Acrocallosal syndrome

Ghada M H Abdel-Salam MD (Dr. Abdel-Salam of the National Research Centre in Cairo, Egypt, 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 November 21, 2018; expires November 21, 2021


Acrocallosal syndrome (ACLS) is a multiple congenital abnormalities/intellectual disability syndrome. The clinical diagnosis is based on the presence of 3 of the 4 major criteria: 1) macrocephaly and facial dysmorphism, 2) partial or total agenesis of corpus callosum, 3) distal limb anomalies, and 4) intellectual disability. Biallelic mutations of K1F7 gene would confirm the clinical diagnosis as it was implicated in typical acrocallosal syndrome. Further, a phenotype consistent with acrocallosal syndrome was identified in 2 patients harboring de novo/dominant mutations in GLI3. The phenotypic spectrum includes a severe form with in utero fetal death known as hydrolethalus-2 syndrome usually presenting with hydrocephalus or anencephaly. This clinical variability can be explained by the action of K1F7, as it is a regulator of the Sonic Hedgehog pathway by preventing an inappropriate activation of Gli2 and the processing of Gli3 into its repressor form. The clinical spectrum of acrocallosal syndrome and differential diagnoses are discussed.

Key points


• Acrocallosal syndrome is a ciliopathy disorder typically characterized by macrocephaly, agenesis/hypogenesis of corpus callosum, polydactyly, and intellectual disability.


• Hydrolethalus-2 is a more severe phenotype, including death in utero.


• Biallelic mutations in K1F7 gene are the most common mutations implicated in acrocallosal syndrome.


• De novo mutations in the GLI3 gene were identified in a few cases with acrocallosal syndrome (Speksnijder et al 2013).

Historical note and terminology

Acrocallosal syndrome (ACLS) was first recognized by Schinzel in 2 separate publications of 2 unrelated Swiss patients with macrocephaly, agenesis of the corpus callosum, hypertelorism, and polydactyly and was termed because of the unique association of corpus callosum and distal acral anomalies most commonly pre and/or postaxial polydactyly (Schinzel 1979; Schinzel and Schmid 1980). Biallelic mutations in KIF7 are delineated in the majority of patients, thus autosomal recessive mode of inheritance. The phenotype is ranging from the lethal anencephaly to a previously unrecognized mild end of the spectrum. In contrast, de novo heterozygous GLI3 mutations were reported in 2 unrelated patients with acrocallosal syndrome. The exact frequency of acrocallosal syndrome is difficult to determine. The clinical spectrum has been broadened not only to include hypogenesis/agenesis of corpus callosum but also cystic malformation of the brain (Thyen et al 1992; Koenig et al 2002). Midline defects such as cleft palate or congenital heart defects have been reported. Furthermore, anophthalmia, lack of nasal structures, and omphalocele have been described (Christensen et al 2000). Nevertheless, hypogenitalism was noted in few patients (Temtamy and Meguid 1989; Ikbal et al 2004; Putoux et al 2012).

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.