Uncharacterized MYH9 Germline Mutations in a Microcystic Adnexal Carcinoma Mimicker: Benign Deep Syringoid Ductal Proliferation (BDSDP) with Elastic Fiber Aggregation

ImportanceMicrocystic adnexal carcinoma (MAC) is a rare, locally aggressive sweat gland neoplasm sometimes misdiagnosed due to its histologic similarities to benign adnexal proliferations. MYH9-associated elastin aggregation syndrome (MALTA) is an inherited condition characterized by benign MAC-like ductal lesions and by abnormal elastic fiber deposition. ObjectiveTo report previously uncharacterized heterozygous germline mutations in the MYH9 gene in a patient presenting benign deep syringoid ductal proliferations and papillary dermal elastic fiber aggregation. Design, Setting, ParticipantsClinical report with genetic and structural analysis. Dermatology outpatient. A male in their 20s presenting with long-standing, stable erythematous nodules on the right infraorbital region and left zygomatic arch. Genetic testing of first-degree relatives and structural simulations were performed to assess variant impact. Main Outcomes and MeasuresHistological evaluation of the patients lesions revealed benign deep syringoid ductal proliferations with papillary dermal elastic fiber aggregation, distinguishing them from microcystic adnexal carcinoma. Germline genetic testing identified three heterozygous MYH9 variants, two previously uncharacterized, all showing Mendelian segregation in first-degree relatives and associated with structural rearrangement. ResultsHistologic evaluation of the facial lesions revealed keratin-filled microcysts and deep dermal and subcutaneous cords with ductal structures resembling MAC. Immunohistochemistry showed apocrine differentiation (EMA+/CD15+/GCDP+) and basaloid myoepithelial cells positive for p63. No evidence of perineural invasion was observed. Elastic tissue staining showed dense, ball-like aggregates of elastic fibers in the papillary dermis. Germline testing identified c.1363G>A (p.Gly455Ser) in the myosin head domain, and c.4490G>A (p.Arg1497Gln) and c.4876A>G (p.Ile1626Val) in the tail domain of Myosin-9. Saliva-based testing confirmed Mendelian segregation in multiple first-degree relatives. Missense mutations were predicted to alter the coiled-coil structure, potentially disrupting chain interactions and affecting the motifs parallel versus antiparallel orientation. Conclusions and RelevanceThis case broadens the phenotypic and genotypic spectrum of MALTA syndrome and introduces the diagnostic term: benign deep syringoid ductal proliferation (BDSDP) with elastic fiber aggregation. The findings underscore the diagnostic challenges in distinguishing BDSDP from MAC and highlight the critical role of integrating histopathologic, immunohistochemical, and genetic data in accurate diagnosis. These results support the need for further investigation into MYH9-associated adnexal neoplasia and its underlying molecular mechanisms. Key PointsO_ST_ABSQuestionC_ST_ABSHow do germline MYH9 variants contribute to the pathogenesis of benign deep syringoid ductal proliferations with elastic fiber aggregation, a phenotype that clinically and histologically mimics microcystic adnexal carcinoma? FindingsGenetic analysis revealed two previously unreported heterozygous variants in the MYH9 gene: c.1363G>A (p.Gly455Ser), located in the myosin head domain, a region previously associated with MALTA syndrome, and a variant in the myosin tail domain, c.4490G>A (p.Arg1497Gln). A third mutation, c.4876A>G (p.Ile1626Val), was also detected. All three variants demonstrated Mendelian segregation from the parents, were identified in multiple family members, and were predicted to cause structural perturbations. MeaningThese findings provide strong evidence for a heritable contribution of these mutations to the observed phenotype. The presence of these MYH9 variants highlights a potential functional impact on protein structure and activity. This pattern supports the hypothesis that MYH9 mutations may underlie or modify the pathogenesis of benign syringoid ductal proliferations, expanding the known spectrum of MYH9-associated conditions and offering a molecular basis for improved diagnosis and familial risk assessment.