Multiple linear papules in a 68‐year‐old man

A 68-year-old man of Russian descent presented with multiple asymptomatic papules on the trunk and both upper arms which had been present for several years. The patient's medical history included a stroke, hearing loss and bilateral cataracts. His medication consisted of aspirin, metamizole and gabapentin. Family history revealed no similar skin manifestations. A daughter had died from endometrial carcinoma at the age of 38, while the remaining three children and grandchildren were healthy. There was no familial predisposition for malignant neoplasms and no consanguinity of the parents. Clinical examination and dermoscopy revealed multiple skin-colored, elongated papules bilaterally on the thorax, abdomen and both upper arms, oriented along the skin tension lines (Figure 1). The head, lower extremities and mucous membranes appeared uninvolved. Two punch biopsies taken from the right flank showed nodular spindle cell proliferations in the dermis (Figure 2a). Immunohistochemistry revealed S100-positive tumor cells (Figure 2b) with demarcation of the stroma by CD34 (not shown). The differential blood count, liver and kidney function parameters, TSH, fT3, fT4, PTH, calcitonin and thyroglobulin were unremarkable. Catecholamines and metanephrines in the urine were within normal limits. A CT scan of the thorax and abdomen revealed a misshapen left adrenal gland with a small hypodense lesion. Thyroid ultrasonography, gastroscopy, colonoscopy and ophthalmological examination were unremarkable. Brain and neck MRI showed mild chronic subdural hematoma, spinal canal stenosis at level C5/6/7 and mild disc herniation at level C5/6. Your diagnosis? … Diagnosis: Multiple cutaneous linear neuromas as an incomplete manifestation of multiple endocrine neoplasia type 2 (MEN2) syndrome Next generation sequencing of DNA extracted from EDTA blood revealed the pathogenic variant c.2410G>A in the receptor tyrosine kinase (RET) gene, leading to substitution of valine by methionine at codon 804 (p.Val804Met), which is typically detected in MEN2A syndrome. Imaging studies gave no evidence of medullary thyroid carcinoma (MTC) or pheochromocytoma. The lesion on the left adrenal gland was evaluated as adenoma. The patient was thoroughly informed about MEN2 and associated neoplasias. Follow-up examinations including assessment of calcitonin, thyroid and abdominal ultrasound every 6 months and annual CT scans were recommended. Genetic testing of the first-degree relatives was advocated, but not desired by the family. MEN2 is an autosomal dominant disorder driven by variants in the RET proto-oncogene, manifesting primarily in two subtypes: MEN2A and MEN2B.1, 2 Classical MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary hyperparathyroidism. Variants include familial medullary thyroid carcinoma (FMTC), MEN2A with cutaneous lichen amyloidosus (CLA) and MEN2A with Hirschsprung's disease.1-3 MEN2B is distinguished by earlier onset of MTC, higher prevalence of pheochromocytoma, oral mucosal neuromas, marfanoid habitus and intestinal ganglioneuromatosis.1-3 There is a strong genotype-phenotype association between specific RET variants and clinical features, including age-specific risk of MTC and other endocrine neoplasias.3-5 Therefore, pathogenic variant-dependent management is recommenend.3, 4 The variant p.Val804Met (c.2410G>A) detected in our patient is the most common variant in MEN2A and associated with a moderate risk for MTC and low risks for pheochromocytoma and hyperparathyroidism.3, 5 It is noted for its highly variable penetrance, with some patients remaining asymptomatic or presenting with unusual features such as CLA.3, 4 Interestingly, at the age of 68, our patient had not developed any endocrine tumors nor exhibited other cutaneous or mucosal manifestations typical of MEN2A or MEN2B. The existence of multiple cutaneous linear neuromas, though rare, has been previously reported in patients with MEN2 and RET variants.6-10 Alegria-Landa et al. described eleven family members with MEN2A and RET p.Val804Met variants, two of which had dermal hyperneury with a very similar aspect as the neuromas seen in our patient, and micro-MTC.6 Baykal et al. reported on a 45-year-old woman with multiple cutaneous linear neuromas, CLA and MTC and a RET p.Glu768Asp variant in exon 13 and discussed either MEN2B with uncommon cutaneous features or an overlap of MEN2A and MEN2B.7 Multiple cutaneous linear neuromas were also described in patients without other features of MEN2 and without pathogenic RET variants,8, 9 and, in publications dating back longer, in patients in whom mutation analysis was not performed but an association with MEN2 considered.10, 11 Our case highlights the importance of thorough tumor screening and genetic testing in patients with multiple cutaneous linear neuromas, as they may be the first manifestation of MEN2. For carriers of the RET c.2410G>A variant, the American Thyroid Association guidelines recommend annual measurement of serum calcitonin and thyroid ultrasound from the age of 6, prophylactic thyroidectomy upon rise of calcitonin, and screening for pheochromocytoma and hyperparathyroidism from 16 years of age.4 None.