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The Nosology of genetic skeletal disorders has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.

Context Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of β-catenin via AXIN stabilization, acting as a negative regulator of the WNT/β-catenin signaling pathway, a central pathway in bone formation. Objective In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1. Results Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1 , coding for β-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the β-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the β-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn β-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn β-catenin. Conclusion In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra‐rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14‐year‐old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C‐terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders. [ABSTRACT FROM AUTHOR]

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadically occurring neurocutaneous disorder characterized by ocular anomalies, mainly choristomas; by skin lesions consisting of hairless fatty tissue nevi (nevus psiloliparus), focal dermal hypoplasia, alopecia, and periocular skin tags; and by CNS anomalies, including intracranial and spinal lipomas and often mental retardation and seizures. Here, we report on three boys with ECCL with typical abnormalities of the eyes, skin and brain and, in addition, coarctation of the aorta. All three children developed multiple cystic bone lesions, which progressively spread throughout the skeleton in Patient 1 and was shown histologically to be non-ossifying fibromas in Patient 2. We hypothesize that ECCL may be caused by mosaicism for a mutated gene involved in benign mesenchymal tumors and in vasculogenesis.

Several authors mentioned the occurrence of articulation problems in the neurofibromatosis type 1 (NF1) population. However, few studies have undertaken a detailed analysis of the articulation skills of NF1 patients, especially in schoolchildren and adults. Therefore, the aim of the present study was to examine in depth the articulation skills of NF1 schoolchildren and adults, both phonetically and phonologically. Speech samples were collected from 43 Flemish NF1 patients (14 children and 29 adults), ranging in age between 7 and 53 years, using a standardized speech test in which all Flemish single speech sounds and most clusters occur in all their permissible syllable positions. Analyses concentrated on consonants only and included a phonetic inventory, a phonetic, and a phonological analysis. It was shown that phonetic inventories were incomplete in 16.28% (7/43) of participants, in which totally correct realizations of the sibilants /[esh]/ and/or /[ezh]/ were missing. Phonetic analysis revealed that distortions were the predominant phonetic error type. Sigmatismus stridens, multiple ad- or interdentality, and, in children, rhotacismus non vibrans were frequently observed. From a phonological perspective, the most common error types were substitution and syllable structure errors. Particularly, devoicing, cluster simplification, and, in children, deletion of the final consonant of words were perceived. Further, it was demonstrated that significantly more men than women presented with an incomplete phonetic inventory, and that girls tended to display more articulation errors than boys. Additionally, children exhibited significantly more articulation errors than adults, suggesting that although the articulation skills of NF1 patients evolve positively with age, articulation problems do not resolve completely from childhood to adulthood. As such, the articulation errors made by NF1 adults may be regarded as "residual" articulation disorders. It can be concluded that the speech of NF1 patients is characterized by mild articulation disorders at an age where this is no longer expected. Learning outcomes: Readers will be able to describe neurofibromatosis type 1 (NF1) and explain the articulation errors displayed by schoolchildren and adults with this genetic syndrome. (Contains 3 figures and 10 tables.)

Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant neurocutaneous disorder with an estimated prevalence of two to three cases per 10 000 population. While the physical characteristics have been well documented, speech disorders have not been fully characterized in NF1 patients. Aims: This study serves as a pilot to identify key issues in the speech of NF1 patients. In particular, the aim is to explore further the occurrence and nature of problems associated with speech as perceived by the patients themselves. Methods & Procedures: A questionnaire was sent to 149 patients with NF1 registered at the Department of Genetics, Ghent University Hospital. The questionnaire inquired about articulation, hearing, breathing, voice, resonance and fluency. Sixty individuals ranging in age from 4.5 to 61.3 years returned completed questionnaires and these served as the database for the study. The results of this sample survey were compared with data of the normal population. Outcomes & Results: About two-thirds of participants experienced at least one speech or speech-related problem of any type. Compared with the normal population, the NF1 group indicated more articulation difficulties, hearing impairment, abnormalities in loudness, and stuttering. Conclusion: The results indicate that speech difficulties are an area of interest in the NF1 population. Further research to elucidate these findings is needed. (Contains 5 tables.)