Acrocallosal Syndrome

A number sign (#) is used with this entry because acrocallosal syndrome (ACLS) and Joubert syndrome-12 (JBTS12), 2 similar disorders, can be caused by homozygous mutation in the KIF7 gene (611254) on chromosome 15q26. Digenic inheritance of Joubert syndrome has also been reported; see MOLECULAR GENETICS.

Description

The acrocallosal syndrome is an autosomal recessive mental retardation syndrome with brain abnormalities such as corpus callosum agenesis and/or Dandy-Walker malformation as well as dysmorphic features, postaxial polydactyly of the hands, and preaxial polydactyly of the feet (Schinzel and Schmid, 1980). It is considered a ciliopathy (Putoux et al., 2011).

Joubert syndrome-12 is a disorder with an overlapping phenotype characterized by the hallmark finding of the molar tooth sign (MTS) on brain MRI. For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.

Hydrolethalus-2 (HLS2; 614120) is an allelic disorder with a more severe phenotype and death in utero.

Clinical Features

Schinzel and Schmid (1980) reported 2 unrelated patients, a 2.5-year-old girl and a 4-year-old boy, with postaxial polydactyly, hallux duplication, macrocephaly, absence of corpus callosum, and severe mental retardation. The boy had previously been reported by Schinzel (1979). The authors favored autosomal dominant mutation, although parental age was little above the mean. They suggested the designation acrocallosal syndrome.

In a report of 2 more patients, an unrelated girl and boy, Nelson and Thomson (1982) stated: 'The triad of hypertelorism, polydactyly (especially of the hallux) and mental retardation strongly suggests the diagnosis which is further supported if the corpus callosum is absent.' CT scan is useful in demonstrating absence of the corpus callosum.

Schinzel (1982) summarized a total of 7 cases, all sporadic. He raised the question of identity to the Greig cephalopolysyndactyly syndrome (GCPS; 175700). The digital changes are similar to those of GCPS. Legius et al. (1985) also raised the question of identity to GCPS. Hendriks et al. (1990) reported a case which suggested that increased birth weight and cerebellar hypoplasia may be features of the acrocallosal syndrome. The finding of an extra bone within the anterior fontanel in their patient suggested similarity to the Xt mouse mutant, which is homologous to GCPS in man. This was taken as additional support for the hypothesis of allelism of the GCPS and acrocallosal syndromes. Brueton et al. (1992) did linkage analysis in a family in which 2 cousins, the offspring of sisters, had acrocallosal syndrome. Using markers known to be flanking the GCPS locus on chromosome 7p, they found evidence that appeared to exclude ACLS from that region.

Schinzel (1982) and Schinzel and Kaufmann (1986) observed 4 additional cases from a restricted and sparsely populated area of Switzerland, including 2 affected sisters with healthy, nonconsanguineous parents (the first familial cases) and male and female first cousins whose mothers are sisters. Thus, the disorder was considered likely recessive. Schinzel and Kaufmann (1986) pointed out that the combination of agenesis of the corpus callosum and pre- or postaxial polydactyly is also found in the Finnish 'hydrolethalus syndrome' (236680). Indeed, they raised the question of whether the latter condition might be a lethal allele of the disorder in the acrocallosal syndrome. Philip et al. (1988) described 2 unrelated 4-month-old boys, each with consanguineous parents. Both exhibited the main features of the syndrome, but neither had partial reduplication of halluces. Consequently, Philip et al. (1988) concluded that preaxial polydactyly of the feet is not a constant feature of the syndrome. Schinzel (1988) described this syndrome in male and female first cousins (referred to earlier). Both patients had a defect of the corpus callosum, macrocephaly with protruding forehead and occiput, hypertelorism, and postaxial polydactyly of the hands. The boy, in addition, had hypospadias, cryptorchidism, inguinal hernias, duplication with syndactyly of the phalanges of the big toe, and a bipartite right clavicle. The girl had an arachnoidal cyst, a calvarian defect, and digitalization of the thumbs. Motor and mental development was retarded in both patients. Yuksel et al. (1990) reported the case of a Turkish boy, born to consanguineous parents, who showed macrocephaly, prominent forehead, hypertelorism, polydactyly of the fingers and toes, severe motor and mental retardation, hypotonia, and absence of the corpus callosum. Turolla et al. (1990) described an infant with all the components of ACLS except preaxial polydactyly. Salgado et al. (1989) reported the case of an affected child whose parents were related as half first cousins. Temtamy and Meguid (1989) saw the disorder in the offspring of double first cousins. The patient of Salgado et al. (1989) and that of Moeschler et al. (1989) had hallucal duplication. The occurrence of Dandy-Walker malformation in the acrocallosal syndrome was indicated by the report of Moeschler et al. (1989). Casamassima et al. (1989) described a case in which severe congenital heart defect was present. Fryns et al. (1991) presented the cases of 2 unrelated males with minor expression of ACLS. Developmental level in both was within normal limits. Lungarotti et al. (1991) described the condition in a 2-month-old infant girl. Gelman-Kohan et al. (1991) described 3 affected sibs from a consanguineous marriage. Cataltepe and Tuncbilek (1992) stated that 21 well-documented cases had been reported. They reported a family in which the parents were first cousins. Their proband had a high birth weight (more than 90th percentile), which had been suggested by others as a feature of the disorder. Additional features included sensorineural hearing loss and diaphragm eventration. An earlier-born sib had anencephaly and postaxial polydactyly.

Kedar et al. (1996) described anencephaly in a brother and sister as apparently a primary manifestation of ACLS (which they abbreviated ACS).

Pfeiffer et al. (1992) reported the case of a child, of normal unrelated parents, who, in addition to typical features of this syndrome, had a mirror duplication of nearly the entire short arm of chromosome 12 (a de novo inverted tandem duplication of 12p13.3-p11.2). Since the manifestations of trisomy and tetrasomy 12p show some overlap with the acrocallosal syndrome (as in the Pallister-Killian syndrome with tetrasomy 12p), Pfeiffer et al. (1992) suggested that the mutation for acrocallosal syndrome may be situated on 12p. (For a discussion of the Pallister-Killian syndrome, see 190070; the KRAS2 gene was used in the study of this syndrome.) This is, of course, inconsistent with the idea that the acrocallosal syndrome is allelic to Greig syndrome, since the latter disorder maps to 7p13. From South Africa, Christianson et al. (1994) reported the disorder in 2 black brothers with first-cousin parents.

Koenig et al. (2002) described 3 patients with ACS demonstrating a spectrum from mild to severe involvement. Two patients had only mild to moderate mental retardation at the age of 2.5 and 4 years, respectively, with surprisingly good speech development. The third patient was severely affected and died at age 7 days because of persistent apnea. All 3 patients had agenesis of the corpus callosum and large intracranial cysts, which in the third case was confirmed as a large arachnoid cyst at autopsy. Cranial cysts were also seen in 10 of 34 published cases of ACS. Thus, intracerebral cysts are a common finding in ACS and may serve in differentiating ACS from Greig cephalopolysyndactyly syndrome.

Aykut et al. (2008) reported a 10-month-old female infant with findings suggestive of acrocallosal syndrome, including optic atrophy, psychomotor retardation, polydactyly, and characteristic facies with prominent forehead, hypertelorism, and high-arched palate. Brain MRI revealed cerebral atrophy, corpus callosum agenesis, dilated lateral ventricles, and unilateral right temporal lobe hypoplasia. Aykut et al. (2008) noted that temporal lobe hypoplasia had not been previously reported and may represent an additional feature in this syndrome.

Putoux et al. (2011) reported 7 families and 2 sporadic individuals with ACLS. Four of the families were of Turkish origin, and the remaining patients were from Pakistan, Finland, Algeria, and Egypt. Seven of the families were consanguineous. The majority of affected individuals had macrocephaly, mental retardation, abnormal facies, and brain abnormalities, including dilated ventricles, corpus callosum agenesis or hypoplasia, and a superior vermis dysgenesis resulting in the molar tooth sign in 7 affected individuals. Seven affected individuals had postaxial polydactyly of the hands. In the feet, polydactyly was preaxial; hallux duplication was postaxial or preaxial and postaxial. Dysmorphic facial features included prominent forehead, frontal bossing, broad nasal bridge, wide nasal bridge, short philtrum, hypertelorism, low-set ears, retrognathia, and dental anomalies. Other more variable features included hypotonia, bilateral optic atrophy, and ventricular septal defect.

Joubert Syndrome 12

Dafinger et al. (2011) reported 2 Egyptian sibs, born of consanguineous parents, with Joubert syndrome-12. The patients had mental retardation, molar tooth sign on brain MRI, and dysmorphic facial features including hypertelorism, triangular mouth, downslanting palpebral fissures, low-set ears, and prominent forehead. One patient had ataxia, agenesis of the corpus callosum, and polydactyly.

Inheritance

The numerous reports of consanguinity in families with ACLS indicate that it is an autosomal recessive disorder (Schinzel, 1988; Philip et al., 1988; Salgado et al., 1989 Temtamy and Meguid, 1989; Yuksel et al., 1990; Gelman-Kohan et al., 1991; Putoux et al., 2011).

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing, Putoux et al. (2011) identified 3 nonsense and 5 frameshift mutations in the KIF7 gene (see, e.g., 611254.0001-611254.0005) in ACLS patients from 6 families and in 2 individual patients. The mutations were presumably homozygous. The findings indicated that ACLS is a ciliopathy.

Elson et al. (2002) identified a child with an ACLS phenotype carrying a heterozygous mutation in the GLI3 gene (165240.0013). We have classified the phenotype in this patient as severe Greig cephalopolysyndactyly syndrome because it is impossible to distinguish the disorders in a simplex case and because the molecular basis of each disorder appears to be established. Biesecker (2008) stated that patients with a phenotype consistent with GCPS and a GLI3 mutation may be diagnosed definitively as GCPS.

Joubert Syndrome 12

Dafinger et al. (2011) identified a homozygous truncating mutation in the KIF7 gene (611254.0006) in 2 Egyptian sibs with Joubert syndrome-12. A third patient with the disorder had a heterozygous mutation (611254.0007), but a second pathogenic allele was not identified. A fourth patient with Joubert syndrome had 2 pathogenic mutations in the TMEM67 gene (609884.0013; 609884.0024), consistent with JBTS6 (610688), as well as a heterozygous mutation in the KIF7 gene (611254.0008). Knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and decreased microtubular dynamics. The findings indicated that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to Joubert syndrome.

Digenic Inheritance

In a German patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 536A-G transition in exon 7 of the CEP41 gene (610523), resulting in an arg179-to-his (R179H) substitution in a highly conserved residue consistent with JBTS15 (614464), and a heterozygous truncating mutation in the KIF7 gene (811delG; 611254.0007), consistent with JBTS12.