Endocrine Abstracts (2019) 64 031 | DOI: 10.1530/endoabs.64.031

A novel pathogenic mutation in neurofibromatosis type 1

Fischler Rebecca, Vandernoot Isabelle, Lucidi Valerio, Corvilain Bernard & Driessens Natacha



Introduction: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic dominant syndrom in men with a prevalence of 1 in 2600 to 3000 individuals worldwide. NIH NF1 diagnostic criteria are driven by the most frequent manifestations of the disease (café au lait macules (CAL), neurofibromas, freckling, optic glioma, Lisch nodules and osseus lesions). There are many clinical manifestations of NF1 (neurological, cardiovascular, gastrointestinal, endocrine and orthopedic features). Phechromocytoma is one of them, occurring in approximately 0.7% of cases.

The protein encoded by NF1 gene, neurofibromin, is a RAS GTPase-activating protein. NF1 belongs to the group of RASopathies which are syndromes predisposing to benign and malignant tumors. There are more than 1400 indentified mutations of NF1 gene of which 50% are singular mutation. NF1 is sporadic in approximately 50% of the cases. The penetrance is complete but there is a lack of genotype-phenotype correlation, except in some cases, probably because of the existence of modifier genes.

Case report: We report the case of a 23-year-old men who complained for recent discomfort characterized by paroxysmal headache, palpitations with unusual fatigue, epistaxis and severe hypertension. He didn’t take any medication or drug. He had no medical history except the removal of an unsightly frontal skin lesion. Clinical examination showed CAL spots and a lesion suspected of neurofibroma on the right forearm. Repeated 24-hours urine fractionated metanephrines and catecholamines measurements showed elevation of catecholamines and (nor)metanephrines level between 7- and 10-fold the upper limit of reference range. Abdominal CT revealed a voluminous mass of 50×30 mm with a high density (+40 HU without contrast) in the left adrenal gland. After adequate preparation, patient underwent left adrenalectomy and excision of the forearm lesion. Histopathology confirmed the suspected diagnosis of pheochromocytoma and neurofibromatosis. A genetic testing to search a NF1 mutation has been performed and revealed an heterozigoty for the variant c.5791T>A(p.TRP1931Arg). No other genetic variant was identified with cDNA sequencing and MLPA. This variant had previously been reported in a adult man with CAL spots and freckling but without neurofibromas. In the LOVD database this variant is reported as a variant of unknown clinical significance. We decided to perform segragation analysis within his family in ordrer to reveal wether this variant is present in the unaffected parents. Target mutation analysis showed the absence of the tested NF1 variant in both parents of the patient, revealing a de novo event in the patient and a new deleterious effect of the NF1 variant c.5791T>A(p.TRP1931Arg).

Conclusion: We report a novel pathogenic mutation responsible for pheochromocytoma.

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