Acrocallosal syndrome

Zully Gelman-Kohan MD (Dr. Gelman-Kohan of Rehovot, Israel has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released July 17, 1995; last updated June 9, 2015; expires June 9, 2018

Overview

Acrocallosal syndrome is a multiple malformations-intellectual disability syndrome with autosomal recessive inheritance. The clinical diagnosis is based on the presence of macrocephaly, facial dysmorphism, preaxial and postaxial polydactyly of hands and feet, partial or total agenesis of corpus callosum, and intellectual disability. The phenotypical spectrum includes cystic brain malformations, other midline anomalies like cleft palate, and congenital heart defects. A severe form with in utero fetal death is known as hydrolethalus-2 syndrome. Familial and sporadic cases have been clinically diagnosed. ACLS syndrome is 1 of the ciliopathy disorders. Putoux and colleagues found nonsense and frameshift mutations in the K1F7 gene on chromosome 15q26.1 by genome-wide linkage analysis followed by candidate gene sequencing. Walsh and associates in 2013 and Karaer and colleagues in 2015 contributed to the knowledge of novel mutations in familial cases of acrocallosal syndrome. Hydrolethalus-2 syndrome and Joubert syndrome 12 have also been found to be due to mutations in the K1F7 gene.

Key points

 

• Acrocallosal syndrome is a ciliopathy disorder due to mutations in the K1F7 gene.

 

• Gene K1F7 is located on chromosome 15q26.1.

 

• Mutations in the K1F7 gene are also responsible for Joubert syndrome 12 (Barakeh et al 2015).

 

• Hydrolethalus-2 is an allelic disorder with a more severe phenotype, including death in utero.

Historical note and terminology

Postaxial polydactyly, hallux duplication, absence of the corpus callosum, macrencephaly, and severe mental retardation were described by Schinzel as a probable new syndromic association (Schinzel 1979). A second, nonrelated patient with the same features further strengthened the hypothesis of a formal genesis syndrome, and the term "acrocallosal syndrome" was suggested (Schinzel and Schmid 1980).

The exact frequency of acrocallosal syndrome is difficult to determine. During the last several years, new cases are known through personal communications or publications of cases with unusual pre- or postnatal phenotypic findings (Gul et al 2004). Initially, acrocallosal syndrome was believed to be an autosomal dominant entity because only sporadic cases without parental consanguinity were seen (Nelson and Thomson 1982; Schinzel 1982a). Autosomal recessive inheritance is now accepted since familial recurrence (Schinzel 1982b; Schinzel and Kaufmann 1986; Schinzel 1988) and parental consanguinity have been documented (Philip et al 1988; Yuksel et al 1990; Gelman-Kohan et al 1991; Christianson et al 1994; Courtens et al 1997; Koenig et al 2002).

The clinical spectrum has been broadened to include severe CNS abnormalities such as anencephaly, (Gelman-Kohan et al 1991; Cataltepe and Tuncbilek 1992; Lurie et al 1994; Kedar et al 1996) or cystic malformation of the brain (Thyen et al 1992; Koenig et al 2002), and less frequent midline defects such as cleft palate or congenital heart defects. An expanded phenotype including anophthalmia, lack of nasal structures, and omphalocele has been suggested by Christensen and colleagues (Christensen et al 2000). Ikbal and colleagues found associated micropenis, which may be a coincidental finding but has to be taken into account as it also represents a midline anomaly (Ikbal et al 2004).

The similarity and, in many cases, overlapping phenotypes between the autosomal dominant Greig cephalopolysyndactyly syndrome and acrocallosal syndrome gave rise to the hypothesis of allelism of both syndromes (Hendriks et al 1990). This was shown to be unlikely by linkage analysis (Brueton et al 1992). Further clinical and molecular studies defined Greig cephalopolysyndactyly as a contiguous gene deletion syndrome due to haploinsufficiency of the GLI3 gene located at 7p13 (Johnston et al 2003), whereas acrocallosal syndrome is considered a ciliopathy due to mutations in the K1F7 gene (Lee and Gleeson 2011). GLI3 mutations in patients clinically diagnosed with acrocallosal syndrome have been reported (Speksnijder et al 2013). By genome-wide linkage analysis and candidate gene sequencing, Putoux and colleagues detected nonsense and frameshift mutations in the K1F7 gene located on chromosome 15q26.1 in familial and sporadic patients affected with acrocallosal syndrome (Putoux et al 2011).

Schinzel and Kaufman suggested that acrocallosal syndrome and hydrolethalus syndrome could be expressions of different mutations at the same, then unidentified, gene (Schinzel and Kaufman 1986). The finding of K1F7 mutations in patients affected with either syndrome confirms this hypothesis and gives evidence for oligogenic inheritance (Walsh et al 2013). Karaer and associates contributed to the knowledge of novel mutations in familial cases of acrocallosal syndrome (Karaer et al in 2015).

Many of the documented cases are located around the Mediterranean basin, and the gene frequency was proposed to be higher in that area (Gelman-Kohan et al 1991). Bias of ascertainment cannot be ruled out, as new cases are seen in different populations (Guion-Almeida 1992; Christianson et al 1994; Christensen et al 2000; Gulati et al 2003; Gupta et al 2003; Shilpa et al 2006).

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