Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study.

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85-90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.

Identification of kinesin family member (KIF22) homozygous variants in spondyloepimetaphyseal dysplasia with joint laxity, lepdodactylic type and demonstration of proteoglycan biosynthesis impairment.

Heterozygous variants in KIF22, encoding a kinesin-like protein, are responsible for spondyloepimetaphyseal dysplasia with joint laxity, leptodactilic type (lepto-SEMDJL), characterized by short stature, flat face, generalized joint laxity with multiple dislocations, and progressive scoliosis and limb deformity. By targeted gene sequencing analysis, we identified a homozygous KIF22 variant (NM_007317.3: c.

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes.

Introduction: Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.

Methods: The training set contained 1,592 ear photographs, corresponding to 550 patients.

European Achondroplasia Forum guiding principles for the detection and management of foramen magnum stenosis.

Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death.

Real-world evidence in achondroplasia: considerations for a standardized data set.

Background: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes.

Methods: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives.

Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.

Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge.

Bone allografting: an original method for biological osteosynthesis and bone reinforcement in children with osteogenesis imperfecta.

Purpose: Osteogenesis imperfecta (OI) is a genetic disorder responsible for various symptoms including deformities and frequent fractures. Bone allografting is poorly documented in this condition. The objective of this study was to describe our experience and assessments in a consecutive series of OI patients.

Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients.

Background: Achondroplasia is the most frequent FGFR3-related chondrodysplasia, leading to rhizomelic dwarfism, craniofacial anomalies, stenosis of the foramen magnum, and sleep apnea. Craniofacial growth and its correlation with obstructive sleep apnea syndrome has not been assessed in achondroplasia. In this study, we provide a multimodal analysis of craniofacial growth and anatomo-functional correlations between craniofacial features and the severity of obstructive sleep apnea syndrome.

Parents' Experience of Administering Vosoritide: A Daily Injectable for Children with Achondroplasia.

Introduction: Vosoritide is the first approved pharmacological treatment for achondroplasia and is indicated for at-home injectable administration by a trained caregiver. This research aimed to explore parents' and children's experience of initiating vosoritide and administering this treatment at home.

Methods: Qualitative telephone interviews were conducted with parents of children being treated with vosoritide in France and Germany.

Clinical heterogeneity of NADSYN1-associated VCRL syndrome.

The NADSYN1 gene [MIM*608285] encodes the NAD synthetase 1 enzyme involved in the final step of NAD biosynthesis, crucial for cell metabolism and organ embryogenesis. Perturbating the role of NAD biosynthesis results in the association of vertebral, cardiac, renal, and limb anomalies (VCRL). This condition was initially characterized as severe with perinatal lethality or developmental delay and complex malformations in alive cases.

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging.

The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study.

Purpose: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues.

Methods: Individuals aged ≤65 years with classical FOP (ACVR1 variant) were assessed at baseline and over 36 months.

Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study.

Purpose: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.

Methods: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.

Results: A total of 363 children were enrolled (28 centers, 8 countries).

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of Gene and Literature Review.

Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the gene. The skeletal disorder is often associated with chronic kidney disease.

Ellis-Van Creveld Syndrome: Clinical and Molecular Analysis of 50 Individuals.

Background: Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The and genes are the major genes causative of EVC syndrome.