C Syndrome

A number sign (#) is used with this entry because of evidence that the C (Opitz trigonocephaly) syndrome is caused by heterozygous mutation in the CD96 gene (606037), which encodes a member of the immunoglobulin superfamily, on chromosome 3q13.

Description

The C syndrome, also known as Opitz trigonocephaly syndrome, is a malformation syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears (summary by Kaname et al., 2007).

C syndrome shows phenotypic overlap with Bohring-Opitz syndrome, or C-like syndrome (605039), a disorder with more severe features than C syndrome, caused by heterozygous mutation in the ASXL1 gene (612990) on chromosome 20q11.

Clinical Features

Opitz et al. (1969) described a brother and sister with a malformation syndrome that included unusual facies, polydactyly, cardiac abnormality and, in the boy, cryptorchidism.

Antley et al. (1981) brought the total number of cases to 11 and pointed (in an addendum) to affected brother and sister reported earlier under another designation. Normal karyotype, normal parents with multiple affected offspring, equal sex ratio of affected persons, and parental consanguinity made autosomal recessive inheritance highly likely.

Sargent et al. (1985) presented 12 cases of trigonocephaly of which 6 were associated with other malformations. Partial or complete obliteration of the metopic suture is characteristic. The forehead is narrow and pointed, often associated with biparietal widening and a triangular shape of the skull when viewed from above. Trigonocephaly has been observed as part of several chromosomal syndromes. The cases of Sargent et al. (1985) included an example of first-cousin parents and a pair of affected sibs. Isolated trigonocephaly is usually a trivial anomaly. Complex trigonocephaly, even after chromosomal aberrations are excluded, may be heterogeneous and the risk of recurrence for the group as a whole is probably on the order of 10% rather than 25% (Sargent et al., 1985).

Lalatta et al. (1990) reported 3 unrelated patients. One had a large omphalocele. De Almeida et al. (1992) reported another example of large omphalocele with the C syndrome.

Stratton et al. (1990) reported a presumed case with apparently normal development, and Camera et al. (1990) reported 2 further cases with typical characteristics. Haaf et al. (1991) described this syndrome in the daughter of consanguineous parents. The child showed striking upslanting of the palpebral fissures, small nose with broad root, abnormally modeled ears, short neck with loose skin, polysyndactyly, and prominent clitoris and labia majora. The patient also had Eisenmenger syndrome (ventricular septal defect with pulmonary hypertension and right-to-left shunt through a persistent ductus arteriosus; see 607411) and was mentally retarded. Glickstein et al. (1995) reported a girl who, in addition to typical manifestations of the C syndrome, had tetralogy of Fallot and agenesis of the corpus callosum. These defects had previously been described in only 1 or 2 patients with this syndrome.

De Koster et al. (1990) described a patient who also had pseudohypoaldosteronism (264350). Since this disorder may represent a defect in the mineralocorticoid receptor (600983), which has been assigned to chromosome 4, De Koster et al. (1990) raised the possibility that the association is due to a cytogenetically undetectable microdeletion in chromosome 4. Schaap et al. (1992) reiterated the suggestion that this disorder may be a microdeletion syndrome which is cytogenetically undetectable. They described 2 cases of trigonocephaly, only one of which appeared to have the Opitz-C syndrome, and reviewed 22 cases from the literature.

Omran et al. (1997) described a probable case of Opitz trigonocephaly syndrome in a patient who presented at the age of 12 years with symptoms of raised intercranial pressure due to medulloblastoma. Both feet featured postaxial hexadactyly.

Clinical Variability

Preus et al. (1975) described 2 similar patients who were unrelated. Oberklaid and Danks (1975) described a patient and suggested that the disorder be called the Opitz trigonocephaly syndrome. They were dubious that the cases of Preus et al. (1975) were the same. The peculiar shape of the skull, the unusual facies, and the bizarre conformation of the palate were illustrated and described. Flexion deformities of the elbows, wrists, and fingers were seen. The child died at 2 weeks of age. About half the patients die in the first year.

Bohring et al. (1999) presented 4 unrelated cases of an Opitz trigonocephaly (C)-like syndrome (605039). These cases differed from C syndrome on the basis of intrauterine growth retardation, cleft lip/palate, exophthalmos, retinal involvement, flexion deformities of the upper limbs, dislocation of radial heads, and forehead hirsutism. The authors also identified 2 cases in the literature, formerly reported as having C syndrome (Addor et al., 1995; Oberklaid and Danks, 1975), with a similar phenotype to their cases. All 6 cases were sporadic. The authors suggested that these infants may represent the most severe form of the C syndrome or a new entity.

Kaname et al. (2007) discussed phenotypic similarities and differences between the C and C-like syndromes and reviewed their delineation. The C syndrome, also known as Opitz trigonocephaly syndrome, is characterized by trigonocephaly and associated anomalies such as unusual facies, psychomotor retardation, redundant skin, abnormalities of joint and limbs, and visceral anomalies.

Osaki et al. (2006) described a newborn infant who had many clinical features similar to those of the C-like syndrome but did not have exophthalmos, which had been regarded as a hallmark of the C-like syndrome. They suggested that the manifestations in this patient are a further indication of overlap between the C-like syndrome and the C syndrome. In the patient reported by Osaki et al. (2006), Kaname et al. (2007) identified a heterozygous mutation in the CD96 gene (606037.0002). Kaname et al. (2007) noted that this patient had relatively severe features for C syndrome, but also stated that it was uncertain whether there is (1) a spectrum in the C syndrome from the mild form (C syndrome) to the severe form (C-like syndrome), or (2) genetic heterogeneity among the patients with the C syndrome.

Cytogenetics

McGaughran et al. (2000) reported a patient with findings consistent with the C syndrome, who had duplication of 3p identified by use of subtelomeric probes. The patient's karyotype was 46,XX.ish der(5)t(3;5)(p26.3;p15.33)(3pter+)de novo.

Chinen et al. (2006) reported a boy, the third child of healthy, nonconsanguineous parents, who had manifestations of Opitz trigonocephaly (C) syndrome and a de novo balanced reciprocal translocation t(3;18)(q13.13;q12.1). He had mild developmental delay and no severe visceral anomalies.

Molecular Genetics

In the patient with C syndrome with a balanced chromosomal translocation t(3;18) reported by Chinen et al. (2006), Kaname et al. (2007) found that the CD96 gene was disrupted at the 3q13.13 breakpoint (606037.0001). In mutation analysis of 9 karyotypically normal patients with diagnoses of the C or C-like syndrome, they identified a missense mutation, T280M (606037.0002), in exon 6 of the CD96 gene in 1 patient with a phenotype consistent with C-like syndrome, except for the absence of exophthalmos (Osaki et al., 2006). Cells with mutated CD96 protein of the T280M type lost adhesion and growth activities in vitro. The findings indicated that CD96 mutations may cause a form of the C syndrome by interfering with cell adhesion and growth.

In the C syndrome, normal chromosomes in most patients, unaffected parents with multiple affected offspring, equal sex ratio of affected individuals, and consanguineous matings all support autosomal recessive inheritance. At the same time, many patients have sporadic disease and the recurrence risk may be estimated to be 10% (Sargent et al., 1985), which suggests the possibility of dominant inheritance or germline mosaicism. The CD96 aberrations (translocation and missense mutation) found by Kaname et al. (2007) were both in the heterozygous state without a copy number variation in the region of the gene, which is consistent with an autosomal dominant condition.