A Rare Form of Microcephalic Primordial Dwarfism due to NSMCE2 Deficiency (Seckel Syndrome Type 10): A Report of Macular Involvement.
TL;DR
An 11-year-old male with compound heterozygous NSMCE2 variants and a phenotype consistent with MPD exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency, which may broaden the phenotypic spectrum associated with NSMCE2-related MPD.
Abstract
Biallelic variants in NSMCE2 (MMS21), which encodes the SUMO E3 ligase subunit of the SMC5/6 chromatin-maintenance complex, have recently been implicated in microcephalic primordial dwarfism (MPD), corresponding to Seckel syndrome type 10 (OMIM #617246). The SMC5/6 complex plays essential roles in genome stability, DNA repair, and replication-fork recovery. To date, only two individuals with NSMCE2-related MPD have been reported. Here, we describe an 11-year-old male with compound heterozygous NSMCE2 variants (c.346del; c.697_700dupAGGG) and a phenotype consistent with MPD, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. This finding may broaden the phenotypic spectrum associated with NSMCE2-related MPD and highlights the importance of considering NSMCE2 in the genetic evaluation of individuals with severe primordial dwarfism presenting with atypical or unexplained retinal findings.