Ritscher-Schinzel (3C) Syndrome and WASH-Commander Complex Disorders

A genetically heterogeneous cranio-cerebello-cardiac malformation syndrome, caused in almost all molecularly diagnosed cases by loss of function of subunits of the SNX17-Retriever-CCC-WASH endosomal recycling machinery (WASH and Commander complexes), with an autosomal dominant form due to DPYSL5 classified in the same series by OMIM but with a distinct mechanism.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

The allelic disorder of WASHC5 is hereditary spastic paraplegia type 8 (SPG8, OMIM 603563, autosomal dominant); Dandy-Walker malformation as an entity and Joubert syndrome enter the differential diagnosis [10, 20].

1. Introduction

1.1. Original description and clinical delineation

In 1987, Ritscher, Schinzel and colleagues, in Zurich, described two sisters, daughters of healthy parents, with a similar pattern of craniofacial anomalies, a posterior fossa malformation and congenital heart disease [21]. Both had macrocephaly, prominent forehead and occiput, parietal foramina, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, narrow palate and apparently low-set ears. The elder had a Dandy-Walker malformation with communicating hydrocephalus, aplasia of the posterior portion of the cerebellar vermis and high insertion of the confluence of the sinuses, and a complete atrioventricular canal; she died at three and a half years, after unsuccessful cardiac surgery. The younger had a Dandy-Walker variant, with vermis aplasia, hypoplasia of the hemispheres, a large cisterna magna and no hydrocephalus, and underwent successful surgery for a mitral cleft and a septum primum defect. Both had moderate intellectual disability and a normal karyotype, and the authors proposed an autosomal recessive syndrome [21]. The family history also included a boy who died shortly after birth from asphyxia with multiple congenital anomalies and a spontaneous miscarriage in the third month [7].

In 1989, Verloes and colleagues, in Liège, described a third child, without parental consanguinity, with wide fontanelles and a dysmorphism reminiscent of cleidocranial dysplasia, relative macroencephaly with vermis hypoplasia, hypertelorism, aplasia of the first ribs, multiple sternal ossification centres, thin bones, septal heart defect, hypotonia and developmental delay, and proposed the acronym "3C" (cranio-cerebello-cardiac) [22]. In the following years reports of isolated cases and sibships multiplied: Marles and colleagues described, in 1995, eight children from the First Nations of Canada (three boys and five girls from seven families, three of them related) with frequent ocular colobomas [23]; Kosaki and colleagues, in 1997, reviewed 19 cases and showed that hypotonia and motor delay improve with age, leaving speech delay as the main limitation, and that the heart defects are distributed between endocardial cushion defects and conotruncal defects [24]. In 1999, Wheeler and colleagues followed from birth a girl with documented growth hormone deficiency, then the oldest published patient, at 13 years [25]. In 2003, Zankl and colleagues re-evaluated at 21 years the surviving sister of the original description, who still had short stature and mild intellectual disability, and showed that the humoral immunodeficiency described in 1989 resulted from secondary loss of immunoglobulin G (IgG) through the gut and not from a primary B-cell defect [9, 26].

1.2. Clinical criteria and heterogeneity before molecular diagnosis

Leonardi and colleagues, in 2001, after four new cases and a literature review, proposed minimum criteria for a sporadic case with normal chromosomes: congenital heart disease other than an isolated patent ductus arteriosus; cerebellar malformation; and cleft palate, or ocular coloboma, or at least four of seven more subjective craniofacial features (prominent forehead, prominent occiput, hypertelorism, downslanting palpebral fissures, low-set ears, depressed nasal bridge and micrognathia) [27]. In 2005, DeScipio and colleagues showed that the 6p25 subtelomeric deletion produces a highly overlapping phenotype, with Dandy-Walker malformation, hydrocephalus, septal defects, anterior chamber anomalies of the eye and intellectual disability [28], and in 2006 Stellingwerff and colleagues, in a segregation analysis of 27 published pedigrees, obtained results consistent with autosomal recessive inheritance, but with wide confidence intervals, and recommended that no case of 3C syndrome be published without assessment of 6p copy number [18].

1.3. Milestones of molecular discovery

The first molecular cause was identified in 2013 by Elliott and colleagues, through homozygosity mapping in an isolated First Nations community in northern Manitoba: all patients were homozygous for a variant at the donor splicing site of intron 27 of the KIAA0196 gene, which encodes strumpellin, a subunit of the WASH complex [29, 30]. In 2012, Voineagu and colleagues had proposed CCDC22 as a candidate gene for syndromic X-linked intellectual disability in a large Australian family [31], and in 2015 Kolanczyk and colleagues identified a missense variant in CCDC22 in two Austrian brothers with a 3C syndrome phenotype, establishing the X-linked form and proposing the term "WASHopathies" [9, 32]. In 2016, Bartuzi and colleagues linked the loss of the CCC and WASH complexes to endosomal sorting of the low-density lipoprotein receptor (LDLR) and to the hypercholesterolaemia observed in patients [33]. In 2017 the Retriever complex, a heterotrimer of VPS35L, VPS26C and VPS29 [34], and the Commander super-complex [35] were described. In 2020, Kato and colleagues identified biallelic VPS35L variants in two Japanese siblings with a severe form of 3C-like syndrome [4], and in 2021 Jeanne and colleagues found a heterozygous DPYSL5 variant in the surviving sister of the Ritscher family, which led OMIM to reclassify the original family as RTSC4 [6, 7]. In 2023, the complete structure of Commander, with 16 subunits, allowed the pathogenic variants to be mapped [36], and in 2025 Kato and colleagues described patients with biallelic variants in COMMD4, COMMD9 and CCDC93 and characterised the syndrome as an endosomal "recyclinopathy" [8].

1.4. Nomenclature and reclassifications

The symbol KIAA0196 was replaced by WASHC5 (WASH complex subunit 5), and C16orf62 by VPS35L [9, 34]. Smith's Recognizable Patterns of Human Malformation writes "KIAA9196", a typographical error for the old symbol [2]. The OMIM numbering RTSC1 to RTSC4 assigns type 1 to WASHC5, type 2 to CCDC22, type 3 to VPS35L and type 4 to DPYSL5 [10, 17, 37]; Gjerulfsen and colleagues, in 2021, used the reverse numbering for the first two types, which makes it necessary to confirm the gene whenever a subtype number is read in the literature [12]. Rodgers and colleagues proposed a dyadic gene–phenotype designation ("CCDC22-related Ritscher-Schinzel syndrome"), which avoids this ambiguity [38]. Kolanczyk's term "WASHopathies" became outdated after the discovery that the forms due to CCDC22, VPS35L, COMMD4, COMMD9 and CCDC93 affect the Commander complex and not WASH; Kato and colleagues propose grouping all forms of the SNX17-Retriever-CCC-WASH pathway as "recyclinopathies" [8]. The inclusion of DPYSL5 in the series is debated: the protein does not take part in this pathway, patients with de novo variants have neither heart disease nor the characteristic face and do have agenesis of the corpus callosum, and Desprez and colleagues and Kato and colleagues argue for treating it as a distinct neurodevelopmental disorder [8, 15].

1.5. Definition of the entities within scope

Ritscher-Schinzel syndrome (RSS) is defined by the association of characteristic craniofacial dysmorphism, posterior fossa malformation (Dandy-Walker malformation, vermis hypoplasia or dysplasia, enlarged cisterna magna) and congenital heart disease, with variable intellectual disability; molecular diagnosis has shown that heart disease or the cerebellar malformation may be absent [9, 12]. The scope covers the entire class: the four forms with an OMIM number (RTSC1 to RTSC4), the proposed forms due to COMMD4, COMMD9 and CCDC93, the overlapping phenotypes due to VPS26C and WASHC4 (autosomal recessive intellectual developmental disorder 43, OMIM 615817) and the attenuated CCDC22 forms, including X-linked epilepsy [8, 10, 17, 39]. Spastic paraplegia type 8 is mentioned as an allelic disorder of WASHC5 [20].

2. Molecular Genetics and Pathophysiology

2.1. The SNX17-Retriever-CCC-WASH endosomal recycling pathway

Membrane proteins internalised by endocytosis reach the early endosome, where they are directed to lysosomal degradation or retrieved and recycled to the cell surface [8, 34]. The Retriever complex, a heterotrimer of VPS35L, VPS26C and VPS29 distantly related to retromer, recognises cargoes through the adaptor SNX17 (sorting nexin 17), which binds cytoplasmic ΦxNPxY/F or ΦxNxxY/F motifs (Φ represents a hydrophobic residue and x any residue); more than 120 surface proteins, including integrins, signalling receptors and solute transporters, depend on SNX17-Retriever to maintain their surface levels [8, 34]. The CCC complex is formed by CCDC22, CCDC93 and ten COMMD proteins (COMMD1 to COMMD10), which make up a heterodecameric ring stabilised by the two CCDC proteins; these form a coiled-coil dimer that links the COMMD ring to Retriever and recruits a sixteenth subunit, DENND10, forming the Commander super-complex [36, 40, 41]. Commander associates with the WASH complex (WASH1, FAM21, strumpellin/WASHC5, SWIP/WASHC4 and CCDC53), which is recruited to endosomes and acts as a nucleation-promoting factor, activating the ARP2/3 complex and the local polymerisation of branched actin required for scission of the tubules that carry the cargo [8, 9, 42].

The cargoes of this pathway include LDLR and LDL receptor-related protein 1 (LRP1), whose loss of recycling in hepatocytes explains the hypercholesterolaemia; integrin β1; megalin (LRP2), whose reduction in the proximal tubule explains the low-molecular-weight tubular proteinuria; LRP4, linked to skeletal development (its loss of function causes Cenani-Lenz syndrome); and LRP8, VLDLR, FGFR2 and proteins of the APP, SLITRK and SEZ6 families, linked to bone and nervous system development [8, 13, 33]. Kato and colleagues concluded that the multisystem phenotypes result from the cumulative reduction in surface expression of many proteins, and not of a single cargo; the mechanism of the heart disease and the cerebellar dysplasia remains to be established [8]. The CCDC22 protein also has a role in the activation of nuclear factor κB (NF-κB): all COMMD proteins bind CCDC22, and cells from patients with the variant of the Australian family show reduced NF-κB activation through decreased ubiquitination and degradation of the IκB inhibitors, which has been associated with the ectodermal dysplasia observed in that family [43].

Animal models support the essential nature of the pathway: Vps35l−/− mice die between embryonic days 7.5 and 10.5 [4, 44]; hepatic inactivation of Commd1, Commd6, Commd9 or Ccdc22 destabilises the whole CCC, reduces surface LDLR and LRP1, raises LDL cholesterol and aggravates atherosclerosis in ApoE3*Leiden mice [33, 45]; dogs with COMMD1 deficiency have raised LDL [33]; zebrafish lacking washc5 have high mortality, growth delay, a short maxilla, delayed ossification, ventricular changes and bradykinesia [46]; and mice with inactivation of Vps35l in the kidney and nervous system (Nestin-Cre) have less LRP2 in the S1 segment of the proximal tubule, without structural changes [8]. These data are preclinical.

2.2. WASHC5 and RTSC1

WASHC5 (8q24.13; OMIM 610657; HGNC:28984; MANE transcript NM_014846.4) encodes strumpellin, a ubiquitous protein of 1159 amino acids and about 134 kDa, with an N-terminal region (amino acids 1–240) of six α-helices and two β-segments, a central region (241–971) with spectrin repeats and a C-terminal region (792–1159) with structural similarity to exportin-5 and importin β-1 [9, 17]. In the First Nations of Manitoba, Elliott and colleagues found in 11 patients homozygosity for a haplotype with three variants in intron 27, in cis: c.3335+2T>A, c.3335+4C>A and c.3335+8A>G; only the first was considered causal, as it abolishes the donor site and causes skipping of exon 27, with a frameshift and a premature stop codon after amino acid 1128 [9, 30]. GeneReviews describes the loss of the 99 C-terminal amino acids encoded by exons 27 to 29, replaced by 68 new residues, a mean 7.8-fold reduction in the transcript, consistent with nonsense-mediated decay (NMD), and a 60% reduction in strumpellin [9, 29]. The c.3335+8A>G variant creates a restriction site that was used to genotype newborn blood spots from the same population, which is why Singla and colleagues present it as the founder variant; the functionally responsible variant is c.3335+2T>A [17, 30]. For the index variant, NM_014846.3 and NM_014846.4 have the same numbering: NM_014846.4:c.3335+2T>A, NC_000008.11:g.125032239A>T, recorded in ClinVar (VCV000092129) as likely pathogenic by one submitter [47, 48]. Outside the First Nations, compound heterozygous patients have been described, such as the four siblings, among live births and fetuses from terminated pregnancies, of one of the two families described by Neri and colleagues in a Danish, Portuguese (Centro de Genética Médica Jacinto de Magalhães, Porto) and North American collaboration [37].

WASHC5 has a second disorder, with a different inheritance: heterozygous variants, mainly missense (described NM_014846.4:c.1411A>G p.(Asn471Asp), c.1857G>T or c.1857G>C p.(Leu619Phe), c.1876G>T p.(Val626Phe) and c.2087G>C p.(Gly696Ala), as well as p.Val676Phe in the published designation, and also splicing variants), cause hereditary spastic paraplegia type 8, a slowly progressive pure spastic paraplegia with onset between 10 and 59 years, estimated penetrance of 90 to 100% and about 4 to 5% of hereditary spastic paraplegias [17, 20, 42, 49]. Saudubray classifies SPG8 among the spastic paraplegias due to defects of vesicular trafficking, alongside the forms due to AP4B1, AP4E1 and NIPA1 [50]. The mechanism of SPG8 has not been established; haploinsufficiency has been proposed, because cells lacking strumpellin have enlarged lysosomes due to defective scission of endosomal tubules, and expression of the p.Leu619Phe and p.Val626Phe variants in zebrafish revealed no toxic gain-of-function effect [20]. This hypothesis contrasts with the observation that heterozygotes for the RSS loss-of-function allele are asymptomatic, according to GeneReviews [9]. ClinGen classifies the WASHC5–RTSC1 relationship as "limited" (April 2025 curation), whereas three other GenCC submitters classify it as "strong", and the relationship with SPG8 as "moderate" [42]. Reporting an SPG8 variant as recessive, or an RSS variant as dominant, misleads counselling and carrier testing [42].

2.3. CCDC22 and RTSC2

CCDC22 (Xp11.23; OMIM 300859; MANE NM_014008.5) encodes a scaffold protein of the CCC with a conserved N-terminal domain (with a calponin homology domain), a COMMD ring-binding domain, a DENND10-binding domain and a C-terminal coiled-coil domain that binds VPS35L [9, 17]. In the Australian family (IGOLD no. 586) of Voineagu and colleagues, six men from three generations were hemizygous for c.49A>G, next to the donor site of intron 1: although the predicted translation is p.(Thr17Ala), the variant reduces the mRNA fivefold and increases the transcripts retaining intron 1, without NMD [9, 51]. In the two Austrian brothers of Kolanczyk and colleagues, the variant c.1670A>G p.(Tyr557Cys), in exon 15 and in the coiled-coil domain, reduced CCDC22 by 50% and increased WASH1 in lymphoblastoid cells [32, 51]. Table 6 of GeneReviews attributes p.Tyr557Cys to Voineagu 2012, but the note to its own Table 1, OMIM and Kolanczyk's abstract place it in the Austrian family, and T17A in the Australian family [9, 32, 51].

Singla and colleagues distinguished two groups of missense variants [17]. The variants p.(Pro172Arg), p.(Glu208Lys) and p.(Arg234Cys) lie in the COMMD ring-binding domain; E208 makes contact with lysine 180 of COMMD4, and E208K and P172R reduce binding to the COMMD proteins, dimerisation with CCDC93 and binding to DENND10 and VPS35L, whereas R234C and Y557C did not alter these interactions in immunoprecipitation assays. The variants T17A and Y557C are associated with a complete phenotype, with posterior fossa malformations and heart disease; P172R, R234C and E208K are associated with intellectual disability and epileptic seizures without severe brain or cardiac malformations [17]. Healy and colleagues showed that the CCDC22 and VPS35L variants cluster at the interface between CCC and Retriever, and that Y557 lies directly at that interface [36]. He and colleagues described three unrelated cases of focal epilepsy with hemizygous missense variants, one with refractory seizures and focal cortical dysplasia (variant in the coiled-coil domain) and two with controlled seizures [39], and Gjerulfsen and colleagues a patient with epileptic encephalopathy and a variant inherited from his healthy mother and grandmother, with an affected maternal uncle who died at 12 months [12]. In a 45-year-old man with intellectual disability, Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis and aggressive NK-cell leukaemia, the variant NM_014008.5:c.112G>A p.(Val38Met) was found; a causal relationship with CCDC22 has not been demonstrated [47, 52]. ClinGen classifies the CCDC22–RTSC2 relationship as "moderate" (2023) [53]. Zhang and colleagues, in an exploratory assessment of 20 predictors on expert-classified missense variants, observed that excluding variants seen in the hemizygous state in gnomAD improves performance, and that ClinPred, M-CAP, MetaRNN and SIFT had balanced accuracies of 84.6%, 80.8%, 78.7% and 76.1%, in a small cohort [54].

2.4. VPS35L and RTSC3

VPS35L (16p12.3; OMIM 618981) encodes the central subunit of Retriever, a solenoid of HEAT-type repeats that binds VPS26C at its N-terminus and VPS29 at its C-terminus, with its own N-terminal extension that contacts VPS29 [36]. Kato and colleagues identified in 2020 two Japanese siblings compound heterozygous for a missense variant unable to form Retriever and a frameshift duplication that triggers NMD [4]. Otsuji and colleagues added three patients from non-consanguineous families and showed that the C-terminal variants (A919T, N996del, P876L and M1020fs, in NM_020314.5 numbering) prevent binding to VPS29, that the in-frame deletion A526_K550del reduces binding to VPS26C and VPS29, that all retain endosomal localisation, and that the residual amount of VPS35L in lymphoblastoid cells was lowest in the most severe patient [13]. Carelli and colleagues described in 2026 an Italian boy homozygous for NM_020314.7:c.881T>C p.(Phe294Ser), with a destabilising effect on structural modelling [14]. The numbering of variants published before 2023 uses NM_020314.5; the MANE transcript NM_020314.7 encodes a protein 89 amino acids shorter, so, according to VariantValidator, NM_020314.5:c.2755G>A p.(Ala919Thr) corresponds to NM_020314.7:c.2488G>A p.(Ala830Thr), and NM_020314.5:c.1097dup p.(Cys366TrpfsTer28) to NM_020314.7:c.830dup p.(Cys277TrpfsTer28) [47]. A report using a transcript different from that of the publication may therefore describe the same variant with a different number.

2.5. COMMD4, COMMD9, CCDC93 and overlapping phenotypes due to VPS26C and WASHC4

Kato and colleagues identified, through GeneMatcher, five patients from three families with biallelic variants in CCC genes: COMMD4 NM_017828.5:c.122T>G p.(Leu41Arg) in the homozygous state, in three siblings born to consanguineous parents who died in early infancy; COMMD9 NM_014186.3:c.208_209del p.(Leu70GlyfsTer5) in the homozygous state; and CCDC93 NM_019044.5:c.1371T>G p.(Tyr457Ter) and c.1891T>G p.(Ser631Ala) in compound heterozygosity [8]. The COMMD9 variant disrupts Commander assembly; COMMD4-L41R and CCDC93-S631A preserve assembly but are degraded faster; fibroblasts from the patient with CCDC93 variants have less CCDC93, CCDC22 and VPS35L; and mice homozygous for Ccdc93 S631A have less CCDC93 in the brain and lower weight at nine weeks [8]. The patient with CCDC93 variants, a 3.9-year-old boy with no parental DNA available, had developmental delay, hypotonia, intellectual disability, poor weight gain, hypoplasia of the cerebellum, brainstem and corpus callosum, a large fontanelle, occipital aplasia cutis, widely spaced upslanting palpebral fissures, high palate, brachydactyly and hypoplastic toenails [55]. The three siblings with COMMD4, from a consanguineous Middle Eastern family and including a pair of dizygotic twins born at 35 weeks, had vermis hypoplasia or reduced posterior fossa structures, dysgenesis of the corpus callosum, small septal defects, retinopathy, anaemia, thrombocytopenia and, in one sister, cholestasis with portal fibrosis; they died at 20 days, 6 months and 8 months; the parents and an unaffected sibling were heterozygous [56]. The boy with COMMD9, aged 4.6 years and born to consanguineous heterozygous parents, had delay from the first year, hypotonia, inability to walk, few words, short stature of −2.5 SD, a relatively large head, aplasia cutis of the vertex with alopecia, hypertelorism, ankylosis of the mandible, radioulnar dysostosis, brachydactyly, rocker-bottom feet, cortical dysgyria, periventricular demyelination, a thin corpus callosum and hypoplasia and malrotation of the vermis [57]. The two cousins from the United Arab Emirates homozygous for VPS26C p.(Glu60Ter) (Beetz and colleagues, 2020), a 13-year-old boy and a 27-year-old woman, had developmental delay, cognitive impairment, short stature with rhizomelia, brachydactyly, contractures and severe midface hypoplasia [58]. OMIM classifies the COMMD4, COMMD9 and VPS26C variants as of uncertain significance and records these associations, and that of CCDC93, as provisional [1, 56–58]. The authors suggest that the extreme severity of the COMMD4 form may result from a second, unidentified variant in the consanguineous family [8].

Biallelic variants in VPS26C (NM_006052.2:c.178G>T p.(Glu60Ter)) and in WASHC4 have been observed in patients with an overlapping phenotype who had not been recognised as having RSS [8, 47]. WASHC4 (SWIP, 12q23.3; OMIM 615748) causes autosomal recessive intellectual developmental disorder 43 (OMIM 615817): in a large consanguineous family, seven affected individuals with moderate intellectual disability and short stature; in two other families, mild intellectual disability, dysmorphism and skeletal anomalies, macrocephaly and subependymal heterotopic nodules in two sisters, congenital absence of the right internal carotid artery and bilateral sensorineural deafness in one of them, and skeletal muscle involvement in two other sisters; fewer than 15 patients have been published [59]. Mice with the Washc4 p.(Pro1019Arg) variant of the original family accumulate lipofuscin and have progressive cognitive decline and motor dysfunction [60]. No human variants have been described in WASHC1, WASHC2 or WASHC3, and WASHC5 is the WASH subunit most coevolved with Retriever and CCC, followed by WASHC4 [17].

2.6. DPYSL5 and RTSC4

DPYSL5 (2p23.3; OMIM 608383; MANE NM_020134.4) encodes CRMP5, a member of the collapsin response mediator protein family, which regulates neuronal migration, axon guidance, dendritic growth and synapse formation in complex with MAP2 and β-III-tubulin [6, 61]. In the surviving sister of the Ritscher family the heterozygous variant p.(Gly47Arg) was found, with transmission consistent with parental gonadal mosaicism, and in eight unrelated patients the recurrent de novo variant NM_020134.4:c.121G>A p.(Glu41Lys); both lie in the same surface loop and reduce the interaction with MAP2 and β-III-tubulin, abolishing the inhibitory effect of CRMP5 on neurite outgrowth [6, 7, 15]. Desprez and colleagues described nine further individuals, three of them fetuses, with six missense variants: p.(Glu41Lys) in two, the recurrent de novo variant NM_020134.4:c.73G>A p.(Glu25Lys) in three (all with agenesis of the corpus callosum and intellectual disability) and p.(Arg231His), p.(Ala253Ser), p.(Arg354Cys) and p.(Arg521Gln), all de novo except in one adopted patient [15]. All published variants are missense; haploinsufficiency is not the demonstrated mechanism, and a deletion of the gene should not be equated with these variants [61]. Kato and colleagues found no interaction of CRMP5 with the SNX17-Retriever-CCC-WASH pathway, nor any change in cargoes in cells lacking DPYSL5 [8]. The CRMP5 protein is also the antigen of the paraneoplastic anti-CV2/CRMP5 antibodies, an acquired autoimmune disease unrelated to the germline variants [61].

2.7. Table of the class: types and genes

2.8. Variants cited, normalised

2.9. Genotype–phenotype correlations, penetrance and expressivity

GeneReviews did not identify genotype–phenotype correlations in WASHC5, because all First Nations patients have the same variant [9]; phenotypic variability is marked even between siblings [2]. In CCDC22, the effect of the variant on CCC assembly distinguishes complete and attenuated forms [17]. In VPS35L, the residual amount of protein tracked severity in three patients [13], and in the CCC inactivation of COMMD9 reduced the cargoes less than that of COMMD4 or CCDC93, which suggests that residual function of the pathway modulates severity [8]. In the recessive forms, heterozygotes have not been described as affected [9]; in CCDC22 carriers, GeneReviews and GeneGuidance describe women as usually unaffected [9, 53].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limitations

The clinical description rests on case reports and small series, many predating molecular diagnosis, and on two recent compilations: Table 1 of Otsuji and colleagues, which compares 8 patients with CCDC22 variants and 10 with WASHC5 variants from the literature, and Table 1 of Singla and colleagues, which breaks down the series by variant [13, 17]. By 2021 only 17 individuals had a published molecular diagnosis [12]. The frequencies cited are proportions of published patients, subject to ascertainment bias, and not population estimates.

3.2. Growth

Most patients with RSS have normal birth weight, mild short stature and, often, obesity from late childhood, which progresses in adulthood; obesity with a short neck increases the risk of obstructive sleep apnoea syndrome (OSAS) [9]. Smith's describes postnatal deficiency of length and weight [2], and Kosaki and colleagues found it in most patients with longitudinal follow-up [24]. Wheeler and colleagues documented growth hormone deficiency in one patient [25]; it is not known what part of the short stature is due to this deficiency [2]. In the Australian family with CCDC22, postnatal short stature was present in 6 of 8 patients [17, 38]. In RTSC3, postnatal growth restriction ranges from −2.1 to −6.5 standard deviations (SD) [13].

3.3. Face and skull

The facial gestalt includes macrocephaly, brachycephaly, flat or prominent occiput, large anterior fontanelle, prominent forehead, hypotonic face with a tendency to tongue protrusion, short midface, flat facial profile, arched and thick eyebrows, downslanting palpebral fissures, widely spaced eyes, depressed nasal bridge, low-set ears with overfolded upper helix, smooth or short philtrum, high or cleft palate and short broad neck with low posterior hairline and webbing [2, 9]. Cleft palate occurs in fewer than 5% and micrognathia in about 20% [9]. In the 10 patients with WASHC5 compiled by Singla, macrocephaly, brachycephaly, prominent forehead, downslanting fissures, widely spaced eyes and low posterior hairline were present in 10 of 10 (macrocephaly in 9 of 10 in another count in the same table), arched eyebrows in 5 of 10 and none of four assessed had cleft palate [13, 17]. In the Australian family with CCDC22, widely spaced eyes were present in 8 of 8, downslanting fissures in 6 of 8, convex nose in 8 of 8, broad nasal tip in 7 of 8 and high palate in 3 of 8, with a cleft in 1 of 8; macrocephaly only in 2 of 8 [17]. Gjerulfsen and colleagues concluded, from one patient and an uncle with CCDC22, that the CCDC22 and WASHC5 forms share the facial gestalt [12].

3.4. Central nervous system and development

The most frequent malformations are Dandy-Walker malformation or its variant, vermis hypoplasia, posterior fossa cysts and, less often, hydrocephalus, which only rarely required shunting [2, 9]. Of the 11 First Nations patients, four had a Dandy-Walker malformation, and there were also enlarged ventricles, vermis hypoplasia and enlarged cerebrospinal fluid (CSF) spaces [1]; in Singla's compilation, 5 of 9 had a posterior fossa malformation, 7 of 9 prominent CSF spaces and 2 of 10 hydrocephalus, whereas 6 of 8 patients in the Australian family with CCDC22 had a posterior fossa malformation and 1 of 8 periventricular heterotopia [17]. In the Colombian series from Medellín, with a clinical diagnosis only, mega cisterna magna (31.8%) and Dandy-Walker malformation (27%) were the most frequent posterior fossa anomalies [64]. Kosaki and colleagues identified patients diagnosed with Joubert syndrome or Dandy-Walker malformation who had RSS and recommended looking for the subtle facial features, coloboma, cleft palate or bifid uvula, short neck, syndactyly and nail hypoplasia in the assessment of any Dandy-Walker malformation [1, 24].

Hypotonia at birth is common and motor coordination and speech are delayed; most patients learn to walk, feed themselves and achieve limited but functional speech [9]. Most have significant intellectual disability [9], but there is variation: Ritscher's surviving sister had mild intellectual disability at 21 years, a 6-year-old child functioned at the level of 4½ to 5 years and another aged 13 had mild impairment [2]; Iyer and Smith described a girl with almost normal development [1]. In the Portuguese, Danish and North American series of Neri and colleagues, all patients had developmental delay, intellectual disability and ataxic gait, and none had epilepsy [37]. Epilepsy appears mainly in the CCDC22 forms (1 of 8 in the Australian family; epileptic encephalopathy in the Danish patient; seizures from 18 months in the two brothers with E208K; focal epilepsy with focal cortical dysplasia in a Chinese case) and in RTSC3 (focal seizures in the Japanese brother) [5, 12, 17, 39]. In the brothers with E208K there was also level 3 autism spectrum disorder in one and cerebral palsy in the other, wide internal auditory canals and foci of parieto-occipital hypomyelination [17]. OMIM also mentions hypogonadotropic hypogonadism among the manifestations added by molecular diagnosis [1], and Neri described delayed puberty in a patient with CCDC22 [37].

3.5. Heart

Heart defects affect more than half of patients and include atrioventricular canal defect, mitral valve anomalies including mitral cleft, atrial septal defect (ASD), ventricular septal defect (VSD), double outlet right ventricle, aortic stenosis, pulmonary stenosis and tetralogy of Fallot [9]; Leonardi added hypoplastic left heart and other valvulopathies [27]. Kosaki distinguished two groups, endocardial cushion defects (from atrioventricular valve anomalies to complete canal) and conotruncal defects [24]; Lurie and Ferencz found at least nine types of malformation in 24 cases, in proportions similar to those of the general population [1]. Heart disease was present in 6 of 10 patients with WASHC5 (VSD 3/10, ASD 3/10) and in 7 of 8 in the Australian family with CCDC22 [17]; Otsuji counts 3 of 8 in the CCDC22 forms and 6 of 10 in the WASHC5 forms [13]. The attenuated CCDC22 forms (P172R, E208K) have no heart disease [17], nor do the patients with de novo DPYSL5 variants [7]. In the pre-molecular era, half of the published cases died before four years of age, mainly because of the severity of the heart disease [2].

3.6. Eyes

Iris and optic nerve coloboma occurs in about 20% [9]; in three of the 11 First Nations patients, and in six of eight in Marles' series [1]. Glaucoma, including congenital glaucoma, heterochromia iridis and posterior embryotoxon have been described [1, 2, 9]. In the Colombian series all patients had ocular abnormalities, with megalocornea in 69% [64]. RTSC3 is associated with choroidal coloboma, microphthalmia, optic atrophy, buphthalmos and congenital glaucoma with blindness [5, 13].

3.7. Skeleton and limbs

Upper limb anomalies are present in most: brachydactyly with greater involvement of the second ray, camptodactyly, proximally placed thumbs and abnormal palmar creases [9]. Friesen and colleagues studied hand radiographs of 8 patients from Manitoba and northwestern Ontario (5 boys and 3 girls, aged 1 month to 26 years and 7 months): generalised brachydactyly, shortening of the first metacarpal and the fifth distal phalanx, a wavy metacarpophalangeal pattern profile (mean Z of −0.15 to −2.13 on the left and 0.53 to −1.73 on the right), reduced carpal height in 6 of 8, normal bone age in all, overtubulation of metacarpals 2 to 4, prominent tufts of the distal phalanges and a hypoplastic fifth distal phalanx [65]. In the Australian family with CCDC22, digital anomalies were present in 8 of 8 and vertebral anomalies in 7 of 8 [17]. Hemivertebrae, absent or hypoplastic ribs, scoliosis, relapsing clubfoot with hip dysplasia and, in the Colombian series, vertical talus have been described [2, 9, 64]. RTSC3 has the most marked skeletal dysplasia: brachytelephalangic chondrodysplasia punctata, short limbs, vertebral hypo-ossification, sternal aplasia, short ulnae with bowing of the radius, hypoplastic ilia and dysplastic acetabulum [5, 13].

3.8. Lipid metabolism

Hypercholesterolaemia due to increased LDL cholesterol is present from childhood, may lead to the formation of atherosclerotic plaques and is not accompanied by xanthomas [9]. Bartuzi and colleagues found it in 6 of 11 patients from two families with CCDC22 [3, 33], Singla in 4 of 8 in the Australian family and in 2 of 2 of the Austrian brothers and the brothers with E208K (fasting total cholesterol of 5.7 and 6.1 mmol/L) [17], and Otsuji in three patients with VPS35L, with increased LDL and intermediate-density particles, in one case with HDL cholesterol of 38.6 mg/dL [13]. In the Australian family ceruloplasmin was also raised in 5 of 8 [17].

3.9. Immunity, kidney, liver and gut

The humoral immunodeficiency of Ritscher's surviving sister (low IgG2 and IgG4, poor response to polysaccharide antigens) was later explained by gastrointestinal loss of IgG [7, 26]. In RTSC3, all patients assessed had low IgG: one had cryptococcal meningitis at 15 years with IgG below 200 mg/dL and another met the criteria for common variable immunodeficiency with recurrent respiratory infections [13]. Fukaura and colleagues described a man aged about 20 years with 3C syndrome and generalised verrucosis treated with subcutaneous IgG [66]. Persistent proteinuria, raised transaminases and protein-losing intestinal lymphangiectasia have been described in RTSC3 [13], and Kato demonstrated a marked increase in urinary β2-microglobulin (tubular proteinuria) in patients with CCDC93 or VPS35L [8]. Seidahmed and colleagues described a consanguineous Saudi family with four patients meeting 3C criteria, alopecia, camptodactyly and significant renal involvement, and two otherwise normal sisters with unilateral renal agenesis [67]. In the Australian family with CCDC22, one patient had sarcoidosis [38].

3.10. Other systems

In fewer than 10% of patients absent ribs, adrenal hypoplasia, anal atresia, congenital glaucoma, clubfoot, aplasia cutis, haemangioma, hemivertebrae, hypospadias, inguinal hernia, intestinal malrotation, nail and nipple hypoplasia, penile hypoplasia, polydactyly and renal malformations have been described; it is not known whether they are rare features of the syndrome or coincidences [9]. Smith's adds bifid uvula, syndactyly, sensorineural deafness, single umbilical artery and hydronephrosis [2]. Genital anomalies (cryptorchidism, micropenis) were present in 7 of 8 patients in the Australian family with CCDC22 [17], and in the IGOLD family there was cryptorchidism in 3 of 5, hypoplastic lung in 2 of 5, malrotation in 1 of 5 and renal agenesis in 1 of 5 [3]. Sleep disturbance and gastrointestinal and feeding problems were recurrent in the same family [17, 38], and Iyer and Smith described gastro-oesophageal reflux and severe feeding difficulties until four years of age [1].

3.11. Differences between forms

In the CCDC22 form, GeneReviews highlights the upslanting palpebral fissures (uncommon in the First Nations), the large protruding tongue and the ectodermal findings (nail hypoplasia, dental anomalies, aplasia cutis congenita) [9]. In the Austrian family there were also a large anterior fontanelle, camptodactyly, clinodactyly, broad halluces and an overlapping fifth toe [3]. The DPYSL5 form frequently has movement disorders (stereotypies, choreoathetosis, ataxia), swallowing difficulties, strabismus, behavioural problems and seizures; five of eight patients with E41K walked between 3 and 7 years and three are non-ambulant [7].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

GeneReviews recommends considering the syndrome in the presence of the association of intellectual disability, characteristic face, heart disease, posterior fossa malformation and characteristic hand radiographs [9]. In the prenatal period, suspicion arises from increased nuchal translucency in the first trimester, followed, in the second trimester, by septal or atrioventricular canal heart disease and posterior fossa malformation; in the Manitoba families, first-trimester nuchal anomalies preceded the malformations detectable in the second trimester in all three fetuses, and in Neri's series nuchal translucency was increased in three fetuses with WASHC5 variants [16, 37]. In the newborn and infant, the warning signs are macrocephaly with a large anterior fontanelle and prominent forehead, downslanting palpebral fissures with hypertelorism, hypotonia with feeding difficulties, heart disease and coloboma [2, 9]. A child with Dandy-Walker malformation, vermis hypoplasia or enlarged cisterna magna should be examined for these features, because some patients diagnosed with Dandy-Walker or Joubert had RSS [24]. In the older child and the adult, the combination of intellectual disability, short stature, obesity, second-ray brachydactyly and hypercholesterolaemia without xanthomas should suggest the diagnosis [9, 65].

4.2. Contexts that change the probability

A patient from the First Nations of northern Manitoba or northwestern Ontario has a high probability of being homozygous for the WASHC5 founder variant [9]. A boy with X-linked intellectual disability, heart disease and ectodermal anomalies, or with upslanting palpebral fissures and a large tongue, points to CCDC22 [9]. A 3C-like picture with severe growth restriction, chondrodysplasia punctata, microphthalmia or proteinuria points to VPS35L [13], and agenesis of the corpus callosum with cerebellar hypoplasia without heart disease, to DPYSL5 [15]. A man with intellectual disability and focal epilepsy without malformations may also have a CCDC22 variant [17, 39].

4.3. Emergency signs

The situations requiring rapid action are severe congenital heart disease, the main cause of early death in the pre-molecular case series, hydrocephalus, feeding difficulties and OSAS [2, 9]. Repeated or severe bacterial infections, such as the cryptococcal meningitis of a patient with RTSC3, should prompt measurement of immunoglobulins [9, 13]. There is no newborn screening for the syndrome; screening of newborn blood spots in the First Nations was used only to estimate carrier frequency [30].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no consensus criteria [9]. The minimum criteria of Leonardi and colleagues, proposed in 2001 on the basis of 28 patients from the literature, require all three elements [9, 27]:

GeneReviews transcribes the third criterion with six features, replacing hypertelorism and low-set ears with "widely spaced eyes" and omitting the ears; the list in the original article has seven [9, 27]. Leonardi considered that only cleft palate and coloboma are objective, and that the other features are subjective and difficult to assess in the newborn or stillborn infant [27]. The criteria exclude molecularly confirmed patients without heart disease or without a cerebellar malformation, and Gjerulfsen and colleagues proposed revising them, because the absence of these malformations does not exclude the diagnosis [1, 9, 12].

5.2. Non-molecular assessment

Brain magnetic resonance imaging (MRI) assesses the posterior fossa, corpus callosum, white matter and heterotopias; echocardiography, the heart disease; hand radiographs, brachydactyly and the metacarpophalangeal profile; ophthalmological examination, coloboma and glaucoma; the lipid profile, hypercholesterolaemia; and polysomnography, OSAS [9, 42, 65]. There is no diagnostic biochemical biomarker [42]. Tubular proteinuria with raised urinary β2-microglobulin has been described in patients with CCDC93 or VPS35L [8].

5.3. Molecular testing strategy

The diagnosis is confirmed by identification of biallelic pathogenic or likely pathogenic variants in WASHC5 (in men or women) or of a hemizygous variant in CCDC22 (in men) [9]. A variant of uncertain significance (VUS) neither confirms nor excludes [9]. When the phenotype is suggestive, GeneReviews proposes targeted testing: sequencing of WASHC5 first in First Nations patients (Indigenous peoples of Canada who are neither Métis nor Inuit) and in women; in men outside this population testing may start with CCDC22; with one or no variant, targeted deletion and duplication analysis; and, preferably, a multigene panel that includes the genes of the differential diagnosis [9]. When the phenotype is atypical, chromosomal microarray and exome or genome sequencing are the best option [9]. As the 2020 GeneReviews chapter does not include VPS35L, DPYSL5, COMMD4, COMMD9 or CCDC93 among the diagnostic genes [9], a panel with only WASHC5 and CCDC22 does not cover the current class, and exome or genome sequencing with copy number analysis allows data to be reanalysed when new genes emerge [1, 8]. Microarray, or copy number analysis from the exome or genome, should exclude the 6p25 deletion, a recommendation of Stellingwerff and colleagues [18].

Source: GeneReviews, Table 1 [9]. These figures refer to the First Nations population and are proportions of variants detectable by method, not the clinical sensitivity of a test in an unselected population.

5.4. Limitations of testing

Sequencing detects small variants but not, as a rule, deletions of exons or of the whole gene; in a man with an X-linked condition, failure to amplify an exon may suggest a deletion [9]. Deep intronic and non-canonical splicing variants, such as CCDC22 c.49A>G, which is annotated as missense but acts on mRNA processing, require RNA studies to assess the effect [51]. Interpretation of CCDC22 missense variants in men should take into account the variants seen in the hemizygous state in gnomAD [54]. The variation in numbering between VPS35L transcripts makes it necessary always to state the transcript and version [47]. In RTSC4, the variants are de novo and the original family shows that gonadal mosaicism can produce recurrence among siblings with unaffected parents [7]. A large Colombian family with RSS without variants in WASHC5 or CCDC22 demonstrates that a negative result does not exclude the clinical diagnosis [9]. GeneReviews recommends DNA banking for probands without a molecular diagnosis [9].

5.5. Reporting and segregation

The report should state the gene, transcript with version (NM_014846.4, NM_014008.5, NM_020314.7, NM_020134.4), HGVS c. and p. nomenclature, zygosity and ACMG/AMP classification, and parental testing should confirm the phase of the variants in the recessive forms and their de novo status in the dominant forms [9, 15, 47]. Functional RNA or protein studies in patient cells (for example, quantification of CCDC22, VPS35L or CCDC93 in lymphoblastoid lines or fibroblasts) were decisive in the classification of several published variants, but are carried out in a research setting [8, 13, 32].

5.6. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [9]. First-trimester ultrasound is recommended in at-risk pregnancies to assess nuchal translucency and heart disease; increased translucency is documented in the WASHC5 form, but not established in the CCDC22 form [9, 16, 37]. Fetal agenesis of the corpus callosum led to the diagnosis of three fetuses with DPYSL5 variants [15].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differentials

The most important differential is the 6p25 deletion: it shares with RSS intellectual disability, Dandy-Walker malformation, hydrocephalus, heart disease, anterior chamber anomalies of the eye and several facial features (prominent forehead, midface hypoplasia, downslanting fissures, hypertelorism, epicanthus, ptosis, proptosis, abnormal ears, flat nasal bridge, short philtrum, high palate), but it has a distinct facial gestalt and is identified by microarray [9]. DeScipio defined a minimal critical region of 1.3 Mb in three families, found no deletions or variants of FOXC1, FOXF1 and FOXQ1 in seven patients with 3C, including the original Ritscher family, and later described isolated 6p25 subtelomeric deletion in 11 individuals with developmental delay, language impairment, deafness and ophthalmological, cardiac and craniofacial anomalies [1, 28, 68]. Joubert syndrome is distinguished by the molar tooth sign on MRI; a patient diagnosed with Joubert reviewed by Kosaki had most of the features of RSS [9, 24]. In Ellis-van Creveld syndrome, polydactyly and short ribs set it apart from RSS [9].

Within the class, the DPYSL5 form departs from the others: patients with de novo variants have agenesis of the corpus callosum, movement disorders, epilepsy and behavioural problems, without heart disease or the characteristic face, and the protein does not take part in the endosomal recycling pathway [8, 15]. The Ritscher family, which defines the syndrome, now has the molecular diagnosis of RTSC4; the heart defects of the two sisters may belong to the DPYSL5 spectrum or correspond to another condition [7]. The attenuated CCDC22 forms enter the differential of non-syndromic X-linked intellectual disability and of focal epilepsy in males; GeneReviews did not know, in 2020, whether the patients with X-linked intellectual disability described by Starokadomskyy had mild RSS or non-syndromic intellectual disability [9, 17, 39].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no disease-modifying therapy for any form of the class [42, 53]. The GeneReviews recommendations are expert opinion and do not derive from trials; no scientific society has published a specific guideline, and ERN ITHACA, the European reference network for rare congenital malformations and rare intellectual disability, had no document of its own for the syndrome when consulted in October 2026 [9, 19, 42]. Management is multidisciplinary and directed at each manifestation, coordinated by a clinical geneticist or developmental paediatrician.

7.2. Assessment after diagnosis

Source: GeneReviews, Table 3 [9]. For the VPS35L and CCC forms, the data of Otsuji and Kato justify adding to the initial assessment testing for proteinuria (dipstick and, if available, urinary β2-microglobulin), transaminases and immunoglobulins even without infections, because proteinuria, raised transaminases and hypogammaglobulinaemia were present in patients without directed symptoms [8, 13]; this extension is an inference from case series and not a guideline recommendation.

7.3. Treatment of manifestations

Source: GeneReviews, Table 4 [9].

7.4. Hypercholesterolaemia

The hypercholesterolaemia of RSS results from defective recycling of LDLR and LRP1 in hepatocytes and is therefore similar in mechanism to a monogenic hypercholesterolaemia, but it is not familial hypercholesterolaemia [8, 13, 33]. There are no data on the response to statins or on cardiovascular events in these patients. In the absence of specific data, the 2015 European Atherosclerosis Society (EAS) consensus on heterozygous familial hypercholesterolaemia in children is the closest reference: healthy lifestyle and a statin from 8 to 10 years of age, with an LDL cholesterol target below 3.5 mmol/L (130 mg/dL) after 10 years, or a 50% reduction from baseline between 8 and 10 years, giving particular weight to cases with very high LDL, raised lipoprotein(a), a family history of premature coronary disease or other risk factors [69]. Applying these thresholds to RSS is an extrapolation; GeneReviews recommends considering statins particularly when other risk factors coexist [9]. The choice of drug and dose follows the paediatric label of the statin and the lipid guidelines, because no regimen has been studied in the syndrome.

7.5. Immunodeficiency and infections

In the presence of repeated bacterial infections, GeneReviews recommends measuring immunoglobulins and vaccine responses and referring to immunology [9]. In RTSC3, a patient with IgG below 200 mg/dL and cryptococcal meningitis started regular subcutaneous immunoglobulin and had no serious infections thereafter, and another had common variable immunodeficiency [13]; Fukaura described generalised verrucosis treated with subcutaneous IgG [66]. Before starting replacement, it is advisable to look for gastrointestinal or urinary protein loss, because the hypogammaglobulinaemia of Ritscher's surviving sister and that of a patient with RTSC3 were due, at least in part, to intestinal loss [13, 26].

7.6. Growth and endocrinology

Growth hormone deficiency was documented in one patient, and Wheeler recommends considering it in the investigation of short stature [25]. The sources consulted do not describe results of growth hormone treatment in this syndrome. Hypogonadotropic hypogonadism and delayed puberty have been described [1, 37], which justifies assessing puberty.

7.7. Development, rehabilitation and feeding

From 0 to 3 years early intervention is recommended (occupational therapy, physiotherapy, speech and feeding therapy); thereafter, preschool and school education with an individual plan and the support of a developmental paediatrician; in adolescence, transition planning [9]. Physiotherapy maximises mobility, occupational therapy activities of daily living, feeding therapy oromotor difficulties, and augmentative and alternative communication supports, without hindering, speech development [9]. The descriptions of support services in GeneReviews refer to the North American system and should be adapted to the services of each country [9]. Severe feeding difficulties and gastro-oesophageal reflux may persist into the preschool years [1, 2].

7.8. Epilepsy, heart disease and hydrocephalus

Epilepsy in the CCDC22 and VPS35L forms was controlled with antiepileptic drugs in some patients and refractory in others [5, 17, 39]; the sources do not describe a preferred drug. Heart disease is treated according to paediatric cardiology standards; the death of the elder sister in the Ritscher family after surgery, and that of the brother of a patient with RTSC3 from sepsis after VSD repair, are reminders of the perioperative risk in these patients [13, 21]. Shunting for hydrocephalus was seldom needed in the case series [2].

7.9. Regulatory status, trials and recent developments

Sources: [9, 70]. The negative search does not prove that no studies exist in other registries.

None of these studies tested a therapy. Kato and colleagues suggest that understanding the recycling pathway opens the way to diagnostic and therapeutic interventions, without proposing any specific one [8].

7.10. Pregnancy, perioperative care and transition

The sources describe no pregnancies in women with RSS; GeneReviews states that affected individuals are not known to reproduce [9]. The sources describe no specific anaesthetic recommendations; micrognathia, cleft palate, short neck, obesity and OSAS are factors to consider in airway assessment, and heart disease and hypogammaglobulinaemia in perioperative risk [9, 13]. Transition to adult medicine should include surveillance of lipids, weight and apnoea, because obesity progresses in adulthood [9].

8. Reproductive Options and Family Counselling

8.1. Autosomal recessive forms (WASHC5, VPS35L and CCC genes)

The parents of a patient are obligate heterozygotes and asymptomatic; each sibling has, at conception, a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier; each sibling of the parents has a 50% chance of being a carrier [9]. Carrier testing of relatives requires prior identification of the familial variants [9]. Affected individuals are not known to reproduce [9]. In the First Nations population of Manitoba, with a carrier frequency of 1 in 9, Elliott and colleagues predicted that 1 in 325 children of the next generation would have the syndrome, which makes counselling of couples from the same community relevant [1, 30]. In consanguineous families, the occurrence of a severe form may result from more than one homozygous pathogenic variant, as Kato suggests for the family with COMMD4 [8]. WASHC5 heterozygotes for RSS alleles have not been described with spastic paraplegia, and the variants that cause SPG8 are usually heterozygous missense variants, with more than 90% of patients having an affected parent [9, 20].

8.2. X-linked recessive form (CCDC22)

The father of an affected man is neither affected nor hemizygous [9]. In a family with more than one affected individual, the mother is an obligate heterozygote; if she has more than one affected son with no other affected relatives and the variant is not detected in leucocytes, germline mosaicism is most likely [9]. In an isolated case, the mother may be a carrier or the variant may have arisen de novo, with unknown frequency [9]. If the mother is a carrier, each pregnancy has a 50% chance of transmitting the variant: sons who inherit it are affected and daughters are carriers, usually unaffected; if the mother does not have the variant in leucocytes, the risk to siblings is slightly higher than that of the population, because of the possibility of germline mosaicism [9]. Maternal aunts may be carriers, and their children at risk depending on sex [9]. To identify heterozygotes, the familial variant is used or, if the affected individual is not available, sequencing followed by deletion and duplication analysis [9]. In families with attenuated forms, the variant passes through several generations of healthy carriers, such as the mother and grandmother of the Danish patient and the mother of the brothers with E208K [12, 17].

8.3. Autosomal dominant de novo form (DPYSL5)

The DPYSL5 variants described are de novo, so the recurrence risk for siblings is low, but not zero: the Ritscher family, with two affected sisters and a boy who died with multiple anomalies, was explained by parental gonadal mosaicism [7, 15]. This family shows that recurrence among siblings with healthy parents does not prove recessive inheritance.

8.4. Prenatal and preimplantation diagnosis and other issues

Once the variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to determine risk, clarify carrier status and discuss these options is before pregnancy, and counselling should be offered to young adults who are carriers or at risk [9]. In at-risk pregnancies, first-trimester ultrasound with assessment of nuchal translucency and the heart is recommended [9, 16]. In Neri's series, three pregnancies with fetuses carrying biallelic WASHC5 variants and increased translucency were terminated [37]. Decisions about prenatal testing are personal and views may differ between professionals and within families [9]. When there is no molecular diagnosis, DNA banking from the proband is recommended [9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Orphanet records 25 cases or families and a point prevalence in the class below 1/1,000,000, without a numerical estimate, based on the 2008 study by Rusnak [11]. GeneReviews gives no overall prevalence and notes that not all reports of "3C syndrome" include the characteristic face, which makes literature counts unreliable [9]. By 2021 there were 17 individuals with a published molecular diagnosis [12]; since then patients with WASHC5, CCDC22, VPS35L, DPYSL5 and CCC genes have been added [8, 13–15, 17, 37, 38]. Kosaki suggested, in 1997, that the syndrome is more frequent than was thought, because some patients carried other diagnostic labels [24].

9.2. Founder populations and regions

The only population with quantitative data is that of the First Nations of northern Manitoba and northwestern Ontario, in Canada: 15 of 133 newborn blood spots were heterozygous for the WASHC5 founder haplotype, a carrier frequency of about 1 in 9, and all patients tested from this population were homozygous [9, 30]. This figure is a carrier frequency in an isolated population and not a disease rate in other populations [42]. In Europe, the molecular forms have been described in families from Austria (CCDC22), Denmark (CCDC22) and Italy (VPS35L), and in a Danish, Portuguese (Centro de Genética Médica Jacinto de Magalhães, Porto) and North American collaboration with one WASHC5 family and one CCDC22 family [12, 14, 32, 37]; Otsuji's VPS35L series brought together centres in Japan, France, the Netherlands and the United Kingdom, and the DPYSL5 form was described in European and North American collaborations [6, 13, 15]. In the USA, Leonardi's series (South Carolina) and the cases of Kosaki (California) and Wheeler (Boston) predate molecular diagnosis [24, 25, 27]. Outside these regions, there are consanguineous families from Pakistan and Saudi Arabia, Japanese and Chinese patients, and a clinical series of 26 patients from Medellín, Colombia (69% male, mean age 30 months, 42% diagnosed before one year of age), in which a large family had no variants in WASHC5 or CCDC22 [1, 4, 9, 63, 64, 67]. The sources consulted contain no data from Brazil; this absence does not demonstrate that no Brazilian patients have been published.

9.3. Special populations

In the X-linked forms, assessment of female carriers revealed no relevant manifestations in the sources [9, 53]. Adults with RSS accumulate obesity, OSAS and hypercholesterolaemia, which shifts the focus of surveillance to cardiovascular risk [9]. In RTSC3 there are adult patients with mild intellectual disability and others with profound impairment and blindness, which requires very different care planning [13].

9.4. Networks and organisations

ERN ITHACA (European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability) is the relevant European reference network [19]. EURORDIS represents European patient organisations for rare diseases [72]. GeneReviews lists MyGene2, a platform where families with the same condition or variants in the same gene can contact each other, the Canadian Organization for Rare Disorders (CORD) and the National Organization for Rare Disorders (NORD) [9, 73–75]. The sources consulted do not identify a patient organisation specific to the syndrome.

10. Illustrative Clinical Case

10.1. Ritscher-Schinzel syndrome 3 due to VPS35L in an adult

Otsuji and colleagues described, in 2023, a 31-year-old man (patient 2 of the series), the son of healthy non-consanguineous parents, identified by trio exome sequencing [13]. He had mild intellectual disability and short stature of −2.1 SD. The face showed thick arched eyebrows, a broad face, telecanthus, a thin upper lip, a long philtrum, macrodontia and brachycephaly; the fingers were short and tapering, with small terminal phalanges and pointed distal ends of the proximal and middle phalanges, and the pelvic radiograph showed hypoplastic ilia, a dysplastic acetabulum and a small femoral epiphysis. T1-weighted MRI at 15 years showed periventricular nodular heterotopia. He was also deaf [13]. The facial photographs, MRI, hands and radiographs are shown in Figure 1 of the article (B to K), consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC10086474/figure/F1/ [13].

At 15 years he had cryptococcal meningitis and was diagnosed with hypogammaglobulinaemia, with IgG below 200 mg/dL; he started regular subcutaneous immunoglobulin and had no further serious infections [13]. Technetium-99m-labelled albumin scintigraphy and α1-antitrypsin clearance demonstrated gastrointestinal protein loss due to intestinal lymphangiectasia, and there were persistent proteinuria, raised transaminases and raised LDL cholesterol [13]. Lipoprotein analysis by chromatography showed LDL esterified cholesterol 57% above the control, HDL cholesterol of 38.6 mg/dL and VLDL and LDL triglycerides 2.4 and 3.1 times higher [13]. Sequencing identified compound heterozygosity for NM_020314.5:c.1650+2T>A (= NM_020314.7:c.1383+2T>A), which causes exon extension with inclusion of 41 nucleotides of intron 16 and NMD (demonstrated by transcript recovery with cycloheximide), and NM_020314.5:c.2988_2990del p.(Asn996del) (= NM_020314.7:c.2721_2723del p.(Asn907del)), whose protein loses binding to VPS29; lymphoblastoid cells had reduced VPS35L and VPS26C, but less so than in the severe patient of the same series [13, 47].

The case illustrates three points: RTSC3 may reach adulthood with mild intellectual disability; hypogammaglobulinaemia may result from intestinal protein loss and present with an opportunistic infection; and proteinuria and hypercholesterolaemia may be present without symptoms. Immunoglobulin replacement in this patient is an individual decision and not a general recommendation, and assessment of intestinal loss before replacement is consistent with the experience of the surviving sister of the Ritscher family [13, 26].

10.2. Attenuated CCDC22 form

Singla and colleagues described two Australian brothers with moderate intellectual disability, the only affected members of a large pedigree, hemizygous for NM_014008.5:c.622G>A p.(Glu208Lys), inherited from their mother [17, 47]. One had level 3 autism spectrum disorder and the other cerebral palsy; both had seizures from 18 months, controlled at 6 years in one and only at 25 years in the other; there was disturbed sleep until puberty, cryptorchidism, adult height at the 10th centile with normal head circumference, a high narrow palate, large upper incisors, spatulate fingertips, fetal fingertip pads, thin ridged nails and fasting total cholesterol of 5.7 and 6.1 mmol/L, without heart disease or brain malformation (Figure 1, consulted at https://pmc.ncbi.nlm.nih.gov/articles/PMC12125813/figure/Fig1/) [17]. Three maternal uncles and two maternal aunts did not have the variant, and a new trio study, ten years after the first, confirmed the result [17].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In the pre-molecular case series compiled by Smith's, half of the published cases died before four years of age, mainly because of the severity of the heart disease; this proportion refers to published patients, with a probable bias towards severe cases, and not to a cohort followed from birth [2]. Orstavik described three siblings who died in the first three months [1]; in RTSC3, one patient died at 28 days and the brother of another patient died of sepsis after cardiac surgery [5, 13]; in the COMMD4 form, all three patients died in early infancy [8]. Survivors reach adulthood: Ritscher's surviving sister was 21 years old with mild intellectual disability and short stature, Friesen's patients were up to 26 years old, and two patients with RTSC3 were 31 and 32 years old [13, 26, 65]. Most walk, feed themselves and have limited but functional speech, and obesity and hypercholesterolaemia increase with age [9]. The sources do not describe life expectancy or the frequency of cardiovascular events in adults.

11.2. Surveillance

The intervals in the first seven rows are those of GeneReviews [9]; the last two rows derive from case series and have no published interval.

12. Summary and Final Considerations

Ritscher-Schinzel syndrome, or 3C syndrome, combines craniofacial dysmorphism (macrocephaly, brachycephaly, prominent forehead, downslanting palpebral fissures, hypertelorism), posterior fossa malformation and congenital heart disease, with variable intellectual disability, brachydactyly with a wavy metacarpophalangeal profile, coloboma in about one fifth of patients, progressive obesity and hypercholesterolaemia. Molecular diagnosis has shown that heart disease and the cerebellar malformation may be absent, and that Leonardi's 2001 criteria are insufficient. In the great majority of forms with a known cause, the syndrome results from loss of function of subunits of the SNX17-Retriever-CCC-WASH endosomal recycling pathway: WASHC5 (autosomal recessive, with a founder variant and a carrier frequency of 1 in 9 in the First Nations of Manitoba), CCDC22 (X-linked, with complete and attenuated forms), VPS35L (autosomal recessive, with severe growth restriction, skeletal dysplasia, proteinuria and hypogammaglobulinaemia) and the proposed genes COMMD4, COMMD9 and CCDC93; defective recycling of LDLR, LRP1, LRP2 and other cargoes explains the hypercholesterolaemia, tubular proteinuria and part of the skeletal and neurological anomalies. The DPYSL5 form, which provided the diagnosis for the original family, is autosomal dominant de novo, has agenesis of the corpus callosum and no heart disease in de novo cases, and is probably a distinct entity. The first test is exome or genome sequencing with copy number analysis, which also excludes the 6p25 deletion; transcripts and versions must be stated, especially for VPS35L. There is no targeted therapy and there are no clinical trials; management follows the 2020 GeneReviews chapter, with surveillance of growth, weight, apnoea, eyes, lipids and development, and, in the Commander forms, also of proteinuria and immunoglobulins. Counselling depends on the gene: 25% recurrence in the recessive forms, 50% for the sons of a carrier in the X-linked form, and a low but real risk, owing to gonadal mosaicism, in the de novo form.

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