Clinical characteristics.

Ritscher-Schinzel syndrome (RSS) is a clinically recognizable condition that includes the cardinal findings of craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome. Dysmorphic facial features may include brachycephaly, hypotonic face with protruding tongue, flat appearance of the face on profile view, short midface, widely spaced eyes, downslanted palpebral fissures, low-set ears with overfolding of the upper helix, smooth or short philtrum, and high or cleft palate. Affected individuals also typically have a characteristic metacarpal phalangeal profile showing a consistent wavy pattern on hand radiographs. RSS is associated with variable degrees of developmental delay and intellectual disability. Eye anomalies and hypercholesterolemia may be variably present.

Diagnosis/testing.

The diagnosis of Ritscher-Schinzel syndrome is established in a proband with suggestive clinical findings, including characteristic dysmorphic facial features, and/or by the identification of biallelic pathogenic variants in WASHC5 in a male or female or a hemizygous pathogenic variant in CCDC22 in a male by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for obesity, obstructive sleep apnea, cleft palate, congenital heart defects, hypercholesterolemia, renal anomalies, immunodeficiency, and developmental delay / intellectual disability.

Surveillance: Measurement of growth parameters (particularly weight); assessment of developmental progress, mobility, self-help skills, and educational needs; and monitoring for symptoms of obstructive sleep apnea at each visit; ophthalmology evaluation annually or as clinically indicated; measurement of lipid profile periodically starting in childhood.

Genetic counseling.

WASHC5-related RSS is inherited in an autosomal recessive manner; CCDC22-related RSS is inherited in an X-linked manner.

• Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• X-linked inheritance. If the mother of the proband has a CCDC22 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will usually not be affected.

Once the causative pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Ritscher-Schinzel syndrome (RSS) should be suspected in an individual with intellectual disability, characteristic facial features, cardiac malformations, malformations of the posterior fossa, and characteristic hand radiographs.

Clinical findings

• Mild-to-severe intellectual disability
• Characteristic dysmorphic facial features
  • Macrocephaly
  • Brachycephaly
  • Flat occiput (prominent occiput in some)
  • Hypotonic face with a tendency to a protruding tongue
  • Short midface
  • Flat appearance of the face on profile view
  • Highly arched and thick eyebrows
  • Downslanted palpebral fissures
  • Widely spaced eyes
  • Depressed nasal bridge
  • Low-set ears; overfolding of the upper helix
  • Smooth or short philtrum
  • High palate or cleft palate
  • Short broad neck with a low posterior hair line and webbing

Imaging findings

• Cardiac malformations (See Clinical Description, Cardiac malformations.)
• Brain MRI
  • Dandy-Walker malformation
  • Hypoplasia or dysplasia of the cerebellar vermis
  • Hydrocephalus
• Hand radiographs
  • Brachydactyly, especially of the second ray
  • Shortening of the first metacarpal and the fifth distal phalanx
  • Characteristic metacarpal phalangeal pattern profile (See Clinical Description, Limb abnormalities.)

Establishing the Diagnosis

The diagnosis of Ritscher-Schinzel syndrome is established in a proband with suggestive clinical findings including characteristic dysmorphic facial features, and/or by the identification of biallelic pathogenic (or likely pathogenic) variants in WASHC5 in a male or female OR a hemizygous pathogenic (or likely pathogenic) variant in CCDC22 in a male by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Ritscher-Schinzel syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Ritscher-Schinzel syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Ritscher-Schinzel syndrome (RSS) is relatively rare but is a clinically recognizable condition that includes characteristic dysmorphic facial and skeletal features. This disorder is associated with variable degrees of developmental delay and intellectual disability. Malformations have involved many organs and systems including the eye, central nervous system (CNS), and cardiovascular and skeletal systems. Cardinal features include craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome.

The following clinical information is based on numerous published reports [Ritscher et al 1987, Lauener et al 1989, Verloes et al 1989, Marles et al 1995, Leonardi et al 2001, Elliott et al 2013, Friesen et al 2013, Kolanczyk et al 2015, Bartuzi et al 2016].

For a concise summary of the timeline from the original description of RSS to the ultimate identification of the underlying molecular mechanisms, click here (pdf).

Growth. Most affected individuals have a normal birth weight. They tend to have mild short stature and many develop obesity in later childhood that progresses in adulthood [Marles et al 1995, Leonardi et al 2001].

Individuals with a short neck who are obese are at increased risk of developing obstructive sleep apnea.

Craniofacial features. The classic dysmorphic craniofacial features are summarized in Suggestive Findings.

• While the palate may be highly arched, fewer than 5% of affected individuals have a cleft palate.
• About 20% of affected individuals have micrognathia.

Eye anomalies. Coloboma of the iris and optic nerve is present in about 20% of affected individuals.

Cardiac malformations. A variety of cardiac malformations have been described affecting more than half of individuals with RSS. These include:

• Atrioventricular canal defect
• Mitral valve anomalies, including cleft mitral valve
• Atrial septal defect
• Ventricular septal defect
• Double-outlet right ventricle
• Aortic stenosis
• Pulmonary stenosis
• Tetralogy of Fallot

Limb abnormalities. Upper-limb abnormalities are present in the majority of affected individuals, including:

• Brachydactyly, with the second ray being the most severely affected [Friesen et al 2013]
• Camptodactyly
• Proximally placed thumbs
• Abnormalities of the palmar creases

A study by Friesen et al [2013] involving eight individuals with RSS from Manitoba and Northwestern Ontario also found significant shortening of the first metacarpal and the fifth distal phalanx. The metacarpal phalangeal pattern profile generated showed a consistent wavy pattern. Also noted were consistent radiographic changes including: overtubulation of the bones (especially metacarpals 2-4), prominent tufts of the distal phalanges and a hypoplastic fifth distal phalanx.

Neurodevelopmental findings. Most individuals with RSS are significantly intellectually impaired. Hypotonia at birth is common. Motor coordination and speech are delayed.

Most affected individuals achieve ambulation and are able to ultimately feed themselves. Most develop limited but meaningful speech.

Brain malformations. The most common CNS malformations are Dandy-Walker malformation or variant, cerebellar vermis hypoplasia, posterior fossa cysts, and (less frequently) hydrocephalus.

Disorders of cholesterol metabolism. Some affected individuals have been found to have hypercholesterolemia, with elevated LDL cholesterol levels that can lead to atherosclerotic plaque deposition. Hypercholesterolemia has been demonstrated to be present in childhood, although xanthomas have not been reported in affected individuals. Hypercholesterolemia is hypothesized to be due to mislocalization of the low-density lipoprotein receptor, accompanied by decreased LDL uptake [Bartuzi et al 2016] (see Phenotype Correlations by Gene).

Other abnormalities. The following have been reported in fewer than 10% of affected individuals; it is unknown whether these are rare features of RSS or if they represent coincidental findings:

• Absent ribs
• Adrenal hypoplasia
• Anal atresia
• Congenital glaucoma
• Clubbed foot [Konya et al 2015]
• Cutis aplasia
• Hemangioma
• Hemivertebrae
• Hypospadias
• Inguinal hernia
• Malrotation of the gut
• Nail hypoplasia
• Nipple hypoplasia
• "Penis hypoplasia"
• Polydactyly, without further description of the location or type
• Renal malformations

In one affected individual, humoral immune deficiency was described [Lauener et al 1989]; it was subsequently found to result from secondary loss of IgG via the gastrointestinal system [Zankl et al 2003].

Phenotype Correlations by Gene

CCDC22. Males with a hemizygous pathogenic variant in CCDC22 are more likely to have:

• Upslanted palpebral fissures, an uncommon finding in those who are of First Nations heritage [Kolanczyk et al 2015];
• A more strikingly large, protruding tongue than seen in individuals with variants in WASHC5;
• Additional ectodermal findings (nail hypoplasia, abnormal dentition and aplasia cutis congenital).

WASHC5. Some individuals with biallelic pathogenic variants in WASHC5 also develop hypercholesterolemia.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified; all individuals identified to date with RSS who are of First Nations heritage have the homozygous variant in WASHC5.

Nomenclature

WASHC5 was previously termed KIAA0196.

Kolanczyk et al [2015] suggested that the group of disorders including the X-linked and autosomal recessive forms of RSS be termed WASHopathies (see Molecular Genetics).

Prevalence

RSS is rare and, although individuals have been reported with "3-C syndrome/RSS," not all reports include those who have the characteristic craniofacial features.

For the First Nations cohort (Northern Manitoba and Northwestern Ontario), the carrier frequency is estimated at 1:9 individuals [Elliott et al 2013].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Ritscher-Schinzel syndrome (RSS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Ritscher-Schinzel syndrome (RSS) caused by pathogenic variants in WASHC5 is inherited in an autosomal recessive manner.

RSS caused by pathogenic variant in CCDC22 is inherited in an X-linked manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one WASHC5 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with RSS are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WASHC5 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the WASHC5 pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the CCDC22 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the CCDC22 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo CCDC22 pathogenic variant, in which case the mother is not a carrier. The frequency of males with a de novo pathogenic variant is unknown.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a CCDC22 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will usually not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the CCDC22 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of proband. Affected males are not known to reproduce.

Other family members. The proband's maternal aunts may be at risk of being carriers for the pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being carriers of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the CCDC22 pathogenic variant has been identified in the proband.

• Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected
• Identification of female heterozygotes requires either (a) prior identification of the CCDC22 pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the RSS-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound findings. RSS caused by pathogenic variants in WASHC5 is associated with increased nuchal translucency thickness [Rusnak et al 2008]. First-trimester prenatal ultrasound is recommended in at-risk pregnancies to evaluate for cardiac anomalies and increased nuchal translucency. It has not been established whether RSS caused by pathogenic variants in CCDC22 demonstrates increased nuchal translucency.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The genes involved in both autosomal (WASH5C) and X-linked (CCDC22) forms of RSS encode proteins belonging to a family known as "WASHopathies" [Kolanczyk et al 2015]. Both proteins encoded by these genes play a role in the function of the WASH and are involved in actin polymerization and multiple endosomal transport processes.

CCDC22 encodes amino acid coiled-coil domain-containing protein 22 that interacts with the functional WASH complex. It is expressed in many human tissues (with highest expression in a number of blood cell lineages) and plays a role in NFκB signaling. CCDC22 contains:

• An N-terminal conserved domain;
• A C-terminal coiled coil domain that is similar to structural maintenance of chromosomes (SMC) proteins.

WASHC5 encodes strumpellin (WASH complex subunit 5), a highly conserved WASH complex protein that is ubiquitously expressed. It is predicted to have several functional domains [Elliott et al 2013]:

• Multiple transmembrane domains, with the N-terminal region (amino acids 1-240) comprising six α helices and two β strand segments
• A central region (amino acids 241-971) comprising spectrin-repeat domains
• A C-terminal region (residues 792-1159) demonstrating structural similarity to exportin-5 and importin β-1

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is required by certain transmembrane proteins in the endosomal compartment to reach their appropriate cellular destinations. The pentameric protein complex, that also consists of WASH1, FAM21, strumpellin, KIAA1033 (aka SWIP) and CCDC53 is recruited to endosomes by the retromer complex. The COMMD/CCDC22/CCDC93 (aka CCC) complex interacts and colocalizes with retromer and the WASH complex (reviewed in Bartuzi et al [2016]). The CCC complex regulates the level of circulating low-density lipoprotein (LDL) cholesterol by mediating the endosomal trafficking of the LDL receptor (LDLR). LDLR is an endosomal cargo of the CCC-associated WASH complex, and inactivation of the complex also results in LDLR mislocalization and impaired LDL uptake, ultimately resulting in hypercholesterolemia in individuals with RSS. See WAS-Related Disorders.

Mechanism of disease causation. RSS occurs through a loss-of-function mechanism.

Western blot analysis revealed that the p.Tyr557Cys variant resulted in a 50% decreased expression of CCDC22 in affected versus control individuals.

The p.Thr17Ala variant resulted in a fivefold decrease in mRNA levels in addition to increased levels of abnormally spliced transcripts retaining intron 1.

The WASHC5 c.3335+2T>A pathogenic variant, common in the First Nations cohort, is predicted to cause exon 27 skipping, resulting in a frameshift and a premature stop after amino acid 1128. The abnormal stumpellin is predicted to lose 99 C-terminal amino acids normally encoded by exons 27-29; these were replaced by 68 novel C-terminal residues. There was a mean 7.8-fold reduction in the relative amount of transcript produced, indicating that the transcript may be targeted for nonsense-medicated decay. The abnormal protein was reduced by 60% as compared to control.

Author Notes

Author's website: www.bcchr.ca/aelliott

Acknowledgments

We are grateful to Courtney B Cook, Dr Jill Mwenifumbo, and Dr Alan Rope for assistance.

Revision History

• 23 January 2020 (ma) Review posted live
• 15 April 2019 (ae) Original submission

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