NEK9 – Nevus Comedonicus Syndrome

NEK9 has been implicated in nevus comedonicus syndrome, a rare mosaic disorder characterized by distinctive skin lesions accompanied by ocular anomalies such as developmental cataract (HP:0000519). Clinical investigations have revealed that mosaic mutations in NEK9 underpin the complex phenotype observed in affected patients, thereby enhancing diagnostic accuracy and guiding patient management.

A detailed case report described a 23‑month‑old boy presenting with congenital pulmonary airway malformation, congenital cataract, and vascular anomalies including an aneurysm. Genetic testing identified the NEK9 c.1755_1757del (p.Thr586del) mutation in affected nevus tissue (PMID:31961058), providing convincing evidence of tissue‑specific mosaicism.

A systematic review further corroborated the association by identifying 43 well‐established cases of nevus comedonicus syndrome, in which a gain‑of‑function, mosaic postzygotic mutation in NEK9 was consistently observed (PMID:33481271). The review outlined various morphological subtypes of the syndrome, emphasizing the recurrent presence of ocular abnormalities such as congenital cataract.

The genetic evidence is strong: the recurrent detection of the NEK9 c.1755_1757del (p.Thr586del) mutation, along with its observation in independent probands and affected tissues, supports its pathogenic role in nevus comedonicus syndrome. Inheritance in this condition follows a mosaic pattern, where the mutation arises postzygotically, leading to segmental distribution of the clinical phenotype.

Experimental findings, although limited in scope, provide moderate functional evidence by demonstrating the mutation’s gain‑of‑function effect. These functional insights align with the clinical observation of diverse phenotypes including ocular, pulmonary, and vascular anomalies, contributing to the overall pathogenic narrative.

In summary, the robust genetic and phenotypic evidence supports a strong gene‑disease association between NEK9 and nevus comedonicus syndrome. This connection not only facilitates targeted genetic testing and refined diagnostic criteria but also holds promise for future therapeutic strategies. Key take‑home: Recognition of NEK9 mosaic mutations is critical for accurate diagnosis and management of nevus comedonicus syndrome.

References

• American journal of medical genetics. Part A • 2020 • Further delineation of the phenotypic spectrum of nevus comedonicus syndrome to include congenital pulmonary airway malformation of the lung and aneurysm PMID:31961058
• Pediatric dermatology • 2021 • Nevus comedonicus syndrome: A systematic review of the literature PMID:33481271

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