Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

A novel GRK2 variant in a patient with Jeune asphyxiating thoracic dysplasia accompanied by Morgagni hernia.

Skeletal ciliopathies constitute a subgroup of ciliopathies characterized by various skeletal anomalies arising from mutations in genes impacting cilia, ciliogenesis, intraflagellar transport process, or various signaling pathways. Short-rib thoracic dysplasias, previously known as Jeune asphyxiating thoracic dysplasia (ATD), stand out as the most prevalent and prototypical form of skeletal ciliopathies, often associated with semilethality. Recently, pathogenic variants in GRK2, a subfamily of mammalian G protein-coupled receptor kinases, have been identified as one of the underlying causes of Jeune ATD. In this study, we report a new patient with Jeune ATD, in whom exome sequencing revealed a novel homozygous GRK2 variant, and we review the clinical features and radiographic findings. In addition, our findings introduce Morgagni hernia and an organoaxial-type rotation anomaly of the stomach and midgut malrotation for the first time in the context of this recently characterized GRK2-related skeletal ciliopathy.

Mexican patient with Ellis-van Creveld syndrome and cleft palate: Importance of functional hemizygosity and phenotype expansion.

BACKGROUND: Ellis-van Creveld syndrome (EvCS) is a chondroectodermal dysplasia caused by germline pathogenic variants in ciliary complex subunit 1 and 2 genes (EVC, EVC2) on chromosome 4p16.2. This disease has a broad phenotype, and there are few described phenotype-genotype correlations. METHODS: Ethical Compliance: Written informed consent was obtained from the parents. Here, we report a genetically confirmed Mexican patient with EvCS having two inherited pathogenic variants in trans in EVC2: c.[1195C>T];[2161delC]. RESULTS: This patient allowed a genotypic-phenotypic comparison with another Mexican subject who presented a more attenuated phenotype; furthermore, our patient also presented cleft palate, a rarely reported feature. CONCLUSION: Our case shows the importance of comparing functional hemizygosity between patient's phenotypes when they share a variant, and our case also supports the association of alterations in the palate as part of the EvCS phenotype.

Síndrome de Ellis Van Creveld: caso clínico / Ellis Van Creveld syndrome: case report

El Síndrome de Ellis Van Creveld es poco frecuente, hereditario de carácter autosómico recesivo no habiendo predilección por sexo. Se caracteriza por acortamiento acromesomélico, polidactilia postaxial bilateral de manos, condrodisplasia de huesos largos y displasia ectodérmica de uñas y dientes. El conocimiento de la misma es imperativo para un diagnóstico temprano y manejo multidisciplinario oportuno que permita una mejor calidad de vida de estos pacientes.

The Ellis Van Creveld syndrome is rare, hereditary autosomal recessive, without no sex predilection. It is characterized by short-limbed dwarfism, bilateral postaxial hand polydactyl, chondrodysplasia of long bones and ectodermic dysplasia affecting fingernails and teeth. The knowledge of it is essential for early diagnosis and appropriate multidisciplinary management that allows a better quality of life for these patients.

Type 1 diabetes in a patient with Ellis-van Creveld syndrome / Diabetes tipo 1 em um paciente com a síndrome de Ellis-van Creveld

CONTEXT: Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disease characterized by disproportionate short stature, narrow thorax, postaxial polydactyly, nail and tooth abnormalities and congenital heart disease. CASE REPORT: The patient was a 22-year-old Caucasian man, the third child of consanguineous parents. He received the diagnosis of insulin-dependent diabetes mellitus (DM) at 16 years of age, and around one year later, he underwent surgery to correct a partial atrioventricular septal defect. Upon physical examination, at 22 years of age, he presented stature of 145.5 cm (P3), weight of 49 kg (P3), head circumference of 54 cm (P2-50), high palate, absence of one of the lower lateral incisor teeth, narrow shoulders, narrowing of the upper thorax, scoliosis, rhizomelic shortening of the upper limbs, brachydactyly, postaxial polydactyly and clinodactyly of the second and third fingers. The lower limbs showed rhizomelic shortening with significant genu valgum (knock-knee deformity), small feet with postaxial polydactyly, syndactyly between the second and third toes and hallux valgus. Multiple melanocytic nevi were evident on the face, thorax and limbs. At that time, he was using neutral protamine Hagedorn (NPH) insulin, with poorly controlled DM. The clinical findings presented led to the diagnosis of EVC syndrome. Only one case of this syndrome has been described with DM so far. Attention is drawn to the fact that the genes associated with this syndrome are located close to those of the Wolfram syndrome, a condition that leads to early-onset diabetes.

CONTEXTO: A síndrome de Ellis-van Creveld (EVC) é uma doença autossômica recessiva rara, caracterizada por baixa estatura desproporcionada, tórax estreito, polidactilia pós-axial, anormalidades em unhas e dentes e cardiopatia congênita. RELATO DO CASO: O paciente é um rapaz caucasiano de 22 anos, o terceiro filho de pais consanguíneos. Recebeu diagnóstico de diabetes melito (DM) insulino-dependente aos 16 anos, sendo que, cerca de um ano depois, foi submetido a cirurgia cardíaca de correção de defeito de septo atrioventricular parcial. Ao exame físico, aos 22 anos, ele apresentava estatura de 145,5 cm (P3), peso de 49 kg (P3), perímetro cefálico de 54 cm (P2-50), palato alto, ausência de um dos dentes incisivos inferiores laterais, ombros estreitos, estreitamento do tórax superior, escoliose, encurtamento rizomélico dos membros superiores, braquidactilia, polidactilia pós-axial e clinodactilia dos segundo e terceiro dedos. Nos membros inferiores, observava-se encurtamento rizomélico com importante geno valgo (deformidade dos joelhos-batidos), pés pequenos com polidactlia pós-axial, sindactilia entre segundo e terceiro dedos, e háluces valgos. Múltiplos nevos melanocíticos eram evidentes na face, tórax e membros. Neste momento ele está em uso de insulina NPH (neutral protamine Hagedorn), com um controle inadequado do DM. Seus achados clínicos levaram ao diagnóstico de síndrome de EVC. Apenas um caso desta síndrome foi descrito com DM até o momento, sendo que chama a atenção o fato de que os genes associados à síndrome se localizam próximo ao da síndrome de Wolfram, uma condição que cursa com diabetes de início precoce.

Ellis-van Creveld syndrome: early prenatal diagnosis with ultrasound

Com base nos dados da literatura mundial, apresentamos o segundo diagnóstico pré-natal da síndrome de Ellis-van Creveld. O diagnóstico foi realizado com base no encurtamento de todos os ossos longos, edema de couro cabeludo e dados anatomopatológicos. Estabeleceu-se diagnóstico apenas com dados ultra-sonográficos, uma vez que näo se efetua fetoscopia no Brasil