Ritscher-Schinzel Syndrome

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, lowset 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 testing for a pregnancy at increased risk 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
  • Lowset 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 variants in WASHC5 in a male or female OR a hemizygous pathogenic variant in CCDC22 in a male by molecular genetic testing (see Table 1).

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).

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