To date, there are very few reports regarding patients with bi-allelic variants in the NIN gene. There is one report of two sisters with severe short stature, microcephaly, and developmental delay with compound heterozygote missense variants in the NIN gene and one paper reporting a homozygote variant in the NIN gene with progressive, high-frequency sensorineural hearing loss in four siblings. The only other report is of four members of a consanguineous family with spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) with a homozygous variant in the NIN gene. Given the scarcity of cases with NIN variants, the relationship between the phenotype and gene is provisional and our case broadens the phenotypic spectrum regarding the phenotype related to NIN gene variants. Here, we report a patient with a homozygous variant in exon 2 of the NIN gene defined as c.3407_3409del (p.Glu1136del). Clinical findings in our patient were characteristic of microcephalic primordial dwarfism (MPD) including microcephaly, prominent nose, intellectual disability and severe short stature. In addition, this patient had bilateral hearing loss, which was not reported in the patients with MPD and variant in the NIN gene before. We identified a novel p.Glu1136del variant in the NIN gene, predicted to disrupt critical centrosome-related pathways. WES was reanalyzed for other genes which are known for deafness and no variant was identified. A family history of deafness was not present in the pedigree. This is the first report of a patient with MPD and deafness associated with the NIN gene.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.