 34 , 35 ], Gardner’s syndrome [ 36 ] and familial adenomatous polyposis ( adenomatous polyposis coli [ APC ]) [ 37 , 38 ].…”

Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

“…Apart from rare cases of germline TP53 mutations, as mentioned before ( 29 , 30 ), ACC in adults may also be associated to other hereditary conditions in some uncommon cases [reviewed in Ref. ( 47 )]: familial adenomatous polyposis (FAP) ( 48 ), multiple endocrine neoplasia type1 (MEN1) ( 49 ), Lynch syndrome ( 50 ), and neurofibromatosis type 1 (NF1) ( 51 ) (Table 1 ).…”

Concurrent primary hyperparathyroidism and pheochromocytoma in a Chinese lady with neurofibromatosis type 1

“…Apart from the frequently found neurofibromas and optic pathway gliomas, patients with NF-1 are at increased risk of various benign and malignant tumours throughout life, including central nervous system tumours, peripheral nerve sheath tumours, gastrointestinal stromal tumours and leukaemia ( 1 , 9 ). Endocrine diseases and neoplasia also occur in patients with NF-1 which may include PPGLs, PHPT, gastroenteropancreatic neuroendocrine tumour, thyroid and other adrenal tumours ( 1 , 2 , 5 , 11 , 12 ).…”