IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences.

By describing 10 new patients recruited in centres for Human Genetics, we further delineate the clinical spectrum of a Crouzon-like craniosynostosis disorder, officially termed craniosynostosis and dental anomalies (MIM614188). Singularly, it is inherited according to an autosomal recessive mode of inheritance. We identified six missense mutations in IL11RA, a gene encoding the alpha subunit of interleukin 11 receptor, 4 of them being novel, including 2 in the Ig-like C2-type domain. A subset of patients had an associated connective tissue disorder with joint hypermobility and intervertebral discs fragility. A smaller number of teeth anomalies than that previously reported in the two large series of patients evaluated in dental institutes points toward an ascertainment bias.

Audiological phenotyping evaluation in KBG syndrome: Description of a multicenter review.

OBJECTIVES: Our objective was to reinforce clinical knowledge of hearing impairment in KBG syndrome. KBG syndrome is a rare genetic disorder due to monoallelic pathogenic variations of ANKRD11.The typical phenotype includes facial dysmorphism, costal and spinal malformation and developmental delay. Hearing loss in KBG patients has been reported for many years, but no study has evaluated audiological phenotyping from a clinical and an anatomical point of view. METHODS: This French multicenter study included 32 KBG patients with retrospective collection of data on audiological features, ear imaging and genetic investigations. RESULTS: We identified a typical audiological profil in KBG syndrome: conductive (71%), bilateral (81%), mild to moderate (84%) and stable (69%) hearing loss, with some audiological heterogeneity. Among patients with an abnormality on CT imaging (55%), ossicular chain impairment (67%), fixation of the stapes footplate (33%) and inner-ear malformations (33%) were the most common abnormalities. CONCLUSION: We recommend a complete audiological and radiological evaluation and an ENT-follow up in all patients presenting with KBG Syndrome. Imaging evaluation is necessary to determine the nature of lesions in the middle and inner ear.

Unequal Impact of COL1A1 and COL1A2 Variants on Dentinogenesis Imperfecta.

Dentinogenesis imperfecta (DI) is the main orodental manifestation of osteogenesis imperfecta (OI) caused by COL1A1 or COL1A2 heterozygous pathogenic variants. Its prevalence varies according to the studied population. Here, we report the molecular analysis of 81 patients with OI followed at reference centers in Brazil and France presenting COL1A1 or COL1A2 variants. Patients were submitted to clinical and radiographic dental examinations to diagnose the presence of DI. In addition, a systematic literature search and a descriptive statistical analysis were performed to investigate OI/DI phenotype-genotype correlation in a worldwide sample. In our cohort, 50 patients had COL1A1 pathogenic variants, and 31 patients had COL1A2 variants. A total of 25 novel variants were identified. Overall, data from a total of 906 individuals with OI were assessed. Results show that DI was more frequent in severe and moderate OI cases. DI prevalence was also more often associated with COL1A2 (67.6%) than with COL1A1 variants (45.4%) because COL1A2 variants mainly lead to qualitative defects that predispose to DI more than quantitative defects. For the first time, 4 DI hotspots were identified. In addition, we showed that 1) glycine substitution by branched and charged amino acids in the α2(I) chain and 2) substitutions occurring in major ligand binding regions-MLRB2 in α1(I) and MLBR 3 in α2(I)-could significantly predict DI (P < 0.05). The accumulated variant data analysis in this study provides a further basis for increasing our comprehension to better predict the occurrence and severity of DI and appropriate OI patient management.

Gnathodiaphyseal dysplasia with a novel R597I mutation of ANO5: Mandibular reconstruction strategies.

Gnathodiaphyseal Dysplasia (GDD) is a rare, often misdiagnosed, autosomal-dominant disorder due to point mutations in the ANO5 gene. GDD combines craniofacial fibro-osseous lesions, dental loss and progressive curvature and cortical thickening of long bones and vertebra, causing pathological fractures. Diagnosis is based on bone pathology and mutation screening. Here we report three GDD cases within a single family with a novel ANO5 mutation: c.1790 G > T (p.Arg597Ile, i.e. R597I) on exon 16. Microsurgical mandibular reconstructions were performed in the three cases. We reviewed the literature on jaw reconstruction in this condition and discussed the challenges of craniofacial reconstruction in GDD due to the diffuse bone anomalies affecting potential flap donor zones and a specific risk for jawbone osteomyelitis.