Ritscher-Schinzel Syndrome 1

A number sign (#) is used with this entry because Ritscher-Schinzel syndrome-1 (RTSC1) is caused by homozygous mutation in the KIAA0196 gene (WSHC5; 610657) on chromosome 8q24.

Description

The 3C syndrome, also known as Ritscher-Schinzel syndrome, is a developmental malformation syndrome characterized by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Facial features include prominent occiput, prominent forehead, low-set ears, downslanting palpebral fissures, depressed nasal bridge, and micrognathia. Cardiac defects can include septal defects and aortic stenosis, among others, and brain imaging shows Dandy-Walker malformation, cerebellar vermis hypoplasia, posterior fossa cysts, and ventricular dilatation. Affected individuals have severe developmental delay (summary by Leonardi et al., 2001; Seidahmed et al., 2011).

Genetic Heterogeneity of Ritscher-Schinzel Syndrome

See also RTSC2 (300963), caused by mutation in the CCDC22 gene (300859) on chromosome Xp11.

Clinical Features

Ritscher et al. (1987) reported the cases of 2 sisters who had brain malformation in the region of the posterior fossa and atrioventricular septal defect together with similar craniofacial anomalies. The craniofacial anomalies included macrocephaly, a prominent forehead and occiput, foramina parietalia, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, narrow palate, and apparently low-set ears. One sister had a Dandy-Walker malformation (220200) with communicating hydrocephalus, aplasia of the posterior portion of the cerebellar vermis, and high insertion of the confluent sinus. In the other sister, a Dandy-Walker variant was found with aplasia of the cerebellar vermis and hypoplasia of the hemispheres, large cisterna magna, high insertion of the confluent sinus, but no hydrocephalus. Both sibs were mildly mentally retarded. The older sister had a complete atrioventricular canal and died after unsuccessful heart operation at 3.5 years of age. The younger sister had a successful heart operation on a cleft mitral valve and septum primum defect. The parents were normal and Ritscher et al. (1987) suggested autosomal recessive inheritance. Lauener et al. (1989) provided follow-up information on the surviving younger sister, who was found to have a humoral immunodeficiency with markedly reduced immunoglobulin levels, especially affecting IgG2 and IgG4 subclasses, and antipolysaccharide antibody formation. Although possibly only coincidence, the authors suggested that the immunodeficiency might be a manifestation of the syndrome.

Verloes et al. (1989) described an isolated case in a daughter of nonconsanguineous parents. The child showed wide fontanels and facial dysmorphism (evoking cleidocranial dysplasia), cerebellar vermis hypoplasia, aplasia of the first ribs, multifocal sternal ossification centers, and cardiac septal defects. Mims and Say (1989) reported a case. Gurrieri and Neri (1992) reported a case of a child who showed camptodactyly of the fifth finger and hypoplasia of terminal phalanges with microonychia. Hoo et al. (1994) described 2 unrelated patients. They emphasized the presence of high and prominent forehead, hypoplastic vermis and cyst of the posterior fossa with or without hydrocephalus, and an atrial or atrioventricular septal defect with or without other heart anomalies.

Marles et al. (1995) observed 3 male and 5 female Canadian children from 7 families with features they considered to represent the Ritscher-Schinzel syndrome. Three of the families were related. The parents of the 2 affected sibs were consanguineous, but the other 2 sets of parents in these 3 families were not, to the best of their knowledge. All parents and other sibs were clinically unaffected, with parental ages ranging from 21 to 33 years. In addition to a distinctive facial appearance, the affected children showed variable combinations of ocular colobomas, hypertelorism, macrocephaly, hand anomalies, congenital heart defects, structural CNS posterior fossa malformations, and mental retardation. Ocular coloboma occurred in 6 of the patients.

Among 162 non-Down syndrome cases of atrioventricular canal, Digilio et al. (1995) found 1 patient they considered to have the 3C (craniocerebellocardiac) syndrome.

Saraiva et al. (1995) described an affected female infant with facial dysmorphism, cerebellar hypoplasia, hydrocephaly, Dandy-Walker malformation, atrial septal defects, abnormal vertebral segmentation, and syndactyly of toes 4-5. In addition to these typical manifestations of the 3C syndrome, the patient also had glaucoma.

In an analysis of cardiovascular malformations (CVM) in the 3C syndrome, Lurie and Ferencz (1996) found at least 9 types of CVM in 24 cases, including 4 cases from the Baltimore-Washington infant study. The proportion of the different CVM forms were similar to that of the general population. They pointed out that the same is also true for many other syndromes of multiple congenital abnormalities (MCA), due either to aneuploidy or to mendelian mutation. They proposed the hypothesis that the basic mutation (or chromosome imbalance) affects cellular homeostasis and leads to the shifting of a threshold to the left. This allows the expression of some genes silent under normal conditions. Fraser (1996) pointed out that their observations drew attention to an important but underappreciated relationship, namely, that factors influencing susceptibility to specific malformations may act by influencing the normal developmental pattern. This idea is based on the multifactorial threshold model, which postulates that many genes and environmental factors interact to determine a continuous distribution of susceptibility (liability), which is separated by a threshold into discontinuous parts, i.e., affected and unaffected. In the view of Fraser (1996), the message of Lurie and Ferencz (1996) is that each embryo has specific constellations of genes that determine its liability to specific malformations; a major insult, such as a 3C mutant gene or an environmental teratogen, may destabilize several developmental systems; the type of malformation produced will depend on how the embryo's genes influence its particular set of developmental patterns and hence its susceptibilities. That may be why the same mutant gene causes different malformations in different embryos. Fraser (1996) suggested that if the above is true the (unexposed) near relatives of children with phenytoin-induced cleft lip may have an increased frequency of cleft lip, and likewise for valproate-induced neural tube defects. The frequency of cleft lip should be higher in sibs when Meckel syndrome (249000) patients have cleft lip than when they do not. A frequency of heart malformations should increase in the sibs of patients with any syndrome in which heart malformations sometimes, but not always, occur.

On review of previously reported cases and study of 2 new cases of Ritscher-Schinzel syndrome, Kosaki et al. (1997) demonstrated: (1) Although varying degrees of vermis hypoplasia are accompanied by hypotonia, delayed gross motor function improves with advancing age, leaving speech delay as the major neurodevelopmental handicap. (2) Two different types of cardiac anomalies occur: defects of the endocardial cushion ranging from anomalies of the mitral or tricuspid valves to complete AV canal, and/or conotruncal defects. (3) Postnatal growth deficiency was seen in most patients in whom longitudinal information was available. In their review of patients with vermis hypoplasia, Kosaki et al. (1997) identified a patient diagnosed as having Joubert syndrome (213300) who had most findings of the Ritscher-Schinzel syndrome, and several other patients diagnosed as having Dandy-Walker syndrome (220200) who likely also had Ritscher-Schinzel syndrome, suggesting that the latter disorder is more common than had been appreciated. Kosaki et al. (1997) suggested that careful search for the subtle facial changes characteristic of Ritscher-Schinzel syndrome as well as coloboma, cleft palate/bifid uvula, short neck, syndactyly, and hypoplasia of the nails is warranted when evaluating patients with Dandy-Walker malformation with or without clinical signs of Joubert syndrome.

Orstavik et al. (1998) described 3 sibs with this disorder, born to consanguineous Pakistani parents. All 3 children had atrial septal defects II and ventricular septal defects and died within 3 months. Two of them had a Dandy-Walker malformation, whereas 1 had only slightly dilated ventricles. One sib had anal atresia, and another a ventrally displaced anus.

Wheeler et al. (1999) stated that at least 20 individuals with this condition had been reported. They described a girl with the 3C syndrome who at the age of 13 years was the oldest patient reported. She had been followed since birth, allowing them to show the evolution of her phenotype. In addition, she had documented growth hormone deficiency. Wheeler et al. (1999) suggested that growth hormone deficiency should be considered as a possible cause of the short stature often seen in this condition.

Leonardi et al. (2001) reported 4 cases of the Ritscher-Schinzel syndrome and reviewed all reported cases. Of the 9 craniofacial anomalies commonly reported as part of the syndrome, they concluded that cleft palate and ocular coloboma are the most readily and objectively ascertainable. The other 7 craniofacial traits, however, are somewhat subjective, require expert interpretation, and are sometimes difficult to ascertain in a newborn or stillborn fetus. The 7 other traits are prominent forehead, prominent occiput, hypertelorism, downslanting palpebral fissures, low-set ears, depressed nasal bridge, and micrognathia. At least 4 of these were present in all cases that had a secure diagnosis of the syndrome. Leonardi et al. (2001) proposed the following criteria for the diagnosis of this syndrome in a chromosomally normal sporadic case: the presence of cardiac malformation other than isolated patent ductus arteriosus (see 607411), cerebellar malformation, and cleft palate or ocular coloboma, or 4 of the 7 more subjective traits.

Papadopoulou et al. (2005) reported a male child with 3C syndrome who, in addition to previously reported features, had Wormian bones of the skull, intraabdominal testes, and posterior embryotoxon.

Iyer and Smith (2005) described a patient with 3C syndrome. The female infant presented with the characteristic features of Dandy-Walker malformation of the brain, congenital cardiac defect, dysmorphic facies, and postnatal growth failure. She had gastroesophageal reflux and severe feeding difficulties which were still present at the age of 4 years. Despite her numerous medical problems, she demonstrated near-normal development.

Craft et al. (2010) reported 2 sibs, a girl and a boy, born of consanguineous Pakistani parents, with features reminiscent of 3C syndrome. Both had delayed psychomotor development and dysmorphic facial features, including downslanting palpebral fissures, prominent nasal bridge, micrognathia, and small head size. Both patients and an otherwise unaffected sister had flexion contractures of the fingers; the affected sister also had flexion contractures of the large joints and scoliosis. The affected sister had marked cerebellar vermis hypoplasia, ventricular septal defect, and mitral valve stenosis, but the affected brother did not have cardiac defect or abnormal findings on brain MRI. Neither had cleft palate/Robin sequence. Craft et al. (2010) noted that there is phenotypic variability in 3C syndrome, but also suggested some overlap with the phenotype (611961) in 2 sisters reported by Stevenson and Carey (2007).

Seidahmed et al. (2011) reported a consanguineous Saudi family in which 4 children had features consistent with the 3C syndrome, including global developmental delay, dysmorphic facial features, congenital heart malformation, and CNS anomalies, including Dandy-Walker malformation, hydrocephalus, and cerebellar vermis hypoplasia. Additional features in this family included sparse hair, camptodactyly, and renal anomalies, such as horseshoe kidney, renal agenesis, or dysplastic cystic kidney. However, 2 girls in the family who had no other features of the 3C syndrome also had genitourinary anomalies, suggesting that 2 different disorders may run in this highly consanguineous family.

Stevens and Lachman (2010) described 2 sibs, a stillborn male born at 27 weeks' gestation and a female born at 31 weeks' gestation who died at 7 days of age, with a phenotype characterized by Dandy-Waker malformation, congenital heart defects, joint contractures, genital hypoplasia, distinctive facial features, rhizomelic and mesomelic limb shortening, hooked clavicles, dumbbell femurs, and absent talus and calcaneus ossification. Because of the bone anomalies, Stevens and Lachman (2010) suggested that the phenotype in these sibs was different from other skeletal disorders with Dandy-Walker malformation, including Ritscher-Schinzel syndrome, and represented a previously undescribed autosomal recessive lethal skeletal dysplasia.

Elliott et al. (2013) reported 11 patients from the First Nation isolated population in northern Manitoba, Canada, with RTSC. Four of the patients had previously been reported by Marles et al. (1995). All patients had intellectual disability and dysmorphic facial features, including macrocephaly, brachycephaly, prominent forehead, low posterior hairline, wide and downslanting palpebral fissures, hypertelorism, and low-set ears. Three patients had ocular coloboma. Six patients had variable cardiac septal defects. Central nervous system abnormalities included Dandy-Walker malformation (4 patients), enlarged ventricles, hypoplasia of the cerebellar vermis, and increased cerebrospinal fluid in various brain regions.

Cytogenetics

DeScipio et al. (2005) noted considerable phenotypic overlap between chromosome 6pter-p24 deletion syndrome (612582) and 3C syndrome. They did not identify deletions of chromosome 6p in 7 additional unrelated patients with 3C syndrome, including the original family reported by Ritscher et al. (1987).

Inheritance

Stellingwerff et al. (2006) performed segregation analysis on 27 pedigrees with 3C syndrome selected from the literature. The results of 3 different methods were consistent with autosomal recessive inheritance. However, the authors emphasized that reporting of patients with 3C syndrome should include evaluation of chromosome 6p copy number, as subtelomeric chromosome 6p deletion has been associated with a similar phenotype (DeScipio et al., 2005).

The transmission pattern of Ritscher-Schinzel syndrome in the families reported by Marles et al. (1995) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 11 patients with Ritscher-Schinzel syndrome from an isolated community in northern Manitoba, Canada, Elliott et al. (2013) identified a homozygous splice site mutation in the KIAA0196 gene (610657.0004). The mutation was found by homozygosity mapping followed by candidate gene sequencing, and segregated with the disorder in the families. Four of the patients had previously been reported by Marles et al. (1995). Analysis of patient cells showed an 8-fold decrease in KIAA0196 mRNA compared to controls, suggesting that the mutant transcript may be subject to nonsense-mediated mRNA decay. Western blot analysis showed that the protein was reduced by 60% compared to controls.

Population Genetics

Marles et al. (1995) and Elliott et al. (2013) reported Ritscher-Schinzel syndrome in First Nation patients from an isolated, remote community in northern Manitoba, Canada. Eleven patients were found to carry the same homozygous splice site mutation in the KIAA0196 gene (610657.0004), consistent with a founder effect. Fifteen of 133 newborn blood spot samples from the same population were heterozygous for the mutation, indicating that 1 in 9 individuals from this region is a carrier of the disorder. This result predicted that 1 in 325 children in the next generation will have the Ritscher-Schinzel syndrome.