Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, EVC and EVC2, showing that several cases were misdiagnosed and were, in fact, other entities. Nevertheless, there has not been any adequate phenotypic characterization of molecularly defined EVC syndrome so far.

We performed a systematic review of case reports of EVC syndrome with molecular confirmation of pathogenic variants in EVC or EVC2. Demographic, genetic, and clinical information of patients was assessed.

We reviewed 725 papers and obtained 54 case reports/series that met the inclusion criteria, with a total subject sample of 310. Of these, 190 had biallelic variants, whereas 28 were affected heterozygotes. Our analysis revealed new phenotypes that have not been classically linked to the syndrome and others that have been linked but are very rare. Monoallelic symptomatic forms had less expressivity, and biallelic cases were milder if associated with EVC and/or missense variants. Finally, we identified CRMP1, a gene whose coding region partially overlaps with EVC, as a potential genetic modifier of the severity of the EVC syndrome.

We provided the first objective clinical characterization of molecularly defined EVC syndrome and identified the first associated genetic modifier, CRMP1, which had not been implicated in human disease before.

Ellis-van Creveld (EvC) syndrome is an autosomal recessive disease, characterized by ectodermal, skeletal, and cardiac anomalies. We report intrafamilial phenotypic variability in three new EvC syndrome cases. Affected males in this study showed only ectodermal abnormalities, whereas an affected female showed the classical presentation of EvC Syndrome, including bilateral postaxial polydactyly of hands and feet, and congenital heart defects. Whole exome sequencing was performed to identify the causative variant, followed by validation and segregation analysis using Sanger sequencing. A homozygous deletion variant (c.731_757del) was identified in exon 6 of the EVC gene (NM_153717.2). The identified variant is considered to be the most likely candidate variant for the EvC syndrome in the family based on previous reports validating the role of EVC variants in the EvC syndrome. The disease correctly segregated in the family members, as all affected members were homozygous, and obligate carriers were heterozygous. Our family is remarkable in highlighting the variable expressivity of the EvC phenotype within the same family, due to a homozygous deletion mutation in the EVC gene. The variable expressivity might be due to the hypomorphic nature of mutation, or the presence of additional variants in modifier genes or in the regulatory regions of the EVC/EVC2 genes.

Osteochondrodysplasias are the result of the expression of gene mutations. The phenotypes in osteochondrodysplasias evolve through life, with the possibility that previously unaffected bones may be involved at later stages of growth. Due to the variable time of onset, the diagnosis may be made prenatally, at birth, or later. Certainty in the diagnosis is sometimes only achieved as the patient matures and the disease evolves. Radiographic evaluation is a fundamental part of the diagnostic work-up of congenital skeletal disorders and in most cases the first tool used to arrive at a diagnosis. This review describes the imaging characteristics, specific signs, and evolution of several skeletal dysplasias in which diagnosis may be directly or indirectly suggested by radiologic findings. A definitive accurate diagnosis of a congenital skeletal abnormality is necessary to help provide a prognosis of expected outcomes and to counsel parents and patients.

Ellis-van Creveld (EVC) syndrome is a relatively rare chondroectodermal dysplasia considered mainly as a generalised disorder of the maturation of endochondral ossification. Congenital heart disease occurs in approximately half of the patients with EVC syndrome, 60% of which is a common atrium. Common atrium is a rare variety of interatrial communication characterised by absence or virtual absence of the atrial septum. Patients with this syndrome rarely survive to an old age. We report a case of EVC who presented for the first time at 60 years of age, as survival to an advanced age is exceptional in case of EVC.

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316-7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc^-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.

To evaluate clinical outcome of patients with Ellis-van Creveld syndrome (EVC) in whom congenital heart disease (CHD) repair was delayed intentionally to reduce the risk of postoperative respiratory morbidity and mortality.

This retrospective review of 51 EVC c.1886+5G>T homozygotes born between 2005 and 2014 focused on 18 subjects who underwent surgery for CHD, subdivided into early (mean, 1.3 months) vs delayed (mean, 50.1 months) repair.

Growth trajectories differed between control subjects and patients with EVC, and CHD was associated with slower weight gain. Relative to controls, infants with EVC had a 40%-75% higher respiratory rates (independent of CHD) accompanied by signs of compensated respiratory acidosis. Blood gases and respiratory rates approached normal values by age 4 years. Hemodynamically significant CHD was present in 23 children, 18 (78%) of whom underwent surgical repair. Surgery was performed at 1.3 ± 1.3 months for children born between 2005 and 2009 (n = 9) and 50.1 ± 40.2 months (P = .009) for children born between 2010 and 2014 (n = 9). The latter had shorter postoperative mechanical ventilation (1.1 ± 2.4 days vs 49.6 ± 57.1 days; P = .075), shorter intensive care duration of stay (16 ± 24 days vs 48.6 ± 44.2 days; P = .155), and no postoperative tracheostomies (vs 60%; P = .028) or deaths (vs 44%; P = .082).

Among children with EVC and possibly other short-rib thoracic dysplasias, delayed surgical repair of CHD reduces postoperative morbidity and improves survival. Respiratory rate serves as a simple indicator for optimal timing of surgical repair.

Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation disorder. Cardiac defects are observed in about 50% of EvC cases. Surgical data is lacking on the prognosis and life expectancy of EvC patients. Herein, we report the case of a 38-year-old man with EvC syndrome who underwent two surgical corrections for cardiac anomalies. This report supplements the available information on the clinical course of EvC syndrome in older patients.

The objective of this case series was to determine the oral, dental and craniofacial features of patients with EvC syndrome.

Eight patients with EvC syndrome were enrolled. A complete family history, pedigree analysis, detailed medical history were collected. Findings of clinical examination, including craniofacial and orodental manifestations, and radiological investigations were thoroughly studied.

All eight patients had characteristic face, hypertrophic frenulum, conical and peg-shaped teeth, hypodontia of deciduous and/or permanent teeth and also skeletal dysplasia, small chest, short stature and hypoplastic nails. Additionally dysmorphic filtrum, serrated appearance of gingiva, diastema, enamel hypoplasia, microdontia, taurodontism, single rooted permanent molar, delayed eruption and high caries rate were observed with varying degrees. Cephalometric evaluation revealed skeletal Class III growth pattern in four subjects and Class II growth pattern in one subject.

Evaluation of craniofacial and orodental anomalies of EvC syndrome is required for accurate differential diagnosis from other congenital syndromes.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. Acromelic shortening of upper and lower limbs, genu valgum, multiple frenula, deformed teeth, short ribs and narrow thorax and congenital heart diseases complete the picture. The patients with the syndrome rarely survive into adulthood. Here, we report a lady with EVC presenting for the first time in middle age.