AMOTL1-Associated Multiple Congenital Anomalies (Craniofaciocardiohepatic Syndrome, CFCHS): A Novel Clinical Spectrum Including Craniofacial, Heart and Liver Abnormalities.

We identified an AMOTL1 variant in a patient that adds evidence supporting the clinical and molecular overlap between AMOTL1-related disorders and other syndromes affecting craniofacial, cardiac, and hepatic development. As more cases are identified, we propose naming this entity as AMOTL1-associated multiple congenital anomalies or craniofaciocardiohepatic syndrome (CFCHS).

Variants in both the N- or C-terminal domains of IHH lead to defective secretion causing short stature and skeletal defects.

Background: Heterozygous Indian Hedgehog gene (IHH) variants are associated with brachydactyly type A1 (BDA1). However, in recent years, numerous variants have been identified in patients with short stature and more variable forms of brachydactyly. Many are located in the C-terminal domain of IHH (IHH-C), which lacks signaling activity but is critical for auto-cleavage and activation of the N-terminal (IHH-N) peptide.

ERN BOND: The key European network leveraging diagnosis, research, and treatment for rare bone conditions.

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise.

Unexpected findings in cervical spine in spondylometaphyseal dysplasia Sutcliff type FN1-related.

The autosomal dominant spondylometaphyseal dysplasia Sutcliff type or corner fracture type FN1-related is characterized by a combination of metaphyseal irregularities simulating fractures ("corner fractures"), developmental coxa vara, and vertebral changes. It is linked to heterozygous mutations in FN1 and COL2A1. Vertebral changes as delayed vertebral ossification, ovoid vertebral bodies, anterior vertebral wedging, and platyspondyly have been observed in this condition, while odontoid abnormalities have not been reported.

Two new patients with acromesomelic dysplasia, PRKG2 type-identification and characterization of the first missense variant.

Acromesomelic dysplasia, PRKG2 type (AMDP, MIM 619636), is an extremely rare autosomal recessive skeletal dysplasia characterized by severe disproportionate short stature presenting with acromesomelia, mild metaphyseal widening of the long bones and mild spondylar dysplasia. To date, only four variants have been reported; one nonsense, one splice-site, and two frameshifts in five AMDP families. Here, we report the first missense variant and a second splice-site variant in PRKG2 in two patients with clinical and radiological features of acromesomelic dysplasia.

New pathogenic variant in : New clues for a clinical spectrum from split-hand-foot malformation to fibular aplasia, tibial campomelia and oligosyndactyly.

FATCO (Fibular Aplasia, Tibial Campomelia and Oligosyndactyly) is a very infrequent skeletal dysplasia classified within the limb hypoplasia-reduction defects group whose genetic cause has not yet been identified. The advent of next-generation sequencing is enabling the diagnosis of diseases with no previously known genetic cause. We performed a thorough autopsy on a fetus whose pregnancy was legally terminated due to severe malformations detected by ultrasound.

Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study.

Background: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults.

Methods: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study.

Case report: A third variant in the 5' UTR of creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of . Although the majority of variants localize in the coding region of the gene, two variants in the 5' UTR have been recently reported to generate novel upstream initiation codons. Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies.

Clinical and Genetic Analysis of Multiple Osteochondromas in A Cohort of Argentine Patients.

Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, and In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes. Of these, a total of 40% ( = 14) had a family history of MO.

Achondroplasia: Update on diagnosis, follow-up and treatment.

Achondroplasia requieres multidisciplinary follow-up, with the aim of preventing and managing complications, improving the quality of life of people who suffer from it and favoring their independence and social inclusion. This review is justified by the multiple publications generated in recent years that have carried out a change in its management. Different guidelines and recommendations have been developed, among which the one made by the American Academy of Pediatrics in 2005 recently updated (2020), the Japanese guide (2020), the first European Consensus (2021) and the International Consensus on the diagnosis, approach multidisciplinary approach and management of individuals with achondroplasia throughout life (2021).

Novel FGF9 variant contributes to multiple synostoses syndrome 3.

Multiple synostoses syndromes (SYNS) are autosomal dominant syndromes characterized by multiple joint fusions commonly involving the carpal-tarsal, interphalangeal, humeroradial, and cervical spine joints. They display genetic heterogeneity with pathogenic variants reported in four separate genes (NOG, GDF5, FGF9, and GDF6) defining four different SYNS forms. FGF9 variants have been reported in SYNS3, a SYNS with multiple synostoses, normal cognition, normal hearing, and craniosynostosis.

Vitamin D-Dependent Rickets Type 1A in Two Siblings with a Hypomorphic Variant Frequent in the African Population.

Vitamin D-dependent type 1A rickets (VDDR-1A) is a rare autosomal recessive disease due to the inability to convert 25-hydroxyvitamin D [25(OH)D] to the active form 1.25-dihydroxyvitamin D [1.25(OH) D] by the enzyme 25(OH)D-1α-hydroxylase leading to low or low-normal serum levels of [1.

Early clinical and radiological improvement in a young boy with metaphyseal anadysplasia type 2.

Metaphyseal anadysplasia is a very rare hereditary skeletal dysplasia with onset occurring normally during the second and third years of life, but unlike many other dysplasias, symptoms appear to resolve by adolescence. Two types exist, the more severe form, type 1, with both autosomal dominant and recessive inheritance due to pathogenic variants in MMP13, whilst type 2, an even rarer form is due to biallelic MMP9 variants. To date, only two metaphyseal anadysplasia type 2 families have been reported.

Prenatal Diagnosis of Acromelic Frontonasal Dysostosis.

Acromelic frontonasal dysostosis (AFND; MIM #603671) is a rare autosomal dominant genetic disorder caused by a heterozygous mutation in the () gene located at chromosome 5q12.1. It is phenotypically characterized by frontonasal malformation with hypertelorism, telecanthus, nasal clefting or bifid nasal tip, wide fontanels and sutures, brachycephaly, and cleft palate.

Description of four patients with TRIP11 variants expand the clinical spectrum of odontochondroplasia (ODCD) and demonstrate the existence of common variants.

More than two decades since the first clinical and radiological description of odontochondroplasia (ODCD) was reported, biallelic loss of function variants in the Thyroid hormone receptor interactor 11 gene (TRIP11) were identified, the same gene implicated in the lethal disorder achondrogenesis (ACG1A). Here we report the clinical and radiological follow-up of four ODCD patients, including two siblings and an adult who interestingly has the mildest form observed to date. Four TRIP11 variants were detected, two previously unreported.

Delineation of the clinical and radiological features of Stuve-Wiedemann syndrome childhood survivors, four new cases and review of the literature.

Stuve-Wiedemann syndrome (SWS; MIM 601559) is a rare autosomal recessive disease caused by mutations in the leukemia inhibitor factor receptor gene (LIFR). Common clinical and radiological findings are often observed, and high neonatal mortality occurs due to respiratory distress and hyperthermic episodes. Despite initially considered as a lethal disorder during the newborn period, in recent years, several SWS childhood survivors have been reported.