Paula and Bobby
Parents of Lillie
Acrocallosal syndrome (ACLS)
What is Acrocallosal syndrome (ACLS)?
This rare disease is a genetic condition which was first identified in 1970 by Dr. Schnizel. Since then there have been just 25 cases diagnosed worldwide to date.
It is a syndrome which affects the development of the brain, and intellectual disability is a defining feature of it.
The syndrome is an inherited condition and due to the severity of its symptoms, it is usually identified at birth.
This syndrome is also known as:
ACS Hallux Duplication; Postaxial Polydactyly; And Absence Of Corpus Callosum Schinzel Acrocallosal Syndrome; Schinzel syndrome
What gene change causes Acrocallosal syndrome (ACLS)?
The syndrome is caused by mutations in the KIF7 gene. It is inherited in an autosomal recessive pattern.
Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.
what are the main symptoms of Acrocallosal syndrome (ACLS)?
The syndrome affects the development of the thick bank of nerve fibers that join the two hemispheres of the brain. This leads to moderate to severe intellectual disability in affected individuals.
Symptoms may vary considerably between individuals including individuals within the same family. But they are usually obvious enough in all affected individuals for the syndrome to be identified at birth.
Features related to the syndrome mainly affect the skull and face. These include a very large head and forehead. Widely spaced eyes, a small nose and broad bridge.
Webbing of the fingers or toes, or missing fingers and toes is also common. As is a short stature.
Possible clinical traits/features:
Phenotypic variability, Frontal bossing, Prominent forehead, Short philtrum, Macrocephaly, Strabismus, Pulmonary valve defects, Heterogeneous, Umbilical hernia, Preaxial foot polydactyly, Open mouth, Sensorineural hearing impairment, Optic atrophy, Nystagmus, Rectovaginal fistula, Triangular mouth, Thin vermilion border, Wide anterior fontanel, Preaxial hand polydactyly, Seizure, Postaxial foot polydactyly, Posteriorly rotated ears, Postaxial hand polydactyly, Preauricular skin tag, Toe syndactyly, Duplication of thumb phalanx, Duplication of phalanx of hallux, Autosomal recessive inheritance, Autosomal dominant inheritance, Aplasia/Hypoplasia of the corpus callosum, Aplasia/Hypoplasia of the cerebellum, Anal atresia, Triphalangeal thumb, Abnormality of the fontanelles or cranial sutures, Abnormality of the clavicle, Abnormal cardiac septum morphology, Cleft palate, Abnormality of the pinna, Wide nasal bridge, Hypertelorism, Hypoplasia of teeth, Hypopigmentation of the fundus, Generalized hypotonia, Prominent
How does someone get tested for Acrocallosal syndrome (ACLS)?
The initial testing for Acrocallosal syndrome (ACLS) can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Acrocallosal syndrome (ACLS)
The main characteristics of this condition consist of mental retardation, agenesis of the corpus callosum and pre-axial polydactyly involving both feet. Retardation is usually severe, and the facial features consist of a prominent broad forehead and hypertelorism (not usually marked). Palpebral fissures have slanted both up and down in the same sibship.
Post-axial polydactyly of both hands is not unusual and the same abnormality may occur in both feet. The diagnosis is made even more difficult by the fact that one of affected cousins reported by Schinzel (1988) had only post-axial polydactyly of the fingers, whereas the other cousin had pre- and post-axial polydactyly of the toes, and post-axial polydactyly of the fingers. Both had agenesis of the corpus callosum. Christianson et al., (1994) reported a similar pair of brothers where only one had pre-axial polysyndactyly. One case had a VSD and ASD. The molar tooth sign on brain MRI has been reported (Krajewska-Walasek et al., (2015).
Cataltepe and Tucbilek (1992) reported an affected boy who also had eventration of the diaphragm and sensorineural deafness. A previous sib had anencephaly and postaxial polydactyly of the fingers but a detailed autopsy and a chromosome analysis was not performed. Lurie et al., (1994) also suggested that anencephaly was part of the clinical spectrum. Kedar et al., (1996) reported an inbred Arab family where a male and female sib had anencephaly, one associated with polydactyly, and other cousins had apparently classical acrocallosal syndrome. Thyen et al., (1992) reported a probable case with a large inter-hemispheric cyst as did Fernandez et al., (2008). Koenig et al., (2002) point out that intracranial cysts are common in the condition, being seen in about 25% of cases. Various cysts have been described, including arachnoid, porencephalin, interhemispheric, supratentorial, and Dandy-Walker cysts. Fragmented dentate nuclei, dysplasic olives amd numerous neuronal heterotopias can occur (Fernandez et al., 2008). Courtens et al., (1997) reported a case with features of the condition but just postaxial polydactyly of the hands. They suggested minimum diagnostic criteria for the condition.
Linkage studies suggest that this disorder is not allelic to Greig syndrome, despite the similarity in facial appearance and the pattern of polysyndactyly (Brueton et al., 1992). Pfeiffer et al., (1992) reported a case with many features of the condition who had a tandem duplication of 12p11.2-p13.3.
Note that Ward et al., (1993) reported a female infant with a de novo reciprocal translocation (46,XX,t(1;18)(p31;q11)) with preaxial polysyndactyly, craniosynostosis and partial agenesis of the corpus callosum.
Christensen et al., (2000) reported male and female sib fetuses with anencephaly, median cleft lip and palate, omphalocele, and pre-axial polydactyly. Both fetuses lacked eyes and a nose. Overlap between the hydrolethalus and acrocallosal syndromes was discussed.
Koenig et al., (2002) reported two possible cases with relatively mild developmental delay. They also reported a more severe case with absence of the cerebellar vermis. Another case without hypotonia or developmental delay (born to cousin parents) was reported by Roida et al., (2009)
The cases reported by Guion-Almeida (1992) are now thought to have a separate condition (see cerebro-fronto-facial syndrome type III). There is also an overlap with Greig syndrome (see elsewhere) and the patient reported by Elson et al., (2002) with severe retardation (unusual in Greig) and considered to have the acrocallosal phenotype had the Greig GLI3 mutation. Mutations in KIF7 which impairs GLI3 processing can also be causative (Putoux et al., 2011). Pitoux et al., (2012) investigated 4 patients and 1 fetus for KIF7 mutations suspected on facial features and brain anomalies (corpus callosum was normal in 1, and another was without polydactyly). Only 1 had hallux duplication. All had mutations. Four were compound heterozygotes
* This information is courtesy of the L M D.
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