Cranioectodermal Dysplasia (Sensenbrenner Syndrome)

Autosomal recessive skeletal ciliopathy of intraflagellar transport, with sagittal craniosynostosis, ectodermal dysplasia, narrow thorax, rhizomelic limb shortening, nephronophthisis, fibrocystic liver disease and retinal dystrophy; it includes types CED1 to CED4 and the forms due to IFT140, IFT52 and CILK1, and belongs to the allelic family of the short-rib thoracic dysplasias.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and place among the skeletal ciliopathies

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder in which a defect of protein transport within the primary cilium produces, in the same patient, a skeletal dysplasia with narrow thorax and short limbs, a craniosynostosis that in most cases involves the sagittal suture, an ectodermal dysplasia (teeth, hair, nails and skin) and a multiorgan disease that mainly affects the kidney, liver and retina [1, 19]. The primary cilium is a sensory organelle present in almost all cells that coordinates developmental signalling pathways such as Sonic hedgehog (SHH) and Wnt; its dysfunction explains the association of retinal degeneration, cystic kidney disease, hepatic fibrosis, polydactyly and skeletal dysplasias that defines the ciliopathy group [49]. Within this group, CED belongs to the skeletal ciliopathies, together with the short-rib thoracic dysplasias (SRTD, formerly Jeune asphyxiating thoracic dystrophy), the short-rib polydactyly syndromes (SRPS), Ellis-van Creveld syndrome (EVC), Mainzer-Saldino syndrome and Weyers acrofacial dysostosis [2, 50]. The feature that distinguishes it from most other ciliopathies is sagittal craniosynostosis, to which the ectodermal defects are added [1, 19].

1.2. Founding descriptions

In 1975, Sensenbrenner, Dorst and Owens described a brother and sister with dolichocephaly and a tendency to premature closure of the sagittal suture, downslanting palpebral fissures with epicanthus, full cheeks, everted lower lip, multiple oral frenula, microdontia with probable enamel defect, low-set, posteriorly rotated ears, short thorax with pectus excavatum, abnormal hair growth and structure, and disproportionate shortening of the fibulae and of the middle and distal phalanges; a paternal aunt had had a stillborn male infant with dwarfism and some of the same features [51]. In 1977, Levin and colleagues, from McKusick’s group at Johns Hopkins, reported five children with dolichocephaly (sagittal synostosis in three), sparse, fine, slow-growing hair, epicanthic folds, hypodontia or microdontia, short arm span, brachydactyly, narrow thorax and normal intelligence, proposed autosomal recessive inheritance and coined the name cranioectodermal dysplasia [1, 52]. Of the five patients published in the original descriptions, three died before 7 years of age, one from cardiac failure, one from interstitial pneumonia and one from an unknown cause [3, 8].

The following two decades extended the phenotype beyond the skeleton and ectoderm. In 1996, Eke, Woodruff and Young described the association of retinal dystrophy and tubulointerstitial nephropathy in CED, presented as a new oculorenal syndrome [53]. In 1997, Savill and colleagues, in Nottingham, reported two sibling pairs with chronic kidney failure due to tubulointerstitial nephropathy and noted that kidney disease was present in 4 of the 7 cases published at that time [54]. In the same year, Amar and colleagues reviewed all known cases in connection with a 27-month-old North American girl and added pre- and postnatal growth retardation, psychomotor delay, microcephaly and photophobia to the phenotype [55]. In 2006, Zaffanello and colleagues, in Rome, showed in a 4-year-old child congenital hepatic fibrosis due to ductal plate malformation associated with nephropathy, and included CED among the hepatorenal fibrocystic diseases [56]. In 2009, Konstantinidou and colleagues described two fetuses and a child from the same family, with microcystic kidneys and persistent ductal plate, and proposed that CED was a ciliopathy [57]; in the same issue of the journal, Fry and colleagues documented connective tissue involvement, with cutis laxa, hernias and joint laxity [58].

1.3. Milestones of molecular discovery

Confirmation that CED is a ciliopathy came in 2010, when Walczak-Sztulpa and colleagues identified, by homozygosity mapping in a consanguineous family (logarithm of the odds, LOD, score of 3.57 at 3q21-q24), biallelic IFT122 variants in patients from three families, and demonstrated a reduction in the frequency and length of primary cilia in fibroblasts [59]. In the same year, Gilissen and colleagues found compound heterozygous WDR35 variants by exome sequencing of two unrelated sporadic patients, in one of the first examples of identification of a Mendelian gene from the exome of a single patient [60]. In 2011 came IFT43 (then C14orf179), described in two siblings from a consanguineous Moroccan family with a variant in the initiation codon [61], and WDR19 (IFT144), found in a Norwegian family with Sensenbrenner syndrome, a Dutch family with Jeune syndrome and a Moroccan family with isolated nephronophthisis, which showed that these three disorders share the same molecular basis [62]. In 2013, Lin and colleagues reviewed 39 patients, found pathogenic variants in 14 of 25 patients tested (56%) and proposed clinical criteria [19]. Of the 14 patients with a molecular diagnosis gathered in that review, six had variants in WDR35, four in IFT122, two in WDR19 and two in IFT43 [8]. IFT52 was associated in 2016 with a child with CED and SRTD overlap [46], and IFT140 in 2017 and 2020 with patients with a CED phenotype [20, 63]. In 2025, Sezer and colleagues described the first CED gene that does not encode an intraflagellar transport protein, CILK1, in five patients from two Turkish families [5].

1.4. Nomenclature and reclassifications

OMIM numbers the types in the order in which the genes were associated: CED1 (IFT122, 218330, 3q21.3-q22.1), CED2 (WDR35, 613610, 2p24.1), CED3 (IFT43, 614099, 14q24.3), CED4 (WDR19, 614378, 4p14) and, since 2025, CED5 (IFT140, 621180, 16p13.3) and CED6 (CILK1, 621337, 6p12.1) [1, 8]. CED3 retains the provisional phenotype–gene relationship sign, because the entry rests on a single family, the Moroccan siblings of 2011 [10]. The CED1 entry also records the synonym Levin syndrome I, and SRTD16 due to IFT52 (617102) is listed as one of the SRTDs, with phenotypic overlap with CED, without a CED number [8, 12]. In its 2023 revision, the Nosology of Genetic Skeletal Disorders abandoned numbering in favour of phenotype–gene dyads; CED appears as “cranioectodermal dysplasia (Levin-Sensenbrenner)” linked to IFT122, WDR35, WDR19, IFT140 and IFT43 (entries 10–0440 to 10–0480 of group 10), whereas IFT52 appears only as SRTD and CILK1, described later, only as endocrine-cerebro-osteodysplasia (ECO) [2]. The same revision acknowledges that the absence of clear genotype–phenotype correlations makes it difficult to separate chondroectodermal dysplasia, SRTD, SRPS and the neighbouring entities [2]. Orphanet groups all forms under ORPHA:1515, including OMIM entry 617102 (SRTD16 due to IFT52) [15, 16].

The reference sources contain numbering errors that are worth knowing. The heterogeneity table of the bone dysplasia atlas assigns CED2 to a truncated designation instead of WDR35, places WDR35 at 2q24.1 instead of 2p24.1, gives CED3 the number 610099 instead of 614099 and presents as the SRTD16 phenotype the number 617094, which is that of the IFT52 gene [1, 3]. The OMIM entries confirm 2p24.1 for WDR35, 614099 for CED3 and 617094 as the number of the IFT52 gene, with 617102 for the phenotype [9, 10, 12]. The 2023 Nosology table writes “IFT40” instead of IFT140 and gives CED due to IFT43 the number 614009, which differs from the 614099 in GeneReviews and OMIM [1, 2]. A gene curation database associates CED1 with ORPHA:93268 (Beemer-Langer syndrome) and with the ICD-10 code Q77.2 and ICD-11 code LD24.B0 of that entity, whereas the official CED entity is ORPHA:1515, with ICD-10 Q87.5 [16, 17]. GeneReviews authorship also differs between databases: the current version is signed by Tan, Lin and Keppler-Noreuil, whereas the same curation database attributes it to Lin, Traum and Sahai, first authors of the 2013 series of 39 patients [1, 17, 19]. OMIM itself has occasional typographical errors: the IFT43 gene entry attributes the SRTD18 variants to “IFT143”, the SRTD9 entry writes “IFT40” in relation to a patient with Jeune syndrome, and the IFT52 gene entry reproduces from an article the location 20q12.13, which the curation itself corrects to 20q13.12 [43, 47, 64]. More important for interpretation is the status of entry 269860: designated SRTD12 and with the synonyms SRPS type IV, Beemer-Langer syndrome and Beemer-type short-rib syndrome, it is a phenotype entry without a confirmed molecular basis, which does not list IFT122 as a gene; some patients with a clinical diagnosis of Beemer-Langer syndrome have IFT80 variants (SRTD2, 611263; AR, 3q25.33; four fetuses from two families in Bizaoui 2019), and NEK1 and DYNC2H1 variants were excluded in seven patients with SRPS type IV [33, 65]. The link of 269860 to the SRPS and SRTD forms due to IFT122 is therefore an attribution of the 2023 Nosology and not of OMIM [2, 33]. Retinitis pigmentosa 81 due to IFT43, supported by a single family, and spermatogenic failure 72 due to WDR19, supported by a single patient, also have a provisional phenotype–gene relationship in OMIM [35, 45].

1.5. Entities within scope

This article treats CED as a class: the six types numbered in OMIM (CED1–CED4, CED5 due to IFT140 and CED6 due to CILK1, the latter described in 2025) and the IFT52 form included in GeneReviews [1, 5, 8]. Because the same genes cause other disorders, the SRTDs and SRPSs due to IFT-A complex genes, Beemer-Langer syndrome due to IFT122, the EVC form due to WDR35, Mainzer-Saldino syndrome due to IFT140 and WDR19, nephronophthisis 13 and Senior-Løken syndrome 8 due to WDR19, the isolated retinopathies and the autosomal dominant polycystic kidney disease of IFT140 carriers are also described, as allelic disorders and differential diagnoses [1, 2, 32]. Nephronophthisis as a kidney disease (isolated forms, management of chronic kidney disease, dialysis and transplantation) provides the framework; only what is specific to CED is described here.

2. Molecular Genetics and Pathophysiology

2.1. The primary cilium and intraflagellar transport

The primary cilium is a microtubule-based organelle present in almost all cells that functions as a signalling centre, a kind of cellular antenna [1, 49]. Because it does not synthesise proteins, it depends on a bidirectional transport system along the axoneme, intraflagellar transport (IFT): anterograde transport, from the base to the tip, is carried out by the IFT-B complex with the heterotrimeric kinesin-2 motor, and retrograde transport, from the tip to the base, by the IFT-A complex with the cytoplasmic dynein-2 motor [1]. The IFT-A complex is a hexamer formed by IFT122 (formerly WDR10), IFT121 (encoded by WDR35), IFT144 (encoded by WDR19), IFT43 (formerly C14orf179), IFT140 and IFT139 (encoded by TTC21B) [1]. In addition to retrograde transport, IFT-A participates in the entry of proteins into the cilium and in transport associated with the ciliary membrane, whereas IFT-B ensures anterograde transport [5]. IFT122 occupies a central position in the IFT-A complex, linking the core to the peripheral subcomplexes [37]. In transfected human cells, IFT-A is organised into a trimeric core (IFT122, IFT140 and IFT144), to which IFT122 binds through its C-terminal region with TPR repeats, and a peripheral subcomplex (IFT43, IFT121 and IFT139), to which it binds through its N-terminal region with WD40 repeats [39]. According to the work of Takahara and colleagues (2018) summarised in OMIM, the CED1 IFT122 missense variants weaken binding to the peripheral subcomplex and compromise assembly of the whole IFT-A; knockout of IFT122 abolishes cilia, whereas knockout of WDR35 (IFT121) leaves cilia with a trafficking defect, and IFT122 constructs carrying CED1 variants restore cilium formation without correcting the localisation of several ciliary proteins [39]. This result is consistent with the hypomorphic nature of CED variants and with a predominant trafficking defect.

2.2. Molecular, cellular and tissue mechanism

The mechanism of the pathogenic variants is loss of function [1]. When IFT-A is altered, the cilia of patient fibroblasts have bulbous tips in which IFT-B proteins accumulate, a sign that transport back to the base has failed; in the IFT43 study, anterograde transport was preserved and the defect was selective for retrograde transport, with an identical finding in fibroblasts from a patient with WDR35 variants [1, 61]. Ciliary shortening was demonstrated in fibroblasts with IFT122 variants [59], but was not constant in other series [1, 62]; in the WDR19 study, the IFT144 protein was absent from cilia and ciliary abundance and morphology were disturbed [62]. In complementation assays in cells lacking IFT144, the missense variant NM_025132.4:c.2129T>C p.(Leu710Ser) corrected the defect of ciliogenesis and ciliary protein localisation, the truncated form c.3307C>T p.(Arg1103Ter) worsened it, and co-expression of the two, which reproduces the genotype of the Norwegian siblings, produced a severe defect, but less severe than that of the truncated form alone [45]. More recent data suggest that CED variants mainly disturb ciliary protein trafficking and to a lesser extent cilium formation [5]. The tissue consequence is dysregulation of the cilium-dependent developmental signalling cascades, in particular the hedgehog pathway and G protein-coupled receptor signalling, with abnormal accumulation of signalling proteins in the cilium [1, 37]. This disturbance explains the simultaneous involvement of the growth plate (short bones, short ribs, brachydactyly), the cranial suture, the ectodermal appendages, the renal tubules (nephronophthisis), the bile ducts (ductal plate malformation) and the photoreceptors, whose outer segment is a modified cilium [49, 56].

Cilium length differs according to the gene. In CED due to WDR35, IFT43 or WDR19, fibroblast cilia are short (about 2.2–2.9 µm), whereas in CED due to CILK1 they are elongated (about 4.6 µm), similar to those of SRTD due to WDR19 or DYNC2H1; the authors interpret defective retrograde transport as a common mechanism, despite the opposite direction of the change in length [5]. Motile cilia may also be involved: in a child with WDR35 variants, nasal biopsy showed immotile or dyskinetic cilia and reduced nasal nitric oxide, without variants in 30 primary ciliary dyskinesia genes, and WDR35 knockdown in human respiratory epithelium altered motile cilium formation [66]. IFT52 encodes a core protein of the IFT-B complex, and its deficiency destabilises IFT-B (reduction of IFT74, IFT81, IFT88 and ARL13B) and interferes with centriole cohesion [15, 67, 68]. In zebrafish lacking ift52, embryos have ventral body curvature, kidney cysts, absence of cilia in multiciliated organs and lower expression of hedgehog pathway target genes [47]. CILK1 encodes a ciliogenesis-associated serine/threonine kinase; in patient cells, the distal frameshift variant reduces the number of cilia, lengthens them and alters the localisation of IFT components, while the ciliary localisation of the kinase itself is maintained [5]. The CILK1 ECO variants lie in the kinase domain and reduce (p.Arg272Gln, with about one third of basal autophosphorylation) or abolish (p.Glu80Lys) catalytic activity; in fibroblasts from the newborn with p.Glu80Lys, cilia were thin, long and twisted and GLI3 processing was altered, and mice homozygous for p.Arg272Gln die shortly after birth from respiratory failure, with reduced lung branching, structural spinal defects and abnormal chondrocyte maturation [48].

2.3. Genetic architecture and diagnostic yield

GeneReviews recognises six genes, all with autosomal recessive inheritance, and their proportion in a set of 71 patients recorded in the HGMD (Human Gene Mutation Database) variant database is as follows: WDR35 23 (32%), IFT122 13 (18%), WDR19 5 (7%), IFT140 3 (4%), IFT43 2 (3%), IFT52 1 (1%) and no gene identified 24 (34%) [1]. These figures are proportions of published patients, subject to publication bias, and other sources give different values: IFT122 and WDR35 would account for about 60% of families according to a 2020 Polish series [20] and about 70% according to a 2022 report [69], and WDR35 for about 45% of cases according to a 2026 review [18]. IFT genes, mainly IFT-A genes, account for about two thirds of patients, and the remaining third still has no known cause [5]. The number of patients with a molecular diagnosis was at least 50, from 38 families, in 2025 [5], and a 2022 report counted more than 70 patients described and 41 families with genetic confirmation [69].

2.4. Gene-by-gene distinction

IFT122 (CED1). The gene was the first to be identified, with a homozygous missense variant in a consanguineous Polish family, a second homozygous missense variant in another family and compound heterozygosity (splice donor variant and missense) in a sporadic patient [59]. The original variant, described as c.1658T>G p.(Val553Gly) in the historical numbering of transcript NM_052985, corresponds to NM_052989.3:c.1505T>G p.(Val502Gly) in the MANE transcript, classified as pathogenic in ClinVar (VCV000004635) [69, 70]. By 2016, biallelic variants had been described in only five families, a number to which three Argentinian patients added six new variants [71]. In a consanguineous Saudi family, a new homozygous variant was associated with CED with severe cutis laxa and intellectual disability [72]. In a Japanese family, the mother had four spontaneous miscarriages between 6 and 8 weeks, a fetal death with hydrops at 13 weeks and two terminations of pregnancy; the 1 base pair (bp) deletion and the p.Gly546Arg missense variant found in compound heterozygosity in the 21-week fetus were also present in the chorionic villi of a miscarriage at 7 weeks [8, 73]. In 2021, a 2-month-old Chinese infant was described, a compound heterozygote, with macrocephaly and dolichocephaly, sparse hair and eyebrows, phocomelia of the upper limbs and postaxial polydactyly of the hands and feet, without functional study of the variants [8]. According to Sezer and colleagues, IFT122 is the only CED gene that is not associated with another distinct skeletal ciliopathy [5], but this statement must be read in the light of the Brazilian fetus with an SRPS type IV (Beemer-Langer) phenotype and biallelic IFT122 variants, interpreted by the authors as a lethal allelic form of the spectrum [38], and of the Japanese and Saudi fetuses with hydrops [37, 73, 74]. GeneReviews, after reviewing the case, considers the phenotype of the Beemer-Langer fetus more consistent with CED, whereas the bone dysplasia atlas suggests that Beemer-Langer syndrome may be the neonatal lethal form of one of the CED genotypes; the two readings converge on the idea of a continuous spectrum [1, 75]. The remaining patients of the 2010 series show the allelic diversity of the gene: a Norwegian boy, the son of fourth cousins, was homozygous for p.Ser373Phe, and an Italian boy was compound heterozygous for an intronic splice variant inherited from his mother (502+5G>A) and for the missense variant p.Trp7Cys, absent in both parents and therefore de novo [39]. In the Brazilian fetus with a Beemer-Langer phenotype, one allele combined a 1 bp duplication followed by a 3 bp deletion, with a frameshift, inherited from the mother, and the other carried the missense variant p.Ala1062Pro in the TPR-like helical domain; the 2021 Chinese infant had an 11 bp deletion in exon 5 and a stop-loss variant in exon 31 (c.3879A>G, p.Ter1293Trpext, in the NM_052985 numbering cited by OMIM, without normalisation to the MANE transcript) [39]. Knockdown of ift122 in zebrafish produces pronephric cysts, cranial distension compatible with hydrocephalus and a reduction of cilia and basal bodies [39].

WDR35 (CED2). This is the most frequent gene [1]. WDR35 is homologous to TULP4, of the Tubby superfamily, and the first splice variant identified, in exon 2, altered ribonucleic acid (RNA) processing and introduced a premature stop codon [60]. The protein coats vesicles derived from the Golgi apparatus and signals their transport to the cilium; specific variants prevent recruitment of the EVC complex and of Smoothened (SMO) to the cilium and cause a form of Ellis-van Creveld syndrome [4, 76]. An exonic deletion of WDR35 causes SRPS with hydrops and absent ossification of the mesial and acral bones, and no deletion or duplication has been described as a cause of CED [1, 3]. The same gene also causes SRTD7 with or without polydactyly (OMIM 614091, which includes the former Verma-Naumoff SRPS), and a patient’s position in this spectrum cannot be predicted from the gene [77]. In four Polish families, five patients shared the same compound heterozygosity, c.1922T>G p.(Leu641Ter) and c.2522A>T p.(Asp841Val) in the numbering of transcript NM_001006657, which in the MANE transcript correspond to NM_020779.4:c.1889T>G p.(Leu630Ter) (VCV000065619) and NM_020779.4:c.2489A>T p.(Asp830Val) (VCV000446645), suggesting Polish founder variants [40, 70]. Other genotypes show the breadth of the spectrum (OMIM protein notation, without the transcript indicated): in a Mexican family with four affected siblings, the only one genotyped was homozygous for p.Leu520Pro, and the picture overlapped with the SRPSs, with cystic hygroma, polydactyly, hepatomegaly and renal and cardiac anomalies, two deaths at 9 and 13 months and a fetus terminated at 21 weeks [9, 78]; an 8-month-old infant with closure of the metopic, left coronal and sagittal sutures and cloverleaf skull was compound heterozygous for p.His1031Tyr and p.Tyr1068Cys [9, 19]; and a 15-year-old Pakistani adolescent, homozygous for p.Trp1153Cys, the most distal variant described at the time, had a mild skeletal phenotype with absence of several permanent teeth, kidney cysts, chronic kidney failure and hypertension [9]. In the two Dutch patients of 2010, both compound heterozygous for a splice or frameshift variant and a missense variant, the picture was skeletal, craniofacial, dental and articular, without kidney or liver disease and with normal intelligence at the time of the report [41]. The 9-year-old Polish girl described in 2017 with the p.Leu641Ter/p.Asp841Val pair had an older sister with more severe expression, who died in early childhood from respiratory, hepatic and renal failure; the p.Leu641Ter allele is listed in population databases with a frequency of about 0.02% [41]. In the SRTD7 spectrum, the known exonic deletion is a 2847 bp in-frame deletion spanning exon 5, homozygous in two Māori siblings from New Zealand with SRPS, acromesomelic hypomineralisation, laterality defects and cystic kidneys; two siblings from Réunion Island, children of first cousins, with a clinical diagnosis of EVC and without variants in EVC or EVC2, were homozygous for the intronic variant c.143-18T>A (NM_001006657.1), which causes exon 3 skipping, and died from cardiorespiratory failure at 5 and 13 months [41, 79]. SRPS with bowed ribs and long bones and a poorly mineralised calvaria due to missense/truncating compound heterozygosity has also been described, with reduced IFT43 in chondrocytes, and IFT43 levels also fall in mouse fibroblasts lacking Wdr35 [41, 79].

WDR19 (CED4). WDR19 has 36 exons and encodes a protein with six WD repeats, transmembrane domains and a clathrin heavy chain repeat [31, 44]. Its spectrum is the broadest in the class: at a skeletal extreme are CED4 and SRTD5 (Jeune); at a renal extreme, nephronophthisis 13 (NPHP13, OMIM 614377); at a retinal extreme, Senior-Løken syndrome 8 (OMIM 616307) and autosomal recessive retinopathy without evident kidney disease [31, 62]. In a systematic review of 94 individuals published in 2026, only 9 had a diagnosis of Sensenbrenner syndrome, 8 of Jeune syndrome, 3 of SRTD5, 1 of SRPS type 4, 2 of thoracic dysplasia not otherwise specified and 2 of Mainzer-Saldino syndrome; the remainder had mainly renal, ocular or hepatobiliary phenotypes [44]. OMIM also lists, as a provisional phenotype, spermatogenic failure due to multiple morphological abnormalities of the flagellum [31]. In the original Norwegian family, the two siblings were compound heterozygous for NM_025132.4:c.2129T>C p.(Leu710Ser) and c.3307C>T p.(Arg1103Ter); the sister had hip dysplasia, tapetoretinal dystrophy with an extinguished electroretinogram at 11 years, recurrent pneumonia, short stature treated with somatropin, idiopathic bone marrow hypoplasia and nephronophthisis-type nephropathy with kidney transplantation at 14 years, and the brother had sagittal synostosis, rod-cone dystrophy and hyperechogenic kidneys without other signs of kidney disease [11, 62]. Two Japanese girls, both compound heterozygous with the recurrent allele c.3533G>A p.(Arg1178Gln), had severe hypertension in the neonatal period and ESKD in the first year of life; biopsy showed infantile nephronophthisis in one and a dysplastic kidney with diffuse glomerular cysts in the other, the first report of this histology with WDR19, and both also had hydrocephalus or subdural hygroma, pancreatic cysts and dilatation of the intrahepatic bile ducts [11]. The same p.(Leu710Ser) allele of the Norwegian siblings causes, in the homozygous state, in a consanguineous French-Canadian family, retinitis pigmentosa with subclinical exophytic kidney cysts and normal kidney function, classified as Senior-Løken syndrome 8; the 50-year-old proband also had mild cognitive impairment [45, 80]. The p.(Arg1178Gln) allele, recurrent in Korean and Japanese families, appeared in the homozygous state in a patient from Oman with ESKD in infancy, polydactyly, intrahepatic bile duct dilatation and retinal dystrophy [45]. In the Moroccan family with NPHP13, the three siblings with nephronophthisis reached ESKD at 13, 19 and 20 years [81]. In Egyptian and Korean patients with NPHP13 or Senior-Løken syndrome 8, intrahepatic bile duct dilatation was constant, with hepatic fibrosis in some and pancreatic cysts in one, and the authors proposed Caroli disease or syndrome as the main extrarenal manifestation of WDR19 [80, 81]. The Dutch patient with SRTD5, homozygous for c.20T>C p.(Leu7Pro), started peritoneal dialysis at 4 years, underwent transplantation at 5 and again at 12 after rejection, and at 22 years lived independently and worked as a nurse, with only slightly reduced exercise tolerance; a Spanish boy with Mainzer-Saldino syndrome due to two missense variants had trigonocephaly due to premature closure of the metopic suture, dialysis from 1 year of age and kidney transplantation at 2 years [82]. Spermatogenic failure 72 rests on a single infertile Chinese man, homozygous for c.3811A>G p.(Lys1271Glu) in the C-terminal domain, with multiple morphological abnormalities of the flagellum and without ocular, skeletal, hepatic or renal involvement [45, 83]; a girl of Filipino ancestry with a complex syndromic picture and c.1483G>C p.(Gly495Arg) in the homozygous state awaits confirmation [45]. The twinkle-toes mouse, with a hypomorphic missense variant in the TPR domain, reproduces skeletal and craniofacial anomalies (exencephaly, cleft lip and palate, short ribs, polydactyly), without a phenotype in heterozygotes [45].

IFT140. The gene has 31 exons (29 coding) and encodes a protein of 1462 amino acids with five WD repeats and nine TPR (tetratricopeptide repeat) repeats [20]. Biallelic variants are mainly associated with Mainzer-Saldino syndrome and SRTD9 (OMIM 266920), and also with Opitz trigonocephaly C syndrome and retinitis pigmentosa 80 (OMIM 617781), which accounts for up to about 1% of non-syndromic retinitis pigmentosa [84–86]. CED due to IFT140 was known in only four patients up to 2023 [87]. A tandem duplication of exons 27–30, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup) in NM_014714.4, which adds 243 amino acids within the TPR region without altering the reading frame, was found in two Polish families with CED and early ESKD and in eight published families, mostly with Mainzer-Saldino syndrome [20]. Monoallelic loss-of-function variants cause a mild form of autosomal dominant polycystic kidney disease (ADPKD), with adult onset [23, 32]. OMIM designates the IFT140 form as CED5 (621180), on the basis of the two Polish boys of 2020 and of a 2-year-old Russian boy with sagittal synostosis and ESKD, compound heterozygous for the tandem duplication and for the 4 bp splice donor deletion c.2767_2768+2del, with both parents carriers [7, 87]. The same pair of variants was found in a 16-year-old Polish adolescent with CED features and in an unrelated Polish boy with Mainzer-Saldino syndrome; only the former had short cilia in fibroblasts and a heterozygous missense variant in INTU, which the authors consider a possible modifier [7]. The 2017 British patient was compound heterozygous for p.Gly212Arg and p.Arg760Ter [7, 63]. Pathogenic variants are distributed throughout the gene, with no demonstrated correlation between variant type and phenotype, and the same allele combinations produced different phenotypes [7]. In Mainzer-Saldino syndrome, the tandem duplication was present on at least one allele in 9 of 11 patients from 10 families, with the same breakpoint and a shared haplotype compatible with a founder effect; one patient in that series had overlap with CED, with craniosynostosis, intracranial hypertension, developmental delay, oculomotor apraxia and ESKD [64]. The clinical details of the patients with CED5 underline the early renal involvement: one Polish boy reached ESKD at 4.5 years, started peritoneal dialysis and underwent transplantation at 6; another presented with proteinuria and haematuria at 8 months, with enlarged kidneys, and was on peritoneal dialysis at 22 months; the 16-year-old Polish adolescent had had ESKD since 9 months of age due to diffuse glomerulosclerosis and fibrosis, bilateral vesicoureteric reflux and, alongside a congenital cytomegalovirus infection, global delay, absent speech, absence seizures and cerebellar ataxia; in the Russian boy, with apparently isolated sagittal synostosis at 6 months, kidney failure was discovered during preparation for cranial surgery, he started dialysis at 9 months and underwent transplantation at 20 months [13]. The 2020 patients had nystagmus, high hypermetropia and, in one of them, strabismus, and the 16-year-old adolescent had retinal dystrophy with optic atrophy [13]. In the 2017 British patient, chronic lung infections required oxygen up to 5 years of age, ESKD appeared at 20 months and kidney biopsy excluded nephronophthisis before transplantation at 4 years [64].

IFT43 (CED3). The two original Moroccan siblings were homozygous for c.1A>G p.(Met1Val) (NM_001102564.3; VCV000031098, pathogenic), with initiation of translation at a downstream ATG codon and production of a shorter protein [61, 70]. The spectrum of the gene includes European fetuses with an SRPS phenotype and biallelic variants, SRTD18 (OMIM 617866) and isolated retinitis pigmentosa 81 (OMIM 617871) due to a hypomorphic allele in a consanguineous Pakistani family [42, 88]. In 2026, a Turkish boy was described with c.55-1G>A and c.175C>T p.(Arg59Ter) in trans, both predicted to be null alleles, but with a mild phenotype and without kidney or retinal disease at 7 years; the authors consider incomplete splicing with residual protein, modifiers or the effect of the allelic combination [42]. The initiation variant p.(Met1Val) leads to use of the next ATG, in exon 2, and to a protein lacking the 21 N-terminal amino acids, about 3 kDa lighter; the other known initiation variant, p.(Met1Lys), and the missense variant p.(Trp179Arg), both in the homozygous state, caused SRTD18, with absent or markedly reduced protein, increased IFT144 and disorganisation of the chondrocyte columns of the growth plate [43]. In SRTD18, the fetuses and the newborn had short, bowed long bones (with reversed campomelia of the humeri), curved ribs, postaxial polydactyly of all four limbs and cerebral, hepatic, pancreatic and renal anomalies; the newborn, born at 30 weeks, died the day after delivery and two pregnancies were terminated after the 18-week ultrasound scan [89]. Retinitis pigmentosa 81 rests on a consanguineous Pakistani family with nine affected members, homozygous for p.(Glu34Lys), with night blindness before 5 years of age, an extinguished ERG between 28 and 46 years and normal physical development; screening of about 1900 patients with inherited retinal dystrophies found no other cases, and isolated retinopathy due to IFT43 is considered rare [35].

IFT52. The homozygous variant NM_016004.5:c.424C>T p.(Arg142Ter) (VCV000253306, pathogenic) was the first association of IFT52 with human disease, in an Indian child with short stature, narrow thorax, short hands and feet, postaxial polydactyly, pigmentary retinopathy and small teeth, overlapping with CED1 [46, 70]. The same child had motor delay, hypoplasia of the corpus callosum, angel-shaped middle phalanges, hypermetropia and a salt-and-pepper fundus with progressive loss of peripheral vision [12]. The other phenotypes described are SRPS due to compound heterozygosity with loss of about 60% of cilia [67], mild SRTD with Leber congenital amaurosis [90] and congenital anomalies of the kidney and urinary tract without skeletal disease due to a hypomorphic missense variant [68]. The clinical validity of the association of IFT52 with SRTD16 is moderate according to the Clinical Genome Resource (ClinGen); the association with CED rests essentially on Girisha’s family [15]. Despite being a nonsense variant, p.(Arg142Ter) causes partial skipping of exon 6 and the production, in reduced amounts, of a protein 24 amino acids shorter with partial function, a finding compatible with the child’s survival [47]. The two fetuses with SRTD16 and polydactyly of 2019 were compound heterozygous for p.(Asn98Ser) and an in-frame indel, and the homozygous missense variant p.(Asp259His), found in a North African fetus with bilateral multicystic renal dysplasia without skeletal disease, is treated in OMIM as a variant of uncertain significance, so that the association of IFT52 with congenital anomalies of the kidney and urinary tract awaits confirmation [47].

CILK1. Biallelic variants in the catalytic domain of this kinase cause perinatal lethal skeletal ciliopathies, ECO (OMIM 612651) and an SRPS, and some heterozygous variants have been associated with susceptibility to juvenile myoclonic epilepsy 10 (OMIM 617924) [5]. In 2025, the variant NM_014920.5:c.1664_1665del p.(Tyr555CysfsTer48) in the homozygous state, located in exon 13 of 14 and in the distal non-catalytic region, was identified in five patients from two Iraqi Turkmen families living in Turkey; the messenger RNA escapes nonsense-mediated decay and is expressed at levels similar to those of controls [5]. The variant is listed in ClinVar as pathogenic (VCV003366972; GRCh38 position chr6:53,006,394, which corresponds to the GRCh37 coordinate chr6:52,871,191 in the article) [70]. None of the 22 heterozygous carriers had epilepsy or developmental delay, and reintroduction of normal CILK1 into the fibroblasts corrected most of the ciliary abnormalities [5]. ECO was described in six infants and fetuses from two Old Order Amish families, homozygous for the missense variant p.Arg272Gln, with hydrocephalus, holoprosencephaly, cleft lip and palate, eyelid fusion, pituitary and adrenal hypoplasia, abnormal differentiation of the external genitalia in 46,XY individuals and postaxial polydactyly; these were followed by a Turkish fetus with an SRTD picture and orofaciodigital defects (p.Gly120Cys) and a newborn with lethal SRTD and complete loss of kinase activity (p.Glu80Lys), which constitutes an allelic spectrum between ECO and SRTD [6]. In the six-generation pedigree of one of the CED6 families, another 11 members of consanguineous branches had suspected CED, without confirmation, and all had died, most between 1 and 13 years of age [14]. Susceptibility to juvenile myoclonic epilepsy 10 rests on a multigenerational family from Belize with the heterozygous missense variant p.Lys305Thr and on rare variants found in 7% of 310 probands with juvenile myoclonic epilepsy, of which only four met pathogenicity criteria; almost all families had asymptomatic carriers, and 11 of the 34 relatives considered affected had only electroencephalographic abnormalities, without seizures, reflecting incomplete penetrance [48, 91]. The ECO allele has a frequency of about 0.97% among the Old Order Amish [48].

2.5. Variant spectrum and nomenclature

The HGVS (Human Genome Variation Society) recommends that variants be referred to a reference transcript with its version, preferably the MANE Select transcript. For IFT122 and WDR35, the historical literature used non-MANE transcripts (NM_052985 and NM_001006657), which produces numbering differences of dozens of codons between articles; conversion should only be done with normalisation tools or through ClinVar, never by hand [70]. The following table brings together the variants cited in this article, with the notation of the source and the correspondence in ClinVar at the date of consultation (28 October 2026).

The most relevant discrepancy concerns the 2026 Chinese fetus with WDR35 variants: the article describes c.1600C>T as the missense variant p.(Arg534Cys), classified as pathogenic with the PS1 criterion and with reference to a ClinVar record, but the c.1600C>T substitution in the MANE transcript changes codon 534 to a stop codon (p.(Arg534Ter)), and there is no record of a p.(Arg534Cys) missense variant [18, 70]. Because the transcript is not indicated in the article and manual conversion is not admissible, the notation remains unresolved; the same article contains other internal inconsistencies, such as contradictory attribution of the maternal and paternal origin of the variants between the figure and the discussion [18]. In the Brazilian fetus with a Beemer-Langer phenotype, the IFT122 variants were written as c.[3184G>C];[3228dupG;3231_3233delCAT] (published designation), without a transcript in the abstract [38]. The tables of IFT122 variants published in 2026 contain internally inconsistent notations (for example, c.3385C>T associated with p.Gln686Glu, whereas in transcript NM_052985.4, which is not the MANE transcript, c.3385C>T corresponds to p.(Arg1129Cys)), which should not be used without normalisation [37].

2.6. Founder variants and populations with recurrent alleles

The WDR35 alleles NM_020779.4:c.1889T>G p.(Leu630Ter) and c.2489A>T p.(Asp830Val), in compound heterozygosity, recur in four apparently unrelated Polish families [40]. The CILK1 variant c.1664_1665del lies on a shared haplotype of about 19 Mb, compatible with a founder effect in the Iraqi Turkmen population of Tal Afar (Nineveh) [5]. The WDR19 variant c.878G>A p.(Cys293Tyr), in the homozygous state, was found in five unrelated patients from an Israeli ethnic minority with adult ESKD and a non-syndromic renal phenotype [44]. Outside the class, Ellis-van Creveld syndrome has in the Amish community of Lancaster (Pennsylvania) the founder allele EVC NM_153717.3:c.1886+5G>T (VCV000005338) [4, 70].

2.7. Genotype–phenotype correlations, penetrance and expressivity

GeneReviews considers that the phenotypes of the six genes are not distinguishable and that there are no confirmed genotype–phenotype correlations [1]. The absence of patients with two null alleles suggests that complete loss of function is embryonic lethal; in almost all patients with CED at least one of the IFT-A variants is a missense variant [5, 50]. The systematic review of WDR19 (72 individuals from 64 families with biallelic variants and at least one pathogenic or likely pathogenic variant) is the only study with statistics: no individual had two truncating variants; the presence of a truncating variant was associated with skeletal involvement (54% versus 23% with missense variants only; odds ratio [OR] 3.88; 95% confidence interval [95% CI] 1.24–13.09) and thoracic involvement (46% versus 7%; OR 11.85; 95% CI 2.70–84.11), and with less hepatobiliary involvement (21% versus 57%; OR 0.20; 95% CI 0.05–0.65) [44]. Among patients with missense variants only, having both variants outside the WD repeats was associated with onset before 16 years of age in 100% of cases, versus 50% and 81% in the other groups (p=0.0042), and ocular involvement ranged from 5% to 75% according to variant location (p<0.0001); the authors urge caution because of domain annotation and cohort characteristics [44]. The most frequent variant, NM_025132.4:c.3533G>A p.(Arg1178Gln), appeared in 26 cases from 24 families; six of the eight homozygotes had ESKD in early childhood and four of those six had retinal dystrophy, and the variant NM_025132.4:c.3703G>A p.(Glu1235Lys) was accompanied by renal and hepatic involvement in all seven carriers [44].

Expressivity is highly variable, including within the same family. Siblings may be discordant for sagittal craniosynostosis [1], a sister with typical CED had a brother with perinatal death [1, 93], and the four Polish families with the same WDR35 genotype differed in skeletal and ectodermal features, in development and in the age and severity of kidney and liver failure, which points to genetic and non-genetic modifiers [40, 94]. A patient with two predicted null alleles in IFT43 had a mild phenotype [42]. It has been suggested that kidney dysfunction is more frequent in boys with IFT122 and WDR35 variants, but the data are insufficient to state this [20]. The proposed modifiers (IFT122, IFT52, GLI3) have not been demonstrated [5], and oligogenic inheritance, modifiers and environment are the explanations invoked for the variability of WDR19 [44]. Penetrance of biallelic variants is considered complete, although some findings (developmental delay, teeth, retina, kidney, liver) may not be present in the newborn [1]. There is one documented exception in the WDR19 spectrum: in the Moroccan family with NPHP13, the asymptomatic mother, the daughter of consanguineous parents, was homozygous for the missense variant NM_025132.4:c.1034T>G p.(Val345Gly), which the authors interpret as a hypomorphic allele, pathogenic in the children only in combination with a truncating allele [45, 81].

2.8. Allelic disorders and atypical inheritance

In addition to autosomal recessive inheritance with carrier parents, GeneReviews admits three situations when only one parent is a carrier: a de novo variant in the proband, a postzygotic de novo variant in a mosaic parent, or uniparental isodisomy [1, 96]. There is a documented example in the IFT140 spectrum: a 10-year-old boy with a Mainzer-Saldino picture was homozygous for p.Gly212Arg due to maternal heteroisodisomy of chromosome 16, with segmental isodisomy at 16p13, and the father was not a carrier [7]. A de novo variant was documented in one of the original patients with CED1, compound heterozygous for a maternal splice variant and a missense variant absent in both parents [39]. Digenic inheritance was proposed in a newborn with SRTD and polydactyly, who died in the neonatal period, double heterozygous for the WDR35 missense variant NM_020779.4:c.932G>T p.(Trp311Leu) and a truncating INTU variant (recorded in OMIM as SRTD7/20), and in ADPKD due to IFT140 seven of the twelve families with several affected members had additional variants in PKD1 or PKHD1 that segregated with the disease [36, 79]. The DVL3 variant found in the exome of the 2026 Saudi proband and absent in the parents and in the affected fetus illustrates the need to interpret additional findings in consanguineous families (artefact, de novo variant or germline mosaicism) [37]. Heterozygous carriers are asymptomatic, with the exception of carriers of loss-of-function variants in IFT140, who may have mild adult ADPKD (section 8) [1, 32].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and frequency of manifestations

Clinical knowledge of CED rests on case reports and small series: the largest clinical review gathered 39 patients [19], GeneReviews describes 44 individuals with biallelic variants from 27 publications between 2006 and 2020 [1], and the most recent comparison used 50 patients from 38 families with a molecular diagnosis [5]. There are no prospective cohorts or population registries, and most patients were described in childhood, so the frequencies below are proportions of published patients and not estimates of lifetime risk [1].

The comparative table of Sezer and colleagues adds proportions that GeneReviews did not quantify: macrocephaly, absolute or relative, in 8 of 15 patients (53%), and enlarged extracerebral spaces or ventriculomegaly in 8 of 18 (44%) [5]. The frequency of retinal dystrophy, classified as occasional in GeneReviews, is probably underestimated, because the retinopathy manifests late and many published children did not have an electroretinogram (ERG) [1, 97].

3.2. Skull and face

The facies is recognisable from birth and is present in almost all patients: frontal bossing, bitemporal narrowing and high forehead; low-set, simple or posteriorly rotated ears; telecanthus, epicanthic folds and downslanting or upslanting palpebral fissures; full cheeks; micrognathia; everted lower lip; and anteverted nares [1]. Dolichocephaly and frontal bossing are usually secondary to sagittal craniosynostosis, generally already present at birth and identified in more than half of the patients in the series of 39 [1, 19]. Craniosynostosis may be multisutural, as in one patient in the 2013 series and in a Polish boy in 2022 [19, 97], or metopic, with trigonocephaly, as in the Turkish patient with IFT43 variants [42]. In the newborn, dolichocephaly may coexist with widely open coronal and lambdoid sutures, and in CED due to WDR35 a large neurocranium with a deep posterior fossa has been documented [3]. Head circumference is normal at birth, but grows disproportionately while linear growth velocity decreases [50]. In patients with CILK1 variants, dolichocephaly was present in four of five, without craniosynostosis in any, and four had relative macrocephaly with external hydrocephalus [5]. Cleft palate, hypertelorism and hypotonia are occasional [50].

3.3. Skeleton

Thorax. A narrow thorax with short dysplastic ribs is common but not universal; it can be seen in mid-gestation and is more often noted at birth, pectus excavatum is frequent, and the rib deformities (short, coat-hanger-shaped ribs) may normalise during childhood [1]. Thoracic narrowing is, as a rule, mild in CED and marked in SRTD, which is accompanied by severe respiratory distress [1, 19]. In a 21-week fetus with IFT122 variants, ribs 3 to 9 were wavy, the humeri bowed outwards and the tibiae angulated, with normal iliac bones; in a 6-year-old child, the clavicles were bowed upwards and the pectus excavatum produced apparent cardiomegaly on the radiograph [3].

Long bones. Shortening and bowing of the proximal bones are detected from 23 weeks of gestation; the upper limbs are shorter than the lower limbs and the humeri are the most affected, with flattened epiphyses and metaphyseal widening [1]. The atlas describes short long bones with mild metaphyseal flaring, bowing of the humeri and femora and osteopenia; in the newborn, humeri and femora with broad, rounded ends and diaphyseal angulation of the tibiae; at 6 years, flat distal femoral and proximal tibial epiphyses, tibiotalar slanting and dislocation of the radial head with bowed humerus and ulna [3]. Other findings are shortening of the fibulae, delayed ossification of the proximal femoral epiphysis, vertebral bodies with convex surfaces and short lumbar pedicles [50]. Hip dysplasia is occasional [1].

Hands and feet. Brachydactyly, due to shortening of the middle and distal phalanges, which are sometimes malformed, is almost constant; postaxial polydactyly can be detected in mid-gestation and cutaneous syndactyly mainly affects the 2nd and 3rd toes [1]. The phalangeal epiphyses may be normal, flattened or cone-shaped; clinodactyly of the 5th finger, abnormal palmar creases, limited finger flexion, a gap between the hallux and the 2nd toe, triphalangeal hallux or thumb and flat foot are also described [1, 50]. The radiological evolution of the hand is characteristic: in the newborn, broad phalanges with rounded ends and progressive shortening from proximal to distal; at 3 years, broad 1st and 5th metacarpals, short, broad middle phalanges, cone-shaped epiphyses and delta-shaped metaphyseal margins; at 15 years, globular middle phalanges [3].

3.4. Growth

Birth length may be normal or below the 3rd centile, and postnatal short stature is one of the frequent manifestations [1, 50]. Chronic kidney disease, liver disease and respiratory infections add to the skeletal dysplasia as causes of growth failure: a Polish boy with CED due to IFT140 measured 102 cm (below the 3rd centile) at 6.5 years, already after transplantation, and at 9 years had short stature with obesity, with more evident brachydactyly and shortening and less evident dolichocephaly [20]. In the IFT43 patient without kidney disease, height at 7 years was 108 cm, below the 3rd centile, with head circumference between the 90th and 97th centiles [42]. A Saudi proband had, at 2 years and 9 months, a height of −2.25 standard deviations (SD) and a head circumference of +0.43 SD [37]. The phenotype changes with age, which makes late recognition difficult [20].

3.5. Ectoderm and connective tissue

Teeth. Eruption is often delayed; the primary teeth are small and widely spaced, and both the primary and permanent dentitions may have hypodontia or oligodontia, enamel defects, taurodontism, fused or conical teeth and cusp malformations [1, 50].

Hair and nails. Hair is sparse and fine in most children, with hypopigmentation, reduced diameter and slow growth, and may normalise during childhood [1, 57]. The eyebrows may also be sparse [42]. The nails are short, broad and slow-growing from infancy [1, 98].

Skin and connective tissue. In the prenatal period, a webbed neck and skin thickening may be seen; later, generalised skin laxity with redundant folds on the neck, wrists and ankles, dry skin and hyperkeratosis [1]. Hypohidrosis has been described [3, 57]. Joint hyperlaxity is present from the neonatal period, and cutis laxa may be severe, as in Fry’s two patients and in the Saudi family with an IFT122 variant [1, 58, 72]. Inguinal hernias, often bilateral, and umbilical hernias appear in the newborn or in the first year [1].

3.6. Kidney

The kidney disease is a nephronophthisis (chronic tubulointerstitial nephritis) and is the main determinant of prognosis. At least 60–70% of published patients had kidney failure [1]. ESKD may already manifest in the second trimester of gestation, with polyhydramnios or oligohydramnios and small, cystic kidneys, but the first signs usually appear at around 2 years of age; the first defect is loss of urinary concentrating ability, with polyuria, polydipsia and nocturnal enuresis, and only later do arterial hypertension, proteinuria, haematuria and electrolyte disturbances appear [1]. In 10 of 21 children with follow-up the disease progressed to ESKD, most between 2 and 6 years of age; the figure is probably underestimated because published follow-up is short [1]. On ultrasound, the kidneys are normal or small, hyperechogenic and with poor corticomedullary differentiation; biopsy shows interstitial fibrosis with focal inflammatory infiltrates, tubular atrophy, thickening of the tubular basement membrane, glomerulosclerosis and, in advanced disease, occasional cysts [1, 50]. By gene, 22 of 26 patients with causal WDR35 variants (85%) had chronic kidney disease [18], and the IFT140 patients described in Poland had ESKD at 4.5 years and dialysis from 8 months [20]. In the Lyon series, all four children with WDR35 or WDR19 variants progressed to ESKD in the first or second decade [99]. The typical interval between the diagnosis of kidney failure and the need for kidney replacement therapy in recessive renal ciliopathies is 5 to 10 years [20].

In the WDR19 review, which includes patients without CED, renal involvement was present in 75% of patients in the main analysis, progression to ESKD occurred in 44 of 94 individuals, and severity ranged from ESKD in childhood to incidental mild proteinuria in adulthood; histology may show immune deposits and mimic immune complex glomerulonephritis, as in the index case, first diagnosed as IgA nephropathy [44].

3.7. Liver

Liver involvement ranges from non-progressive hepatosplenomegaly to recurrent hyperbilirubinaemia and cholestasis with neonatal admission, and includes cirrhosis, severe cholestasis with ductular proliferation, acute cholangitis in infants and liver cysts, described as early as 10 months and at 3–4 years [1]. The underlying lesion is a ductal plate malformation with congenital hepatic fibrosis, which places CED among the hepatorenal fibrocystic diseases [56, 69]. Some degree of liver involvement is reported in about 40–50% of patients, regardless of the gene, and severe liver disease is less common [69]. Severe cases progress to portal hypertension with splenomegaly, hypersplenism, oesophageal varices, ascites and coagulopathy, and may require liver transplantation, as in the 7-year-old boy with WDR35 variants and repeated variceal bleeding [100] and in the clinical case in section 10 [69]. In two siblings with WDR35 variants, severe hepatic fibrosis led to liver failure and early death [78]. In the patients with CILK1, liver enzymes were elevated in all and one died at 9 years from chronic liver disease [5]. There are no longitudinal data, and GeneReviews considers the long-term hepatic prognosis probably unfavourable [1]. In the WDR19 review, all patients with hepatobiliary disease also had kidney disease, and the forms described include congenital hepatic fibrosis, Caroli disease and polycystic liver disease [44].

3.8. Eye

Retinal dystrophy manifests as nystagmus and night blindness in the first years; the scotopic and photopic ERG was already abnormal between 4 and 11 years of age and the fundus showed attenuated arteries and bone-spicule deposits between 5 and 11 years [1]. The natural history has not been published, and GeneReviews expects, by analogy with Bardet-Biedl syndrome, progression to legal blindness in young adulthood [1]. Refractive errors (hypermetropia, myopia, astigmatism), esotropia and euryblepharon also occur [1]. The retinopathy may be early: a Polish boy with WDR35 variants was diagnosed at 3.5 years, which led the authors to recommend ophthalmological assessment at least once before 4 years of age [97]. Ocular findings (nystagmus, high hypermetropia, strabismus, retinal dystrophy) were frequent in the patients with IFT140 [20], and in CED due to WDR35 a retinal dystrophy with optic disc drusen has been described [101]. In patients with WDR19, ocular involvement was the second most frequent (51% in the main analysis) and includes retinitis pigmentosa phenotypes, Stargardt-like cone-rod dystrophy and a “bear-track” maculopathy in French-Canadian families homozygous for p.(Leu710Ser) [44, 102]. In a series of four patients with WDR19, foveal sparing, present in three, was accompanied by relatively preserved acuity [102]. CED is among the less frequent ciliopathies with syndromic retinitis pigmentosa [103].

3.9. Respiratory system

Neonatal respiratory distress due to pulmonary hypoplasia may be fatal, and recurrent respiratory infections are frequent in infancy and early childhood; asthma and pneumothorax are also described [1]. Many of the children who died did so from respiratory distress after birth or from pneumonia in early childhood, and infections tend to decrease with age [1, 50]. Respiratory complications are generally less severe than in SRTD [19]. The motile cilia dysfunction demonstrated in a child with WDR35 (neonatal respiratory distress, restrictive disease with an obstructive component, infections and atelectasis, immotile or dyskinetic cilia and low nasal nitric oxide) suggests that some of the infections result from defective mucociliary clearance, masked by thoracic restriction [66].

3.10. Heart

The heart defects described are patent ductus arteriosus, atrial and ventricular septal defects, thickening of the mitral and tricuspid valves, ventricular hypertrophy or dilatation and peripheral pulmonary stenosis; one child had an arrhythmia and an atrial septal defect that resolved by 3 years of age [1]. The series of 39 patients recorded mild heart defects, but no atrioventricular septal defect or heterotaxy, which are common in EVC [19]. The Saudi proband with IFT122 had compensated neonatal heart failure with patent foramen ovale, patent ductus arteriosus, mild mitral regurgitation and left ventricular hypertrophy [37].

3.11. Central nervous system and development

Most patients have normal development or mild delay, mainly motor: sitting unsupported between 9 and 15 months and walking at 3 years, and speech ranging from a few words at 19 months to none at 5 years in one report; cognition and socialisation are usually normal, and intellectual disability occurs in a minority [1]. Global delay or cognitive impairment is reported in fewer than 15% of patients [42]. Neuroimaging may show cortical atrophy, ventriculomegaly, a large cisterna magna, hypoplasia of the corpus callosum, enlarged extracerebral spaces, a posterior fossa cyst and Dandy-Walker malformation [1, 57]. The table of extraskeletal anomalies in the bone dysplasia atlas marks “no” for brain anomalies in CED, which differs from these reports [1, 95].

3.12. Other manifestations

Severe primary hypothyroidism was described in a 6-year-old Saudi girl with liver failure and ESKD and reversed completely after combined kidney and liver transplantation; this is a single case, without a demonstrated association [104]. Conductive hearing loss was recorded in an Argentinian patient [71], and bilateral cryptorchidism in the Turkish patient with IFT43 [42]. In the patients with CILK1, rectal prolapse, chronic constipation and an accessory spleen were described, the latter suggestive of a laterality defect [5]. Fertility is unknown and no patient with CED has published offspring [1].

3.13. Prenatal forms and severe forms

Some patients manifest in utero with more severe pictures than classical CED. The prenatal findings described are increased nuchal translucency (NT), cystic hygroma, skin thickening, short proximal bones, polydactyly, hyperechogenic or cystic kidneys with oligohydramnios or polyhydramnios, generalised oedema and non-immune hydrops [1, 18]. In eight prenatal cases of CED due to WDR35, renal hyperechogenicity and limb shortening were present in four of the seven previous cases, increased NT in three, and all had a poor outcome [18]. A Chinese fetus at 12 weeks and 4 days with WDR35 variants had lymphoedema, omphalocele, hydrops, hypoplasia of the radius and ulna, agenesis of the ductus venosus and ventricular and atrial septal defects, findings not previously described in CED2 [92]. IFT122 variants are associated with hydropic fetuses and recurrent pregnancy loss [37, 73, 74], and at the extreme of the spectrum lies Beemer-Langer syndrome [38]. In the Saudi family, the proband was born after polyhydramnios, hygroma and hydrops, and a brother was stillborn with the same findings [37].

3.14. Phenotype by gene

The differences between genes rest on few patients and do not allow the clinical course of an individual patient to be predicted [1].

3.15. Natural history and treated disease

The mortality described mainly reflects the natural history in older series. Of the 65 children gathered in GeneReviews, 10 died before 7 years of age from respiratory failure, cardiac failure, hypovolaemic shock due to coagulopathy or unknown cause, a figure that may be higher owing to lack of follow-up; at least three patients survived into young adulthood [1]. ESKD is cited as the most frequent cause of death, often in infancy and childhood [50]. The treated disease has a different profile: dialysis and kidney transplantation, performed between 2.5 and 14 years of age in the patients with a genetic diagnosis published up to 2021, and liver transplantation have allowed survival into adolescence in recent reports [69, 105]. Of the patients with CILK1, all five survived into childhood and one died at 9 years [5]. The absence of series with follow-up into adulthood prevents estimation of life expectancy in the treated disease [1].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

Prenatal period. Suspicion arises in the presence of short proximal long bones (mainly the humeri) from 23 weeks, polydactyly, narrow thorax, webbed neck or skin thickening, hyperechogenic or cystic kidneys and changes in amniotic fluid volume on the second-trimester ultrasound scan [1]. Increased NT in the first trimester may be the first sign, in isolation, and the combination of increased NT, short proximal bones and normal-sized hyperechogenic kidneys is the one that the authors of a 2026 review identify as suggestive [18]. Cystic hygroma, generalised oedema and non-immune hydrops should prompt inclusion of CED, mainly due to IFT122 or WDR35, in the differential diagnosis of fetal skeletal dysplasias [37, 74, 92]. The absence of craniosynostosis in a fetus does not exclude the diagnosis, because in the fetuses described by Konstantinidou the sagittal suture was not closed [57].

Newborn and infant. The most suggestive picture is the association of dolichocephaly with frontal bossing and high forehead, short limbs with a rhizomelic pattern, brachydactyly, narrow thorax and inguinal hernias, possibly with polydactyly, sparse hair and lax skin [1, 69]. Neonatal respiratory distress, neonatal cholestasis and recurrent respiratory infections are additional modes of presentation [1, 66].

Child with sagittal craniosynostosis. Scaphocephaly surgery may precede diagnosis of the syndrome: in the Lyon series, two of the four children had undergone surgery in the first months of life before CED was recognised, which led the authors to advocate systematic multidisciplinary assessment of sagittal craniosynostoses [99]. The presence of short limbs, brachydactyly, narrow thorax, fine hair, abnormal teeth or polyuria in a child with scaphocephaly justifies renal and genetic assessment [22, 99].

Child with kidney disease. In a child with polyuria, polydipsia, secondary enuresis, anaemia or kidney failure with normal-sized or small hyperechogenic kidneys, the coexistence of short stature, brachydactyly, narrow thorax or dental and hair anomalies points to a syndromic ciliopathy and, if dolichocephaly is present, to CED [1, 49].

Adolescent and adult. Attenuated forms, mainly due to WDR19, may present in young adulthood as chronic kidney disease of unexplained cause, with a non-specific biopsy or one suggestive of glomerulonephritis, and only later reveal Caroli disease and retinal dystrophy [44].

4.2. Warning and emergency signs

4.3. Newborn screening

There is no biochemical newborn screening or population screening programme for CED, and the sources consulted do not describe newborn sequencing studies targeting this disorder. Early detection depends on clinical and ultrasound recognition and, in families with an index case, on targeted testing of the newborn [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal criteria. GeneReviews adopts the proposal of Lin and colleagues: the clinical diagnosis is established in a proband with suggestive clinical and radiographic features that include two frequent findings and two other anomalies, at least one of which is an ectodermal defect (teeth, hair or nails) [1, 19]. The core elements proposed by Lin are the distinctive craniofacial appearance, ubiquitous brachydactyly, ectodermal anomalies and sagittal craniosynostosis [19]. The molecular diagnosis is established with suggestive findings and biallelic pathogenic or likely pathogenic variants in one of the associated genes; two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1, 106]. Craniosynostosis is not mandatory: it is absent in some patients with WDR35 and IFT122 variants, in all patients with CILK1 and in fetuses [5, 57].

5.2. Initial evaluation after diagnosis

5.3. Imaging

The main radiological findings are sagittal synostosis, short long bones with mild metaphyseal flaring and bowing of the humeri and femora, short middle and distal phalanges with cone-shaped epiphyses, narrow thorax with pectus excavatum and rib deformities, and osteopenia [3]. The pelvis looks closer to normal than in EVC and SRTD, without the trident acetabular roof typical of those conditions [4, 107]. Three-dimensional CT defines the sutures involved, as in the patient with trigonocephaly due to metopic fusion identified at 16 months [42]. The European craniosynostosis guideline recommends MRI at referral of multisutural craniosynostoses, to look for hydrocephalus and Chiari malformation [22]. Renal ultrasound shows normal or small, hyperechogenic kidneys with poor corticomedullary differentiation and, in some cases, cysts [1]. In CED due to IFT140, enlarged kidneys (61 and 63 mm at 8 months) with poor differentiation have been described [20].

5.4. Genetic tests: choice and order

GeneReviews proposes two approaches. In the first, a multigene panel that includes the CED genes and those of the differential diagnosis, an option that limits VUS and unrelated findings; the genes included, sensitivity and methods vary between laboratories [1]. In the second, exome sequencing (the most used) or genome sequencing, when the phenotype cannot be distinguished from other ectodermal or skeletal dysplasias [1]. In a child with craniosynostosis and other malformations or delay, the European guideline recommends array, targeted testing, a craniosynostosis panel or trio sequencing for multiple congenital anomalies [22]. The authors of the CILK1 study recommend including this gene in CED panels [5]. In a Turkish cohort of 20 patients with suspected skeletal ciliopathy, the exome provided a molecular diagnosis in 16 (80%), one of which was CED [108]. Tests that study cilia in fibroblasts (frequency, length, accumulation of IFT proteins) are research tools and not clinical tests [17].

The percentages of detectable variants refer to the proportion of published variants that each method identifies, and not to the clinical sensitivity of the test: one third of published patients still have no gene identified, so the sensitivity of a complete panel for a patient with a typical phenotype will be, at most, around two thirds [1, 5].

5.5. Limitations of the tests

A negative result does not exclude CED. The known limitations are as follows. First, the IFT140 tandem duplication was detected neither by the exome nor by the next-generation sequencing panel in the Polish patients, and was only identified by quantitative polymerase chain reaction (PCR), duplex PCR and Sanger sequencing of the breakpoints; in two other patients with Mainzer-Saldino syndrome, the panel and the exome found a single variant and only genome sequencing revealed the duplication [20, 87]. In unexplained CED with a single heterozygous IFT140 variant, the authors recommend targeted testing for this duplication [20]. Second, panels predating 2025 do not include CILK1 [5]. Third, deep intronic and non-canonical splice variants require RNA studies, such as the messenger RNA analysis that confirmed two WDR35 splice variants in a fetus [92], and the Turkish patient with a canonical acceptor variant in IFT43 did not have an RNA study [42]. Fourth, virtual panels applied to the exome may not cover all ciliopathy genes: in the adult WDR19 case, the 174-gene panel used left out 123 ciliopathy genes [44]. Fifth, allelic heterogeneity and phenotypic overlap make the finding of a single variant frequent, and it should not be interpreted in isolation [1].

5.6. Report content and variant interpretation

The report should state the gene, the reference transcript with its version (MANE Select), the variant in HGVS nomenclature at the complementary deoxyribonucleic acid (DNA) and protein levels, the zygosity, the phase (cis or trans, confirmed by parental testing) and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [1, 106]. Classification may differ between laboratories and databases: the two IFT140 variants of the Polish patients were considered likely pathogenic by the authors, but are listed in ClinVar as VUS and as conflicting classifications [20, 70]. In the 2026 Saudi family, the homozygous IFT122 variant remained a VUS despite segregation in an affected fetus and a compatible phenotype, for lack of a functional study [37]. In the adult WDR19 case, one variant was classified as likely pathogenic with the PM3 criterion at very strong level and the other as a VUS [44]. In these situations, family segregation, phenotypic concordance and periodic reassessment are the tools available.

5.7. Practical algorithm

5.8. Prenatal and preimplantation diagnosis

When the familial variants are known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [1, 18]. In a pregnancy without a known familial variant, the second-trimester ultrasound scan may detect kidney cysts, limb shortening or polydactyly, but its sensitivity has not been established [1]. In the presence of fetal findings, the karyotype and chromosomal microarray are normal and the diagnosis depends on the exome, preferably in trio [18, 92]. A systematic review cited in the 2026 report found pathogenic or likely pathogenic variants by exome in 4% (95% CI 2–6%) of fetuses with increased NT and a normal karyotype, which gives an idea of the yield of the exome in this context [18]. The prenatal ultrasound features of CED were also described in an Australian series [109].

6. Differential Diagnosis

6.1. Comparative table

6.2. Short-rib thoracic dysplasias

SRTD is the closest differential diagnosis, because it shares genes, polydactyly, brachydactyly, rhizomelic shortening and the renal, hepatic and retinal manifestations [1]. A narrow thorax is present in both, but it is usually mild in CED and marked in SRTD, where it causes severe respiratory failure; in an older review of 10 newborns and infants with SRTD, six died from respiratory failure [1, 111]. CED is distinguished by the craniofacial anomalies with dolichocephaly and prominent forehead and by the dental and ectodermal defects, and SRTD has no craniosynostosis [3, 95]. OMIM groups these disorders in the short-rib thoracic dysplasia phenotypic series (PS208500), and the 2023 Nosology acknowledges that distinguishing between them is difficult as long as there are no clear genotype–phenotype correlations [1, 2]. In SRTD, the genotype may help predict the likelihood of kidney failure and the severity of respiratory failure [49]. The short-rib thoracic dysplasias and Ellis-van Creveld syndrome enter the differential diagnosis.

6.3. Ellis-van Creveld syndrome

EVC shares with CED the ectodermal dysplasia, short limbs and narrow thorax, and the same gene, WDR35, can cause both [4, 76]. EVC is distinguished by constant postaxial polydactyly, dysplastic nails, multiple oral frenula, heart disease in about 60% (mainly atrial septal defects and atrioventricular septal defect) and the characteristic pelvis; CED has craniosynostosis, kidney failure, liver disease and retinal dystrophy, and polydactyly is uncommon in it [3, 4, 107]. The long bones of the upper limbs may be similar in both, and oral anomalies, heart disease and polydactyly are rare in CED [3]. The series of 39 patients recorded no atrioventricular septal defects or heterotaxy [19].

6.4. Mainzer-Saldino syndrome and conorenal syndromes

The association of cone-shaped epiphyses with kidney disease descriptively defines the conorenal syndromes, which include Mainzer-Saldino syndrome, SRTD and CED itself [110]. Mainzer-Saldino syndrome may have a narrow thorax and scaphocephaly, but retinal dystrophy is invariable and ectodermal features are usually absent; in the child, hair, teeth and nails are the elements that distinguish CED, and dolichocephaly due to sagittal synostosis also points towards it [1, 4, 110]. The overlap extends to Opitz trigonocephaly C syndrome, described with IFT140 variants [85, 110]. The initial descriptions, from 1970 and 1976, associated renal dysplasia, pigmentary retinal dystrophy, cerebellar ataxia and skeletal dysplasia, and the term “conorenal syndrome” was coined in 1979 from eight children with chronic kidney failure and cone-shaped phalangeal epiphyses, half with retinitis pigmentosa [64]. In the 2012 series of 15 families, the three criteria were early-onset retinal dystrophy, cone-shaped epiphyses and kidney disease, with craniosynostosis in two patients from the same family, short thorax in two and a clinical diagnosis of Jeune syndrome in a third, usually preserved cognition and liver involvement in a minority [64]. Follow-up of one of the 1979 patients to 40 years of age showed that the cone-shaped phalangeal epiphyses are no longer visible in adulthood, leaving mild shortening of the middle phalanges, which limits the value of this radiological sign after childhood [64]. In a screening of 66 probands (64 with a diagnosis of Jeune syndrome and 2 of Mainzer-Saldino syndrome), 6 had biallelic IFT140 variants, including the two with Mainzer-Saldino syndrome, all with kidney disease in early childhood, frequent retinopathy and a non-lethal thoracic course [64]. The Mexican infant with trigonocephaly and IFT140 variants also had postaxial polydactyly, cone-shaped epiphyses, renal and pancreatic cysts and congenital hepatic fibrosis, and died at 1 month from severe pneumonia, seizures and acute kidney failure [64].

6.5. Short-rib polydactyly syndromes and Beemer-Langer syndrome

The SRPSs are lethal in the perinatal period and have extremely short limbs and ribs, polydactyly and malformations of several organs [1]. Beemer-Langer syndrome (SRPS type IV) has cleft lip and palate, genital malformations and brain anomalies, and the fetus described in Campinas with IFT122 variants showed that it belongs to the same allelic spectrum [38, 95]. The boundary between severe fetal CED with hydrops and an SRPS is, in these cases, a matter of degree, and the Nosology groups the SRPS and SRTD forms due to IFT122 under the same OMIM number (269860) [2, 37]; in OMIM, however, entry 269860 (SRTD12) has no confirmed molecular basis, and some patients with the clinical diagnosis have IFT80 variants [33]. The syndrome was delineated in 1983 in two newborns with hydrops, ascites, median cleft of the upper lip, narrow thorax and short, bowed limbs [33]. The absence of polydactyly, initially used to separate it from Majewski syndrome, ceased to be discriminating when a review of affected siblings found preaxial polydactyly in half; the same review recorded brain anomalies in 16 of 26 cases and oral anomalies (cleft tongue, natal teeth, frenula) in 13 of 29 [33]. In a geographically isolated Hungarian Roma community, nine patients from seven families died between the 1st and the 45th day of life, with an estimated annual incidence of about 1 in 2000 births in that community [33].

6.6. Isolated nephronophthisis, Senior-Løken syndrome and other ciliopathies

Isolated nephronophthisis, Senior-Løken syndrome, Joubert, Meckel-Gruber and Bardet-Biedl syndromes and the isolated retinal dystrophies share renal, hepatic or retinal manifestations with CED, but not the combination of craniosynostosis, skeletal dysplasia and ectodermal dysplasia [1]. More than half of families with isolated retinitis pigmentosa have autosomal recessive inheritance, with more than 50 genes, about two thirds of which encode ciliary proteins [1]. The renal forms due to WDR19, TTC21B and other genes enter the differential diagnosis of nephronophthisis. In NPHP13 and Senior-Løken syndrome 8 due to WDR19, the Korean biopsies showed chronic tubulointerstitial nephritis with diffuse global glomerulosclerosis in 40–65% of glomeruli, and intrahepatic bile duct dilatation accompanied all cases in that series [80, 81]. Retinitis pigmentosa 80 due to IFT140 ranges from isolated forms, with night blindness from childhood and without skeletal anomalies or kidney failure from 13 to 67 years of age (one British patient also had progressive hearing loss from 4 years), to a severe congenital retinopathy resembling Leber congenital amaurosis [34]. In this form, described in 11 Saudi probands, 10 of them homozygous for the recurrent allele NM_014714.4:c.1990G>A p.(Glu664Lys), the fundus is almost normal in the first year, the ERG is unrecordable, seven had developmental delay and the five with hand radiographs had cone-shaped epiphyses, which blurs the boundary with Mainzer-Saldino syndrome; in a child with retinal dystrophy due to IFT140, the skeletal signs may only be evident on the radiograph [34].

6.7. Hepatorenal fibrocystic diseases

The liver disease of CED (fibrosis, defective ductal plate remodelling, cholestasis) overlaps with that of Caroli disease and syndrome and that of ARPKD. Caroli disease is characterised by cholangitis, intrahepatic and gallbladder lithiasis and, in Caroli syndrome, congenital hepatic fibrosis with progressive portal hypertension, with cystic kidney disease or medullary sponge kidney [1, 69]. In ARPKD liver involvement is constant, but in the neonatal period kidney disease predominates, with enlarged kidneys and 1–2 mm collecting duct microcysts, poorly visible on ultrasound [69]. In CED, the kidney disease is a nephronophthisis with normal or small kidneys and kidney failure usually appears between 2 and 6 years of age [69]. Caroli disease is part of the WDR19 spectrum [31, 44].

6.8. Discrepancies between sources in the differential diagnosis

The bone dysplasia atlas classifies CED as without brain anomalies or cleft palate, whereas GeneReviews and recent series describe ventriculomegaly, cortical atrophy, Dandy-Walker malformation and cleft palate in two reports [1, 5, 95]. The EVC GeneReviews writes “IFT40” instead of IFT140 in the CED row, a typographical error repeated in the Nosology [2, 4]. Dolichocephaly and scaphocephaly are not exclusive to CED: they may occur in Mainzer-Saldino syndrome [1].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of the recommendations

There is no therapy that corrects the ciliary defect, and there are no interventional clinical trials in CED; treatment is directed at each manifestation and requires a team with experience in craniosynostosis, skeletal dysplasias, paediatric nephrology and transplantation, hepatology and ophthalmology, ideally in a reference centre [1, 99]. The only disease-specific guidance is that of GeneReviews, which is an expert consensus without grading of evidence [1]. The remaining recommendations apply by extrapolation from guidelines for conditions with the same clinical problem, which is stated in each case: the European craniosynostosis guideline for sagittal or multisutural synostosis [22], the ESPN recommendations for somatropin in paediatric chronic kidney disease [21] and the guidelines for chronic kidney disease and nephronophthisis. There is also no ClinGen clinical actionability curation for the CED genes, which reflects lack of assessment and not lack of effective measures [17].

7.2. Treatment by manifestation

7.3. Craniosynostosis

GeneReviews indicates surgery for sagittal craniosynostosis usually before 1 year of age [1]. The 2021 European guideline, coordinated by the group that gave rise to ERN CRANIO, does not mention CED, but its recommendations for sagittal synostosis and for multisutural or syndromic forms apply by extrapolation [22]. In sagittal synostosis, surgical correction is recommended (level 4, expert opinion, because there is no spontaneous improvement), preferably before 6 months, with a minimally invasive technique if the child is referred before 5.5 months and open surgery after 6 months, and remodelling in the first year; the minimally invasive technique is associated with less blood loss, fewer transfusions and shorter operating time and hospital stay, with a similar aesthetic result (level 2) [22]. Referral should be well before 6 months, because papilloedema was found in 10% of scaphocephalies operated on at a mean age of 11 months, versus 2.5% in those operated on at 6 months; the prevalence of intracranial hypertension before surgery is 2.5–14% in sagittal synostosis, increases with age, and at follow-up after correction is 2–9% [22]. In multisutural or syndromic forms, surgery is recommended, with remodelling between 6 and 9 months or a minimally invasive technique before 6 months, frequent screening for intracranial hypertension if there is no surgery, MRI at referral for hydrocephalus and Chiari malformation, and neurocognitive and visual assessment at 7 years [22]. In CED, cranial surgery often coincides with the phase in which kidney disease appears; renal assessment before anaesthesia is a practical consequence of the natural history, and not a recommendation of the sources [1, 99].

7.4. Chronic kidney disease, dialysis and kidney transplantation

Management of nephronophthisis and chronic kidney disease (water and sodium balance in polyuric children, blood pressure and proteinuria, anaemia, acidosis, mineral and bone disorder, nutrition, vaccination, dialysis and transplantation) follows the general guidelines for paediatric chronic kidney disease. The CED GeneReviews refers to nephrology and indicates kidney transplantation in advanced stages [1]; in nephronophthisis, transplantation is the preferred modality because the disease does not recur in the graft [31]. Recessive renal ciliopathies have no therapy that significantly delays ESKD, and the interval of 5 to 10 years between the diagnosis of kidney failure and kidney replacement therapy is the window to prepare for transplantation, preferably pre-emptive [20].

In the 2022 review, published kidney transplants in patients with a genetic diagnosis were performed between 2.5 and 14 years of age: seven with WDR35, two with IFT140 and three with WDR19, in addition to the IFT122 patient in the clinical case in section 10; an eighth patient with WDR35 underwent liver transplantation at 7 years [69]. The series describe peritoneal dialysis from 8 months and transplantation at 6 years in a patient with IFT140 [20], transplantation at 2 years and 5 months in a boy with WDR35 [97], and, in the woman with WDR19, peritoneal dialysis at 26 years and living donor transplantation (a paternal aunt) 8 months later [44]. The 2025 KDIGO guideline considers genetic testing useful in the selection of a related living donor [23]; in CED, testing for the familial variants excludes affected siblings who do not yet have clinical disease, and a carrier of an IFT140 loss-of-function variant has their own risk of ADPKD, which weighs on the donation decision [23, 32]. The sources consulted do not describe a contraindication to donation by heterozygous carriers of the other genes in the class; in the New Zealand WDR19 case, the donor was a paternal aunt, with no mention of her genotype [44]. The post-transplant immunosuppression described in the reports (corticosteroid, tacrolimus and mycophenolic acid) follows paediatric transplant protocols, and the sources do not give CED-specific doses [69]. Somatropin is stopped at the time of transplantation (section 7.6).

7.5. Liver disease and liver transplantation

Liver disease requires monitoring of synthetic function, portal hypertension and biliary complications, with endoscopic band ligation of oesophageal varices when present [1, 69]. Liver transplantation is indicated in the advanced stage: in the Houston boy with WDR35, cirrhosis with severe portal hypertension and several life-threatening variceal haemorrhages led to liver transplantation at 7 years; he had stage 3 chronic kidney disease and a combined transplant was considered, but only the liver was transplanted because of the severity of the liver disease, and the authors recommend early referral for transplantation in severe cases [69, 100]. In 2025, the same centre reported a kidney transplant 5 years after the liver transplant, with 3 years of follow-up without kidney graft complications and with stenosis of the portal vein of the liver graft that required revision; the abstracts do not allow it to be stated whether this is the same patient as in 2018 [100, 105]. A 6-year-old Saudi girl underwent combined kidney and liver transplantation [104]. In the Polish case in section 10, liver transplantation was performed at 12 years, 5 years after the kidney transplant, with splenectomy immediately beforehand [69]. The choice between isolated liver, isolated kidney, sequential or combined transplantation is individual and depends on the relative severity of the two diseases [69].

7.6. Growth and somatropin

Indication and rationale. GeneReviews accepts growth hormone when the usual criteria are met and only in children with severe growth failure in whom a response is expected [1]. CED is not an approved indication for somatropin; the applicable indication is growth disturbance associated with chronic kidney disease, so use in a child with CED without chronic kidney disease would be off-label [112, 113]. The 2019 ESPN guideline is the reference for dose and criteria, and the labels are cited for comparison [21]. The growth response in a syndromic skeletal dysplasia has not been studied: the ESPN asks that the pros and cons be discussed with the family especially in syndromic kidney diseases (grade X, moderate recommendation), points out that syndromic patients were excluded from the trials and identifies syndromic kidney disease as a possible cause of poor response [21].

Criteria for starting (ESPN). Before starting: measure height (supine length before 2 years of age) and growth velocity for at least 6 months on standardised charts; estimate growth potential from the parental target height and a left wrist radiograph; correct protein-energy malnutrition, metabolic acidosis, hyponatraemia, dehydration and mineral disturbances, including secondary hyperparathyroidism (grade A, strong); achieve the target haemoglobin; and obtain creatinine and estimated glomerular filtration rate (eGFR), urea, calcium, phosphate, alkaline phosphatase, bicarbonate, parathyroid hormone (PTH), 25-hydroxyvitamin D, albumin, fasting glucose, glycated haemoglobin, thyroid-stimulating hormone (TSH), free triiodothyronine and insulin-like growth factor 1 (IGF-1), fundoscopy and Tanner stage [21]. Candidates are children with stage 3 to 5 chronic kidney disease or on dialysis, older than 6 months, with height persistently below the 3rd centile and growth velocity below the 25th centile, after treatable factors have been corrected and with growth potential (grade B, moderate); it may be considered with height between the 3rd and 10th centiles and growth velocity below the 25th centile (grade D, weak) [21]. After transplantation, somatropin is started 1 year after transplantation if there is no catch-up growth and corticosteroids cannot be withdrawn (grade B, moderate) [21].

The guideline dose coincides with that of the European SmPC and with the ceiling of the US label; the difference is that the SmPC allows higher doses and the guideline does not, and that the guideline accepts somatropin after transplantation, a situation outside the conditions of both labels [21, 112, 113].

Contraindications. The ESPN advises against starting somatropin with closed epiphyses, hypersensitivity, refusal, severe secondary hyperparathyroidism (PTH above 500 pg/ml), proliferative or severe diabetic retinopathy, in the first year after transplantation, in critical acute illness and in active neoplasia [21]. The SmPC adds critical acute illness after cardiac or abdominal surgery, multiple trauma or acute respiratory failure [112].

Monitoring and adverse effects. Benign intracranial hypertension occurred in 3 of 1376 patients with chronic kidney disease in a registry, which justifies baseline fundoscopy and fundoscopy in the presence of persistent headache or vomiting; in CED, this surveillance adds to that of the craniosynostosis [21, 22]. Blood glucose is monitored mainly in obese patients; somatropin is stopped if PTH exceeds 500 pg/ml and resumed when it is within target; slipped capital femoral epiphysis requires a radiograph in the presence of symptoms and discontinuation if confirmed; kidney function (for example, every 3 months in stages 3–4) did not deteriorate faster in 10 years of data, but somatropin is stopped in the event of an unexplained fall in eGFR; Tanner stage is assessed annually after 10 years of age and bone age annually [21]. The SmPC also mentions central hypoadrenalism, altered insulin sensitivity, hypothyroidism (monitor thyroid function) and secondary neoplasms in cancer survivors [112]; the US label mentions avascular necrosis in patients with advanced osteodystrophy and attenuation of the effect by corticosteroids [113]. There was no increase in neoplasms or in rejection (relative risk 1.56; 95% CI 0.97–2.53) in transplant recipients [21].

Response and discontinuation. An adequate response is an increase in growth velocity of more than 2 cm/year over baseline in the first year [21]. Discontinuation is considered if the response is inadequate for at least 6 months, and is mandatory at kidney transplantation, on reaching target height, in an adolescent with growth velocity below 2 cm/year or epiphyseal fusion, and in the event of a serious adverse effect, serious illness or trauma [21].

7.7. Respiratory system and infections

A newborn with pulmonary hypoplasia may need mechanical ventilation [1]. Pneumonia is treated after a chest radiograph and sputum examination, with antibiotic therapy according to the organism and context, and GeneReviews recommends long-term antibiotic prophylaxis in children with recurrent infections, without specifying the drug, dose or duration [1]. The sources consulted do not identify a validated regimen for CED; the choice follows local protocols for prophylaxis of recurrent respiratory infections. The demonstration of motile cilia dysfunction in a child with WDR35 suggests that airway clearance measures may be of interest, but there are no interventional studies [66].

7.8. Other manifestations

Low-vision aids and adapted educational programmes are the treatment of retinal dystrophy; gene and editing therapies are at the preclinical stage (section 7.12) [1, 102]. Dental anomalies are treated by a dentist or oral surgeon, with early intervention in oligodontia [1]. Polydactyly is corrected surgically if the family so wishes, hip dysplasia follows the usual orthopaedic treatment, and inguinal and umbilical hernias are repaired surgically [1]. Heart disease is followed by cardiology [1]. Developmental delay justifies speech therapy, physiotherapy and early intervention [1]. In the girl with severe primary hypothyroidism, the authors recommend monitoring thyroid function before and after hepatorenal transplantation, a recommendation based on a single case [104].

7.9. Agents and circumstances to avoid

In patients with kidney disease, nephrotoxic drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), are a relative contraindication, and the nephrologist may recommend reducing dietary potassium and phosphate [1]. Iodinated contrast with eGFR below 60 ml/min/1.73 m² follows the acute kidney injury precautions of the KDIGO guidelines, applied to nephronophthisis [31]. The doses of all renally eliminated drugs are adjusted to eGFR. In heterozygous IFT140 carriers with ADPKD, the data do not support the use of tolvaptan, because it is not known whether it is effective in the forms due to minor genes [23, 114].

7.10. Regulatory status

No medicine has an approved indication for CED in any jurisdiction. The only drug with a relevant approved indication is somatropin, through the route of growth disturbance associated with chronic kidney disease [112, 113].

In Portugal, Omnitrope® is centrally authorised and its European SmPC is the applicable one; the national SmPCs of other somatropins were not consulted for this article [112].

7.11. Clinical trials

There is no interventional clinical trial in CED: a search of ClinicalTrials.gov on 28 October 2026 with the disease and gene terms found only one retrospective observational study from the Hospices Civils de Lyon (NCT04184531), on prognostic factors of chronic kidney disease, with four patients planned and unknown status since 2019 [99, 116]. The evidence on the only relevant pharmacological intervention, somatropin, comes from trials in paediatric chronic kidney disease in general, from which syndromic patients were excluded [21].

These results cannot be transposed directly to CED. The trials included children with non-syndromic chronic kidney disease, were small and old, and the ESPN acknowledges the limited quality of the evidence [21]. Short stature in CED has an intrinsic skeletal component that somatropin does not correct, and there are no response data in ciliary skeletal dysplasias; the decision is individual and should weigh the expected response, the burden of daily injections and the risks [1, 21]. There are no negative, suspended or withdrawn trials in CED because there have been no trials.

7.12. Therapies under preclinical investigation

Reintroduction of normal CILK1 into fibroblasts from patients with CED due to CILK1 corrected most of the ciliary abnormalities, and the Caenorhabditis elegans model reproduced the phenotype [5]. Kidney organoids derived from induced pluripotent stem cells from a patient with Mainzer-Saldino syndrome due to IFT140 had short cilia, corrected by CRISPR-Cas9 editing [20]. A theoretical analysis showed that the six WDR19 variants of four patients with retinopathy would be correctable by prime editing, without any cellular or animal experiment [102]. None of these approaches has reached human studies.

7.13. Developments in the last 6–12 months

In the same period, there were no regulatory opinions or authorisations for CED, nor registrations of interventional trials [116].

7.14. Special populations: pregnancy, perioperative care and transition

Pregnancy and lactation. There are no published pregnancies in women with CED, and fertility is unknown [1]. The sources consulted give no specific guidance; a pregnancy in a woman with chronic kidney disease, a transplant or liver disease would follow the recommendations for those conditions. The recommendation of caesarean section in pregnant women with EVC and pelvic anomalies refers to another disorder and has not been studied in CED [77].

Perioperative care. The sources do not describe anaesthetic complications specific to CED. In the Polish case, liver transplantation required continuous venovenous haemodiafiltration for 5 days in the perioperative period [69]. The risk factors arising from the phenotype — thoracic restriction and respiratory infections, reduced kidney function, coagulopathy and thrombocytopenia due to liver disease, joint laxity — are the same ones that guide the pre-anaesthetic assessment of other skeletal ciliopathies, but there are no published recommendations directed at CED [1, 69].

Transition to adulthood. At least three patients with CED have survived into young adulthood and the woman with WDR19 is the best documented adult patient, with dialysis and kidney transplantation, Caroli disease and retinal dystrophy diagnosed between 19 and 31 years of age [1, 44]. Transition requires coordinated transfer of renal, hepatic, ophthalmological and transplant care, and reproductive counselling of the young adult [1].

7.15. Guideline recommendations and discrepancies

8. Reproductive Options and Family Counselling

8.1. Inheritance pattern and recurrence risks

All forms of CED are autosomal recessive [1, 5]. The parents of an affected individual are, as a rule, obligate heterozygotes and asymptomatic, and their status should be confirmed by molecular testing, which also establishes the phase of the variants [1]. When both parents are carriers, each pregnancy has, at conception, a 25% chance of an affected child, 50% of an asymptomatic carrier and 25% of an unaffected non-carrier child [1]. Manifestations may differ greatly between affected siblings, including the presence of craniosynostosis, the age at ESKD and survival, so the phenotype of the index case does not predict that of a sibling [1, 93, 94]. The parents’ siblings have a 50% chance of being carriers [1]. As for the offspring of affected individuals, fertility is unknown and there are no published children; all children of an affected individual would be obligate carriers [1].

8.2. Particular genetic situations

In consanguineous families, homozygosity by descent may reveal more than one rare variant, and the 2026 Saudi family showed an additional DVL3 variant, compatible with another syndrome in the differential diagnosis, that did not segregate with the disease [37]. In communities with a founder effect, such as the Iraqi Turkmen community with the CILK1 variant, the authors propose carrier screening and cascade testing targeted at the community [5]. In Poland, the recurrence of the same combination of WDR35 variants in four families suggests that targeted testing for these alleles would have a high yield in that population [40].

8.3. Carriers, cascade testing and the particular case of IFT140

Carrier testing in at-risk relatives requires prior identification of the variants in the index case [1]. Heterozygous carriers of the IFT122, WDR35, WDR19, IFT43, IFT52 and CILK1 genes are asymptomatic; none of the 22 carriers of the CILK1 variant had epilepsy or developmental delay, despite the association of other heterozygous variants of this gene with juvenile myoclonic epilepsy [1, 5].

IFT140 is the exception. Monoallelic loss-of-function variants cause a mild ADPKD: in a multicentre study, they were identified in 12 families with several affected members and 26 isolated cases, and accounted for 1.9% of families with a clinical diagnosis of ADPKD without previous genetic testing; the phenotype is of few, large cysts, with limited kidney failure and rare liver cysts [32]. The 2025 KDIGO guideline includes this form in the ADPKD group under the designation ADPKD-IFT140, estimates that it accounts for 1–2% of cases, describes large, bilateral cysts with kidney function usually preserved until advanced age, and points out that, in a US health system, only 2.5% of carriers of IFT140 variants had a coded diagnosis, which reflects low clinical penetrance [23]. OMIM classifies the association as susceptibility (PKD9, 621164) and summarises later series: among 368 carriers of predicted loss-of-function variants with kidney disease, 223 (60.6%) had a polycystic phenotype, the most frequent variants were NM_014714.4:c.2399+1G>T (16.6%) and c.1377G>A p.(Trp459Ter) (15.8%), and kidney failure appeared later and progressed to ESKD less often than in other forms of polycystic kidney disease; in an Italian series, IFT140 accounted for 3 of 129 patients with ADPKD tested (2.3%), with large cysts, hypertension in the older patients, rare liver cysts and two asymptomatic carriers at 24 and 26 years; none of these variants was studied functionally [7]. The susceptibility entry adds population-based data: in the Genomics England 100K project, 40 of 152 carriers of variants predicted to be pathogenic (26.3%) had kidney cysts; in the UK Biobank, loss-of-function variants were more frequent in patients with cystic kidney disease than in controls (2.69% versus 0.21%); in a genotype-first approach in a regional health system, only 5 of 205 carriers (2.5%) had a clinical diagnosis of ADPKD; in the initial series, the mean age at diagnosis was 52.7 years and hypertension affected two thirds of patients with information [36]. Adults on dialysis at 34 and 59 years have been described, as has a 6-year-old girl with a large simple cyst, initially mistaken for a cystic nephroma, and an exon 13 deletion inherited from her mother, who also had kidney and liver cysts [36]. In a family with recessive disease, the heterozygous mother of a boy with Mainzer-Saldino syndrome due to a homozygous IFT140 frameshift variant had several bilateral kidney cysts [36]. OMIM stresses that none of these series included functional studies and that transmission shows incomplete, age-dependent penetrance, with oligogenic inheritance in several families [36]. The same guideline recommends that, for genes that also cause recessive disorders, carriers be counselled about that risk and that testing be offered to the partner when the couple is planning children [23]. For adults at risk of ADPKD, it recommends abdominal ultrasound as the first screening examination (recommendation 1B), and for children at risk it recommends shared decision-making with the parents and with the mature child and annual blood pressure measurement from birth [23]. Three children, from the prenatal period to 14 years of age, with ADPKD due to IFT140 and normal kidney function have been described, whose cascade screening revealed undiagnosed ADPKD in adult relatives [117]. It follows, as an implication and not as an explicit recommendation of the CED sources, that the parents and heterozygous relatives of a patient with CED due to IFT140 loss-of-function variants may have their own risk of adult ADPKD and benefit from information and possibly renal ultrasound; the monoallelic effect of the tandem duplication, which preserves the reading frame, and that of missense variants have not been studied [20, 32, 114]. The proximity between IFT140 and PKD1 (about 0.5 Mb at 16p13.3) may cause confusion in the interpretation of tests [32].

8.4. At-risk siblings

When the familial variants are known, testing of at-risk infants allows diagnosis and early surveillance of respiratory, renal, hepatic and visual manifestations [1]. When they are not known, the newborn should be examined by a paediatrician and a geneticist; renal and hepatic assessment (ultrasound, blood pressure, creatinine and liver enzymes) is performed by 3 months of age and repeated every 6 months, and the parents should be alerted to polydipsia and jaundice [1].

8.5. Prenatal diagnosis and preimplantation genetic testing

With the familial variants identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing, with in vitro fertilisation and intracytoplasmic sperm injection, are options, alongside natural conception with or without prenatal diagnosis [1, 18]. GeneReviews notes that perspectives on prenatal testing vary between professionals and families, and that the best time to discuss the risk and the options is before pregnancy [1]. The second-trimester ultrasound scan may detect kidney cysts, short limbs or polydactyly, but its sensitivity has not been established and a normal scan does not exclude recurrence, as shown by the fetuses with late findings [1, 18]. In the 2026 Chinese case, after termination of pregnancy, counselling included the 25% recurrence risk and the three reproductive options [18].

8.6. Counselling of minors and DNA banking

GeneReviews directs reproductive genetic counselling to young adults who are affected, carriers or at risk of being carriers, the age at which individuals can decide for themselves about carrier testing, which has no medical consequence in childhood [1]. The situation of siblings at risk of being affected is different, because early diagnosis changes surveillance [1]. When the molecular diagnosis has not been confirmed, storing the patient’s DNA is recommended, because methods and knowledge of the genes evolve [1, 118].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and incidence: what each figure measures

There are no population-based studies of CED. The figures available are counts of published patients: more than 40 cases in the 8th edition of a dysmorphology textbook, fewer than 100 individuals according to GeneReviews, more than 70 patients and 41 families with genetic confirmation up to 2021, at least 50 patients from 38 families with a molecular diagnosis in 2025 and about 100 individuals in 2026 [1, 5, 42, 50, 69]. Orphanet assigns it the worldwide point prevalence class below 1/1,000,000, with about 60 cases, which is a class limit and not a measured rate [17]. The incidence of “about 1 in 1,000,000 live births” in the USA, cited in a transplant report and repeated in another, is an estimate by the authors without a population source and should not be used as a prevalence [69, 100]. Diagnostic labelling is inconsistent between CED, SRTD and Mainzer-Saldino syndrome, which makes any count dependent on the definition used [2, 44].

9.2. United States and Europe

The founding descriptions are North American (Johns Hopkins, 1975 and 1977) and the largest clinical series was assembled in Boston [19, 51, 52]. The reports of liver transplantation and sequential transplantation come from Houston [100, 105]. In Europe, Poland has the largest number of published families, with patients due to IFT122, WDR35 and IFT140 and with WDR35 founder variants [20, 40, 59]. There are series and cases from the Netherlands, Norway, the United Kingdom, Greece, Italy, France (Lyon) and Russia [54, 56, 57, 60, 62, 87, 99]. None of these countries has prevalence estimates.

9.3. Populations with a founder effect, consanguinity or particular distribution

Consanguineous families are overrepresented among published cases: the Moroccan family with IFT43, the Saudi families with IFT122 (2014 and 2026), the Indian child with IFT52, the Iraqi Turkmen families with CILK1 and the Pakistani family with retinitis pigmentosa due to IFT43 [5, 37, 42, 46, 61, 72]. The CILK1 variant c.1664_1665del has a founder effect in the Tal Afar community, and the WDR19 variant c.878G>A p.(Cys293Tyr) in an Israeli ethnic minority with adult ESKD [5, 44]. In East Asia, the published Japanese and Chinese cases mainly include prenatal diagnoses with hydrops or severe findings [18, 73, 74, 92]. In Turkey, a cohort of 20 patients with suspected skeletal ciliopathy had one diagnosis of CED [108]. In the same group of genes, outside CED, there are alleles with a defined population distribution: the IFT140 tandem duplication, with a founder haplotype in European patients with Mainzer-Saldino syndrome and CED5; IFT140 c.1990G>A p.(Glu664Lys) in Saudi congenital retinopathy; CILK1 NM_014920.5:c.815G>A p.(Arg272Gln) in ECO among the Old Order Amish; and an SRPS type IV with an estimated incidence of about 1 in 2000 births in a Hungarian Roma community [33, 34, 48, 64].

9.4. Portugal and Brazil

The sources consulted contain no cases or epidemiological data from Portugal. From Brazil, the group at the State University of Campinas described the fetus with an SRPS type IV (Beemer-Langer) phenotype and biallelic IFT122 variants that established Beemer-Langer syndrome as an allelic ciliopathy of CED1 [38]. In Latin America, three Argentinian patients with six new IFT122 variants have also been described [71]. Physicians in both countries have access to the somatropins approved by the EMA (Portugal) and registered with ANVISA (Brazil) [112, 115].

9.5. Special populations

Young children account for most of the mortality (respiratory, cardiac and due to coagulopathy) and for the phase of greatest renal risk, between 2 and 6 years of age [1]. Fetuses and newborns with severe forms approach SRPS [18, 37]. Adults are few and are mainly among patients with WDR19 variants, whose phenotype may be limited to the kidney, retina and liver [1, 44]. Transplant recipients need combined surveillance of the graft and of the other manifestations [69].

9.6. European Reference Networks and patient organisations

There is no ERN dedicated to CED, and the patient is followed by the network for each main manifestation: ERKNet, for rare kidney diseases, with working groups on congenital malformations and ciliopathies, paediatric chronic kidney disease, paediatric dialysis and paediatric kidney transplantation [24]; ERN BOND, for bone dysplasias [25]; ERN CRANIO, for craniosynostoses [26]; ERN-EYE, for retinal dystrophies [27]; ERN RARE-LIVER, for fibrocystic liver disease [28]; ERN ITHACA, for rare malformation syndromes [29]; and ERN TransplantChild, for paediatric transplantation [30]. The Lyon series advocates follow-up in rare disease reference centres with craniofacial, skeletal and renal experience [99]. Among patient organisations, the Ciliopathy Alliance, in the United Kingdom, brings together patient groups, researchers and professionals in the ciliopathies [119], and the National Foundation for Ectodermal Dysplasias, in the USA, supports patients with ectodermal dysplasias and maintains an international registry [1, 120]. No patient organisation specific to CED was identified in the sources consulted.

10. Illustrative Clinical Case

10.1. Kidney transplantation followed by liver transplantation in a child with CED1 (Ryżko and colleagues, 2022)

A Polish boy, the second child of healthy consanguineous parents, was born at 38 weeks after an uneventful pregnancy, weighing 3.54 kg (above the 50th centile), with a length of 56 cm and a head circumference of 40.5 cm (both above the 98th centile) and an Apgar score of 7 at one minute [69]. At birth he had short limbs, a narrow thorax, brachydactyly, large bilateral inguinal hernias, dolichocephaly, prominent auricles, a small, flat nose and hypertelorism. The photographs published at 1, 5, 9 and 16 years show the evolution of the facies, with dolichocephaly, high forehead, epicanthus, telecanthus, broad nasal root, full cheeks and low-set ears (Figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC8914039/, whose legend was consulted) [69]. His older sister had the same picture [69].

Genetic study of the family, within the research project that identified the gene, showed in both siblings the IFT122 variant c.1658T>G p.(Val553Gly) in the homozygous state, with heterozygous parents; in the numbering of the MANE transcript, the variant is NM_052989.3:c.1505T>G p.(Val502Gly), classified as pathogenic in ClinVar, whereas the authors classified it as likely pathogenic according to the ACMG criteria in 2022 [59, 69, 70]. The patient’s skin fibroblasts had fewer and shorter primary cilia than controls [59, 69].

Creatinine was elevated from infancy and kidney function deteriorated progressively to kidney failure at 3.5 years, requiring chronic dialysis; at 7 years he underwent deceased-donor kidney transplantation, with triple immunosuppression (corticosteroid, tacrolimus and mycophenolic acid) [69]. At that time he already had splenomegaly, without complications of portal hypertension and with preserved hepatic synthetic function; three years after the kidney transplant, oesophageal varices appeared and were ligated [69]. At 12 years he was admitted with hepatic decompensation with ascites: elevated urea and creatinine, hypoproteinaemia and hypoalbuminaemia (albumin 36.3 g/l), coagulopathy (international normalised ratio [INR] 1.64; fibrinogen 1.08 g/l), anaemia (haemoglobin 10.6 g/dl), leucopenia (2.2×10³/µl) and thrombocytopenia (58×10³/µl); ultrasound showed a small, irregular, fibrotic liver and a spleen of 14×8 cm, later 20×10 cm [69]. He underwent paracentesis (about 4 litres), diuretics and albumin, with reduction of the abdominal girth, which had reached about 100 cm, to the values before decompensation and a loss of about 8 kg, and gastroscopy showed oesophageal varices along their entire length, which were ligated [69]. Because of the severity of the portal hypertension, ascites and hypersplenism, he was proposed for liver transplantation and received a deceased-donor liver, with splenectomy immediately beforehand; in the perioperative period he required continuous venovenous haemodiafiltration for 5 days [69]. The explant showed fibrosis with features of cirrhosis, abnormal morphogenesis of the intrahepatic bile ducts resembling ductal plate malformation and severe focal cholestasis (Figure 2 of the article, legend consulted) [69].

Three years after the liver transplant, at 16 years, liver function was normal, but the kidney graft showed chronic nephropathy with an eGFR of 44 ml/min/1.73 m², and the authors anticipated a new kidney transplant within the following 5 years; he remained on tacrolimus, mycophenolate mofetil and prednisolone [69]. The 16-year course is summarised in Figure 3 of the article (legend consulted) [69]. The authors presented it as the first sequential liver transplant after a kidney transplant in a child with CED and concluded that regular follow-up by hepatology and nephrology and an individual decision on the type of transplant are needed [69].

10.2. What the case teaches

The case brings together the typical sequence of the treated disease: ESKD at preschool age, within the 2 to 6 year range described in GeneReviews; kidney transplantation at school age; and a fibrocystic liver disease that progresses silently after the kidney transplant to decompensated portal hypertension [1, 69]. Splenomegaly at 7 years was the first sign of portal hypertension, and endoscopic surveillance allowed the varices to be treated before bleeding [69]. The choice between sequential and combined transplantation has no established rule: in the Houston boy with WDR35, with stage 3 chronic kidney disease, only liver transplantation was performed [69, 100]. The measures described (dialysis, immunosuppression, splenectomy before transplantation) are decisions of one centre and not a routine recommendation; they do not differ from the general transplantation guidance and GeneReviews does not specify them [1]. The serial photographs document the change in the facies with age, also described in the patients with IFT140 [20].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis depends mainly on kidney disease, liver disease and, in the first years, respiratory function. In the GeneReviews compilation, 10 of 65 children died before 7 years of age, from respiratory failure, cardiac failure, hypovolaemic shock due to coagulopathy or unknown cause [1]. At least 60–70% of patients have kidney failure, and 10 of 21 children with follow-up reached ESKD, most between 2 and 6 years of age; ESKD is cited as the most frequent cause of death in the untreated disease [1, 50]. In the more recent series with dialysis and transplantation, survival into adolescence is the rule in published reports, and the kidney graft may fail due to chronic nephropathy, as in the case in section 10 [69, 105]. The long-term hepatic prognosis is probably unfavourable, without longitudinal data; two patients died at 4 months from renal and hepatic failure and one patient with CILK1 died at 9 years from liver disease [1, 5, 69]. Retinal dystrophy may progress to legal blindness in young adulthood, by analogy with Bardet-Biedl syndrome [1]. Intellectual development is usually normal, which is important for school planning and transition [1, 50].

11.2. Prognostic factors

There are no validated prognostic factors. The gene does not predict the course, and variability within families is large [1, 40]. In the WDR19 review, no genetic characteristic predicted the onset of kidney disease, and six of the eight homozygotes for c.3533G>A had ESKD in early childhood [44]. Prenatal presentation with hydrops or increased NT is associated with a severe outcome in published cases, with selection bias towards severe cases [18]. Male sex has been suggested as a factor for greater kidney dysfunction with IFT122 and WDR35, without confirmation [20]. The Lyon observational study on prognostic factors of kidney disease has no published results [116].

11.3. Surveillance table

11.4. Long-term follow-up and transition

Follow-up is multidisciplinary and lifelong, coordinated by a centre with experience in ciliopathies and paediatric transplantation [1, 99]. After kidney transplantation, liver surveillance continues, because liver disease may progress independently, as in the case in section 10 [69]. The adult patient with CED or with a WDR19 phenotype needs renal (graft or native disease), hepatic (Caroli disease, fibrosis) and ophthalmological follow-up, and reproductive counselling, although fertility is unknown [1, 44]. In the New Zealand patient, Caroli disease was discovered after kidney transplantation and retinopathy at 30 years of age, which shows that new manifestations may appear in adulthood [44].

12. Summary and Final Considerations

Cranioectodermal dysplasia is an autosomal recessive skeletal ciliopathy in which the defect of retrograde intraflagellar transport, almost always due to biallelic variants in IFT-A complex genes, produces a recognisable combination of dolichocephaly due to sagittal craniosynostosis, a facies with frontal bossing and full cheeks, brachydactyly, rhizomelic shortening, narrow thorax and ectodermal dysplasia, to which nephronophthisis, fibrocystic liver disease and retinal dystrophy are added [1, 19]. WDR35 and IFT122 are the most frequent genes; WDR19, IFT140, IFT43 and IFT52 account for a minority; CILK1 was added in 2025 as the first non-IFT gene; and about one third of published patients still have no molecular diagnosis [1, 5]. The same genes cause the short-rib thoracic dysplasias, the short-rib polydactyly syndromes, Mainzer-Saldino syndrome, a form of Ellis-van Creveld syndrome, nephronophthisis and isolated retinopathies, and the 2023 Nosology treats these entities as points on a spectrum designated by the phenotype–gene dyad [2, 44].

The clinical diagnosis rests on Lin’s criteria (two frequent findings and two other anomalies, one of them ectodermal), and the molecular diagnosis on a skeletal ciliopathy panel that includes CILK1 or on exome or genome sequencing [1, 5, 19]. A negative result does not exclude the disease, and the IFT140 tandem duplication, invisible to the exome, is the clearest example of the limitations of sequencing [20, 87]. The nomenclature of IFT122 and WDR35 variants requires the MANE transcript, because the historical literature uses transcripts with different numbering, and the notation of at least one variant published in 2026 is incompatible with ClinVar [18, 70].

Treatment is symptomatic and multidisciplinary: craniosynostosis surgery preferably before 6 months with subsequent screening for intracranial hypertension; conservative management of chronic kidney disease, dialysis and kidney transplantation, usually between 2.5 and 14 years of age in published patients; surveillance for portal hypertension and liver transplantation, isolated, sequential or combined; somatropin according to the criteria for paediatric chronic kidney disease, at a dose of 0.045–0.05 mg/kg/day, with the response not studied in this dysplasia; and visual, dental and developmental support [1, 21, 22, 69]. Renal and hepatic surveillance should start at diagnosis and, in at-risk siblings, by 3 months of age, with six-monthly repetition, and ophthalmological assessment should be performed before 4 years of age and annually thereafter [1, 97].

Genetic counselling follows the autosomal recessive model, with a 25% recurrence risk and options of prenatal and preimplantation diagnosis once the variants have been identified; carriers of IFT140 loss-of-function variants are the exception, with their own risk of mild adult autosomal dominant polycystic kidney disease [1, 23, 32]. The main gaps are the absence of longitudinal series into adulthood, of population prevalence estimates, of data on pregnancy and anaesthesia and of any therapeutic trial; follow-up in reference centres linked to the European Reference Networks for kidney, bone, craniofacial, eye, liver and transplantation disorders is the framework available [1, 24, 99].

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