Haploinsufficiency resulting from the degradation of mutant Collagen Type X Alpha 1 Chain (COL10A1) mRNA by nonsense-mediated decay (NMD) has been attributed to the pathogenesis of Schmid-type metaphyseal chondrodysplasia (SMCD) in cases involving nonsense mutations. However, this mechanism does not fully explain the complexity of SMCD. In this study, we identified a c.1951_1952 InsT (p.W651 fsX666) mutation in exon 3 of COL10A1 that is associated with chondrodysplasia phenotypes in a two-generation family with SMCD. The mRNA decay of the mutant COL10A1 (named as affected E666X-COL10A1) is caused by the p.W651fsX666 mutation, which also disrupts the trimerization of normal collagen X. However, the mutant mRNA decay of affected exogenous E666X-COL10A1, as well as the complete degradation of E666X-COL10A1 mRNA in the proband, is not significantly induced by the W651fsX666 mutation. In vitro trimerization analyses results indicate that the trimerization of normal collagen X and wild-type collagen X are disrupted by W651fsX666 and E666X-collagen X mutations, respectively, suggesting that the mutant allele collagen X may impose a dominant-negative effect on the normal collagen X. Our results are the first to reveal that the impaired trimerization of normal collagen X is caused by the W651fsX666 mutation and a dominant-negative effect on the normal allele collagen X exerted by the mutant allele collagen X, causing impaired trimerization of collagen X, which will interpret the phenotype variability among the affected individuals in the pedigree with metaphyseal chondrodysplasia type Schmid (MCDS) studied.

Metaphyseal chondrodysplasia type Schmid (MCDS), a rare skeletal disorder caused by COL10A1 mutations, exhibits significant phenotypic heterogeneity, yet genotype-phenotype correlations remain poorly defined. We aim to determine the clinical and radiographic manifestation, mutational features, and genotype-phenotype relationships by characterization of 4 patients with MCDS and literature review. The four patients presented with short stature or waddling gait, flattened vertebrae, and irregular femoral epiphyses. We identified two novel COL10A1 variants (c.1925 T > A, c.1903C > G) and reported the first case harboring both a de novo nonsense (c.2001 T > G, p.Tyr667Ter) in the non-collagenous 1 (NC1) domain and a missense (c.1438A > T, p.Ile480Leu) in the helix domain. Genotype-phenotype analysis of 124 cases previously reported and 4 new cases revealed that NC1 domain mutations were associated with an earlier onset of MCDS than non-NC1 mutations (median 12 vs. 72 months, P = 0.0014). Patients carrying a missense mutation in COL10A1 showed significantly lower height Z-scores (- 3.62 ± 1.95 vs. - 1.99 ± 1.28, P = 0.013) at first and more metaphyseal irregularities in the distal radius/ulna than those with truncating mutations (P = 0.019). Structural modeling indicated that NC1 mutations may disrupt collagen X structure via electrostatic alterations or steric clashes. These findings expand the mutational spectrum of MCDS and establish that COL10A1 genotype correlates with severity of MCDS, which will help to identify patients with severe phenotypes through molecular testing and to develop effective treatment strategies for MCDS.

Osteochondrodysplasias are a heterogeneous group of abnormalities in bone and cartilage development. Metaphyseal chondroplasia Schmid type is the most frequent within its subgroup, however it has a low incidence when compared to skeletal disorders that appear in childhood, which limits its diagnostic suspicion due to the limited knowledge about this pathology. It is caused by a variant of the COL10A1 gene, which alters endochondral ossification. It is characterized by short limbs with genu varum or valgus, in addition to increasingly shorter stature with age. This case is related to a female patient of 4 years old, who presented adequate anthropometric development until the age of one year old and exhibits currently pathological proportionate short stature with an evident varum deformity. Sequence and deletion/duplication analysis was performed by a skeletal disorders panel, n which a variant in the COL 10A1 gene is reported, which together with the phenotypic and radiological findings, confirms the diagnosis. The confusion arises from the fact of considering that all bowlegs are due to rickets or the categorization of these children as idiopathic genu varum. It is important to know the osteochondrodysplasias to be able to make an adequate diagnostic suspicion in a patient with these characteristics, which are not explained under another pathology. The importance of an early diagnosis lies in the implementation of a multidisciplinary treatment, to avoid limitations in mobility and chronic pain in the patient. In addition to the family genetic screening due to its genetic dominance, facilitating genetic counseling if the biological couple is in reproductive age.

Malformations of cortical development (MCDs) are a diverse group of disorders that result from abnormal neuronal migration, proliferation, and differentiation during brain development. Head computed tomography (CT) has limited use in the diagnosis of MCDs and should be reserved for selected cases with specific indications or when magnetic resonance imaging is not available or contraindicated. CT can detect brain calcifications associated with MCDs, thus helping in the differential diagnosis between acquired and genetic MCDs or in the identification of different genetic patterns. Moreover, CT can provide high-resolution images of the skull and bones, thus identifying associated malformations, such as craniosynostosis, inner and middle ear malformations, and vertebral anomalies. In this chapter, we review the CT scan technique, data analysis, and indications in the investigation of MCDs.