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The prevalence is not known but fewer than 50 cases have been published since the first description in 1979.

In acrocallosal syndrome (ACS), craniofacial anomalies include macrocephaly with prominent forehead and occiput, hypertelorism, large anterior fontanel, short nose with broad nasal bridge and anteverted nostrils, and short mandible. Cases of anencephaly were observed as well as an extra bone within the anterior fontanel, a calvarian defect or a Dandy-Walker malformation. CC hypoplasia or agenesis is the main distinctive feature of ACS. It may be associated with arachnoidal cysts in about one third of cases and with various other brain abnormalities (medulla oblongata, temporal lobe or pons hypoplasia, micropolygyria and hypoplasia or agenesis of cerebellar vermis with a molar tooth sign). Distal anomalies of limbs include preaxial or postaxial polydactyly or polysyndactyly of toes and/or hands. The large majority of ACS patients have intellectual disability that is severe in 80% of cases, and substantial global developmental delay. Additional malformations have been described occasionally: short philtrum/upper lip, high-arched palate, cleft lip/palate, heart defects, hypospadias and inguinal and umbilical hernias.

Mutations in kinesin KIF7 (15q26.1) and, rarely, in the transcriptional activator GLI3 (7p14.1) are responsible for ACS. Both genes are involved in the ciliary sonic hedgehog pathway and their mutations most likely influences the early development of midline structures during embryogenesis.

Given the high variability of phenotypes, any two of the following criteria evokes the ACS diagnosis: (1) total or partial absence of the CC, (2) minor craniofacial anomalies, (3) moderate to severe global developmental delay with hypotonia and (4) polydactyly. Molecular genetic testing can be used to confirm the diagnosis and to guide genetic counseling.

Differential diagnosis includes Greig cephalopolysyndactyly syndrome, syndrome orofaciodigital type I, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, Gorlin syndrome, Aicardi syndrome, as well as Meckel-Gruber syndrome and hydrolethalus in the extreme forms.

Antenatal diagnosis is based on ultrasonography examination from the 20th week of gestation and magnetic resonance imaging (MRI) of the fetus.

ACS is an autosomal recessive disease. For parents of an affected individuals, there is therefore a 25% recurrence risk for a subsequent pregnancy. If the gene mutation in the kinesin/transcriptional activator genes has been identified in an affected sibling, molecular genetic diagnosis can be offered after chorionic villus sampling.

Surgical intervention may be considered for the polydactyly. Management is otherwise supportive with periodical evaluation by a child neurologist/neuropsychiatrist in order to monitor the evolution of the intellectual development or onset of seizures, as well as enabling and supporting therapies (including non-verbal communication) and special education programs.

Prognosis depends on the severity of malformations and hypotonia, and on the occurrence of seizures.