Acrocallosal syndrome, Schinzel type
Schinzel syndrome 1; Acrocallosal syndrome; ACS; Schinzel acrocallosal syndrome; Absence of corpus callosum with unusual facial appearance, mental deficiency, duplication of the halluces and polydactyly; ACLS
Acrocallosal syndrome is a rare condition characterized by a brain abnormality called agenesis of the corpus callosum, the presence of extra fingers and toes (polydactyly), and distinctive facial features.
This condition appears to be rare. Only a few dozen cases have been reported in the medical literature.
- Mutations in the KIF7 gene have been found to cause acrocallosal syndrome.
- Mutations in another gene, GLI3, can also cause features of this disorder.
- However, the signs and symptoms overlap significantly with those of a similar disorder called Greig cephalopolysyndactyly syndrome (which is also caused by GLI3 gene mutations), so acrocallosal syndrome resulting from GLI3 gene mutations is sometimes considered a severe form of that condition.
- The proteins produced from the KIF7 and GLI3 genes play critical roles in the normal shaping (patterning) of many tissues and organs before birth.
- The proteins are part of a chemical signaling pathway called Sonic Hedgehog signaling.
- This pathway is involved in cell growth, cell specialization, and the patterning of structures such as the brain and limbs.
Mutations in either the KIF7 or GLI3 gene are thought to impair Sonic Hedgehog signaling, which has wide-ranging effects on development before birth. The roles of these genes in brain and limb patterning may help explain why mutations lead to agenesis of the corpus callosum, polydactyly, and the other features of acrocallosal syndrome.
- When acrocallosal syndrome is caused by KIF7 gene mutations, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
- Acrocallosal syndrome (or severe Greig cephalopolysyndactyly syndrome) resulting from GLI3 gene mutations is considered autosomal dominant , which means one copy of the altered gene in each cell is sufficient to cause the disorder. This condition results from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.
The signs and symptoms of this disorder are present at birth, and their severity varies widely among affected individuals.
Signs and symptoms
Agenesis of the corpus callosum occurs when the tissue that connects the left and right halves of the brain (the corpus callosum) fails to form normally during the early stages of development before birth. Other brain abnormalities, including the growth of large cysts in brain tissue, have also been reported in people with acrocallosal syndrome. The changes in brain structure associated with this condition lead to delayed development and intellectual disability, which is most often moderate to severe. Some affected individuals also experience seizures. Extra fingers and toes are common in people with acrocallosal syndrome. The extra digits can be on the same side of the hand or foot as the pinky or little toe (postaxial polydactyly) or on the same side as the thumb or great toe (preaxial polydactyly). Some affected individuals also have webbed or fused skin between the fingers or toes (syndactyly). Distinctive facial features that can occur with acrocallosal syndrome include widely spaced eyes (hypertelorism) and a high, prominent forehead. Many affected individuals also have an unusually large head size (macrocephaly).
For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 100% of people have these symptoms
80%-99% of people have these symptoms
- Duplication of phalanx of hallux(Duplication of big toe bone)
- Duplication of thumb phalanx
- Hypertelorism(Wide-set eyes)
- Intellectual disability, severe(Early and severe mental retardation)
- Macrocephaly(Increased size of skull)
- Postaxial foot polydactyly(Extra toe attached near the little toe)
- Postaxial hand polydactyly(Extra little finger)
- Preaxial foot polydactyly
- Preaxial hand polydactyly(Extra thumb)
30%-79% of people have these symptoms
- Broad forehead(Increased width of the forehead)
- Dandy-Walker malformation
- Downslanted palpebral fissures(Downward slanting of the opening between the eyelids)
- Epicanthus(Eye folds)
- Failure to thrive(Faltering weight)
- Finger syndactyly
- Growth delay(Delayed growth)
- Inguinal hernia
- Preauricular skin tag
- Prominent occiput(Prominent back of the skull)
- Short nose(Decreased length of nose)
- Sloping forehead(Inclined forehead)
- Toe syndactyly(Fused toes)
- Triphalangeal thumb(Finger-like thumb)
- Umbilical hernia
- Wide anterior fontanel(Wider-than-typical soft spot of skull)
5%-29% of people have these symptoms
- Abnormal clavicle morphology(Abnormal collarbone)
- Aplasia/Hypoplasia of the cerebellum(Absent/small cerebellum)
- Coloboma(Notched pupil)
- Congenital diaphragmatic hernia
- Cryptorchidism(Undescended testes)
- Hearing impairment(Deafness)
- Micropenis(Short penis)
- Nystagmus(Involuntary, rapid, rhythmic eye movements)
- Optic atrophy
- Posteriorly rotated ears(Ears rotated toward back of head)
- Sensorineural hearing impairment
- Tall stature(Increased body height)
- Tapered finger(Tapered fingertips)
Diagnosis is based on physical examination and, given the high variability of phenotypes, a consensus on minimal diagnostic criteria has been established, with 3 of the 4 following criteria being necessary to suspect the ACS diagnosis: (1) total or partial absence of the CC, (2) minor craniofacial anomalies, (3) moderate to severe psychomotor retardation with hypotonia and (4) polydactyly.
Differential diagnosis Differential diagnosis includes Greig cephalopolysyndactyly, oral-facial-digital I and II, Meckel-Gruber, Smith-Lemli-Opitz, Rubinstein-Taybi, cerebrooculofacioskeletal, Aicardi, Neu-Laxova, pseudotrisomy 13, Toriello-Carey, otopalatodigital II and Da Silva syndromes .
Antenatal diagnosis Antenatal diagnosis is based on ultrasonography examination from the 20th week of gestation and magnetic resonance imaging (MRI) of the fetus.
Surgical intervention may be considered for the polydactyly.
Prognosis depends on the severity of malformations and hypotonia, and on the occurrence of seizures.
NIH genetic and rare disease info
Acrocallosal syndrome, Schinzel type is a rare disease.
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