Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive skeletal dysplasia caused by mutations in the DYM gene. It is characterized by progressive spondyloepimetaphyseal dysplasia, short stature, coarse facial features, microcephaly and intellectual disability. While it clinically resembles Morquio syndrome (mucopolysaccharidosis type IV, MPS IV), DMC is distinguished by cognitive impairment, absence of corneal clouding, normal urinary glycosaminoglycans and distinctive radiological features. We reported three siblings with DMC syndrome. Two 4-year-old monozygotic male twins, born to consanguineous parents, presented with growth retardation and developmental delay. Radiographs showed generalized platyspondyly, rhizomelic shortening and metaphyseal dysplasia, while biochemical tests excluded MPS IV. Molecular tests revealed a homozygous deletion in exon 16 of the DYM gene. The third sibling, with Down syndrome, also exhibited similar skeletal features and carried the same DYM deletion. The clinical and radiological features of our patients were consistent with DMC syndrome, with partial overlap with MPS IV. This case series represents the first reported coexistence of DMC and Down syndrome. In addition, we identified a novel homozygous deletion in exon 16 of the DYM gene, which broadens the known mutational spectrum. This finding also highlights the importance of comprehensive genetic testing when standard sequencing results are inconclusive. The presence of neurological findings, such as seizures, further supports the need for combined genetic and neurological evaluation in these patients.

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.

Biallelic variants in PISD cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. PISD encodes the mitochondrial-localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self-cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17-year-old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous PISD variants c.569C>T; p.(Ser190Leu) and c.799C>T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2-deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in Escherichia coli suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel PISD p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient.

Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis. Therefore, we performed panel sequencing of 386 bone-related genes in 7 highly consanguineous families from Pakistan and 27 cases from India affected with SKDs. In the highly consanguineous families, we were able to identify the underlying genetic cause in five out of seven families, resulting in a diagnostic yield of 71%. Whereas, in the sporadic and familial SKD cases, we identified 12 causative variants, corresponding to a diagnostic yield of 44%. The genetic heterogeneity in our cohorts was very high and we were able to detect various types of variants, including missense, nonsense, and frameshift variants, across multiple genes known to cause different types of SKDs. In conclusion, panel sequencing proved to be a highly effective way to decipher the genetic basis of SKDs in highly consanguineous families as well as sporadic and or familial cases from South Asia. Furthermore, our findings expand the allelic spectrum of skeletal dysplasias.

Dyggve-Melchior-Clausen (DMC) disease is a rare autosomal recessive disorder primarily characterized by spondylo-epimetaphyseal dysplasia, intellectual disability, and distinctive facial features. Patients typically present with severe developmental delays and cognitive impairments, defining features of the syndrome. This case report examines a 13-year-old Moroccan child diagnosed with DMC disease, presenting classical skeletal abnormalities, including spondylo-epimetaphyseal dysplasia, as confirmed through exome sequencing. Notably, the child exhibited a mutation recurrently identified in the Moroccan population. However, the patient showed no signs of developmental delay or intellectual disability, a marked deviation from the traditionally described phenotype. This finding suggests a broader clinical variability associated with DMC disease, emphasizing the importance of individualized assessments. This atypical presentation expands the phenotypic spectrum of DMC disease, challenging its conventional diagnostic criteria. Further research is required to elucidate the factors influencing phenotypic variability in DMC and to explore potential genotype-phenotype correlations. Early identification and documentation of such atypical cases are critical for refining diagnostic and management strategies for rare disorders. The purpose of this GeneReview is to: 1.. Describe the clinical characteristics of type II collagen disorders; 2.. Provide an evaluation strategy to identify the genetic cause of a type II collagen disorder in a proband; 3.. Review the differential diagnosis of type II collagen disorders with a focus on genetic conditions; 4.. Review management of type II collagen disorders; 5.. Inform genetic counseling of family members of an individual with a type II collagen disorder.