Skeletal ciliopathies are a group of rare genetic disorders characterized by overlapping clinical features and a heterogeneous molecular etiology, posing diagnostic challenges in pediatric populations. This study aimed to assess the clinical, radiographic, and molecular features of patients with skeletal ciliopathies and to explore oxidative stress in this group. A total of 20 patients with suspected skeletal ciliopathy were enrolled, with evaluation of their clinical and radiographic features alongside whole exome sequencing to elucidate the molecular etiology. Oxidative stress parameters were measured and compared with those of a healthy control group. A molecular diagnosis was established in 16 of 20 patients (80%). Based on clinical and molecular data, six patients were diagnosed with Ellis-van Creveld syndrome, six with Oral-Facial-Digital syndrome, five with short-rib thoracic dysplasia, one with Meckel-Gruber syndrome, one with cranioectodermal dysplasia, and one with an undefined skeletal ciliopathy. The most frequently detected variants were in EVC, followed by DYNC2H1. Among the identified variants, nine novel variants were described. Among oxidative stress markers, nitrite/nitrate levels were significantly higher in ciliopathy patients, whereas malondialdehyde levels were higher in controls; no significant differences were observed in the other markers. This study broadens the clinical and genetic landscape of skeletal ciliopathies and highlights the value of genetic testing. In our study, we highlighted the presence of overlapping phenotypes among skeletal ciliopathy disorders and identified causal variants in genes previously associated with distinct ciliopathy phenotypes. By comparing the observed phenotypic severity with patients reported in the literature, we aimed to contribute to a better understanding of genotype-phenotype correlations. Additionally, we sought to draw attention to the clinical and radiographic features of skeletal ciliopathies, which are part of the spectrum of skeletal dysplasias encountered in pediatric practice. We also examined oxidative stress markers in patients with skeletal ciliopathies, providing preliminary evidence of alterations.

Cranioectodermal dysplasia (CED) is a ciliopathy characterized by skeletal and ectodermal abnormalities, renal failure, and liver fibrosis. Pathogenic variants in genes that encode the intraflagellar transport (IFT) complex components, particularly IFT-A, are responsible for approximately two-thirds of the CED cases. However, the cause of the remaining cases remains unknown. Ciliogenesis-associated kinase 1 (CILK1) is a highly conserved ciliary serine/threonine kinase with an N-terminal catalytic domain responsible for kinase activity and a C-terminal non-catalytic domain that interacts with the IFT-B complex. Biallelic variants in the catalytic domain are associated with lethal skeletal dysplasia, endocrine cerebroosteodysplasia, and short-rib polydactyly syndrome. No human disease has been linked to biallelic variants in the non-catalytic domain. We present a homozygous frameshift variant in the CILK1 gene that affects the distal part of the non-catalytic domain, causing CED in five patients from two pedigrees. All the patients survived into childhood and had disproportionately short stature, skeletal abnormalities, ectodermal dysplasia, renal issues, and liver complications. Functional data from patient-derived cells and the C. elegans model indicate that the variant reduces cilia number, increases cilia length, and disrupts the localization of IFT components. In contrast, the ciliary localization of CILK1 bearing the variant itself remains unaffected. Notably, we rescued the majority of these abnormalities by reintroducing CILK1 into patient-derived cells. Finally, our study describes CILK1 as a novel causal gene and the first non-IFT protein-encoding gene in the etiology of CED, thus expanding the known genotypic, mechanistic, and phenotypic spectrum of CED.

Sensenbrenner syndrome, or cranioectodermal dysplasia (CED), is a rare autosomal recessive ciliopathy characterized by craniofacial, skeletal, ectodermal, and renal abnormalities. Ocular involvement, though infrequent, can include retinal dystrophy with early-onset visual impairment. We report a case of a 2-year-old boy with classic clinical features of CED and significant ocular findings. Genetic testing revealed two novel compound heterozygous variants in the WDR19 gene-c.1778G>T and c.3536T>G-expanding the known mutational spectrum associated with this condition. Ophthalmologic evaluation demonstrated bilateral optic nerve hypoplasia, high hyperopia, and severely reduced ERG responses, consistent with global retinal dysfunction. Fundoscopy revealed optic disk pallor, vessel attenuation, and peripheral pigment changes. Multisystem findings included postaxial polydactyly, brachydactyly, short stature, hypotonia, and stage 2 chronic kidney disease. This case highlights the importance of early ophthalmologic screening in suspected CED and underscores the utility of ERG in detecting early retinal involvement. The identification of two previously undescribed WDR19 variants contributes to genotype-phenotype correlation in CED and emphasizes the need for ongoing documentation to guide diagnosis, management, and genetic counseling.

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive ciliopathy with significant involvement of the skeleton, ectoderm, retina, kidneys, liver, lungs, and occasionally the brain. Cranioectodermal dysplasia-2 (CED2) is caused by homozygous or compound heterozygous mutation in the WD repeat-containing protein 35 (WDR35). However, the current understanding of the CED2 prenatal phenotype is limited. Here, we describe the fetus at 12 + 4 weeks gestation from a Chinese family with healthy parents. The fetus presented with lymphedema, omphalocele, hydrops fetalis, abnormal posturing, hypoplasia of the ulna, hypoplasia of the radius, femoral bowing, short femur, ductus venosus agenesis, ventricular septal defect, and atrial septal defect. To our knowledge, apart from lymphedema and hydrop fetalis, no other phenotypes of the fetus described in this study have been reported in the CED2 prenatal phenotype. Compound heterozygous variants (c.3155-1G>A and c.215-8T>G) in the WDR35 were identified via trio-based exome sequencing and confirmed pathogenicity through mRNA splicing analysis in vivo. Collectively, we clarified the genetic diagnosis for the fetus with multiple ultrasound abnormalities, which is helpful for genetic counseling and early prenatal diagnosis. Meanwhile, a definitive genetic diagnosis could aid in assessing the risk of recurrence during reproduction and support further pre-implantation or prenatal diagnoses for the family. Additionally, the novel c.3155-1G>A variant expands the spectrum of WDR35 variants. The presence of omphaloceles, abnormal posturing, hypoplasia of the ulna, hypoplasia of the radius, femoral bowing, short femur, ductus venosus agenesis, ventricular septal defect, and atrial septal defect in fetus with WDR35 variants may expand the prenatal phenotypic spectrum of CED2.

Cranioectodermal dysplasia (CED) is a rare ciliopathy that causes mortality through its impact on liver and kidney dysfunction. To date, there has only been a single report of a successful kidney-liver transplant in a pediatric patient with CED. We present a pediatric patient who received a sequential liver-kidney transplant due to progressive organ dysfunction caused by CED. At the age of 7, the patient underwent a liver transplant, followed sequentially by a kidney transplant 5 years later. We provide a 3-year follow-up to the kidney transplantation. The liver transplant was complicated by a portal vein stricture causing portal hypertension, which required revision. The patient had no complications from the kidney transplant despite comorbidities related to the CED diagnosis, such as thrombocytopenia. We discuss the viability of the sequential liver-kidney transplant for patients with CED and suggest that physicians consider this sequence if their patients with CED present with corresponding sequential organ failure.