Acrocallosal syndrome (also known as ACLS) is an extremely rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

syndrome characterized by corpus callosum agenesis,

polydactyly Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes). Signs and symptoms In humans ...

, multiple

dysmorphic feature A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, Genetics, genetic syndrome or birth defect. Dysmorphology is the stud ...

s, motor and intellectual disabilities, and other symptoms. The syndrome was first described by Albert Schinzel in 1979. Mutations in ''

KIF7 Kinesin family member 7 (KIF7), also known as kinesin-4, is a human protein encoded by the gene KIF7. It is part of the kinesin family of motor proteins. Function KIF7 depolymerises the growing plus-end of microtubules, and is involved in regula ...

'' are causative for ACLS, and mutations in ''

GLI3 Zinc finger protein GLI3 is a protein that in humans is encoded by the ''GLI3'' gene. This gene encodes a protein that belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription f ...

'' are associated with a similar syndrome.

Signs and symptoms

Acrocallosal syndrome (ACLS, ACS, Schinzel-type, Hallux-duplication) is a rare, heterogeneous autosomal recessive disorder first discovered by Albert Schinzel (1979) in a 3-year-old boy. Characteristics of this syndrome include

agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres ...

macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...

, poor motor skills,

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...

, extra fingers and toes (particularly

hallux Toes are the digits (fingers) of the foot of a tetrapod. Animal species such as cats that walk on their toes are described as being '' digitigrade''. Humans, and other animals that walk on the soles of their feet, are described as being '' pl ...

duplication), and

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...

Seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s may also occur.

Mechanism

Mutations in the ''

'' gene are causative for ACLS. KIF7 is a 1343 amino acid protein with a kinesin motor, coiled coil, and Gli-binding domains. It is associated with ciliary motor function and is a key factor in the ciliary

Hedgehog signaling pathway The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...

that is crucial during embryogenesis. Mutations in Hedgehog signaling components such as ''KIF7'' and ''GLI3'' may lead to ciliopathies and defects in the brain and other areas associated with ACLS and related disorders. Mutations in the ''

'' gene may cause ACLS or similar syndromes such as

Greig cephalopolysyndactyly syndrome Greig cephalopolysyndactyly syndrome is a disorder that affects development of the limbs, head, and face. The features of this syndrome are highly variable, ranging from very mild to severe. People with this condition typically have one or more ...

Pallister–Hall syndrome Pallister–Hall syndrome (abbreviated PHS) is a disorder that affects the development of many parts of the body. It is named for Judith Hall and Philip Pallister. Presentation Most people with this condition have extra fingers and/or toes (po ...

, or certain types of

. KIF7 interacts with Gli transcription factors, so mutations in the KIF7 gene may be upstream effectors of GLI3, resulting in similar symptoms.

Diagnosis

ACLS is typically diagnosed on the basis of physical examination. At least three of four core criteria published by Courtens et al. (1997) must be present: # Total or partial

# Minor craniofacial anomalies such as

# Moderate to severe

psychomotor retardation Psychomotor may refer to: * Psychomotor learning, the relationship between cognitive functions and physical movement * Psychomotor retardation, a slowing-down of thought and a reduction of physical movements in an individual * Psychomotor agitatio ...

with

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

Polydactyly Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes). Signs and symptoms In humans ...

The differential diagnosis includes

orofaciodigital syndrome Orofaciodigital syndrome or oral-facial-digital syndrome is a group of at least 13 related conditions that affect the development of the mouth, facial features, and digits in between 1 in 50,000 to 250,000 newborns with the majority of cases bein ...

types I and II,

Meckel–Gruber syndrome Meckel-Gruber syndrome is a rare, lethal ciliopathic genetic disorder, characterized by renal cystic dysplasia, central nervous system malformations (occipital encephalocele), polydactyly (postaxial), hepatic developmental defects, and pulmonary ...

Smith–Lemli–Opitz syndrome Smith–Lemli–Opitz syndrome is an inborn error of cholesterol synthesis. It is an autosomal recessive, multiple malformation syndrome caused by a mutation in the enzyme 7-Dehydrocholesterol reductase encoded by the DHCR7 gene. It causes a bro ...

Rubinstein–Taybi syndrome Rubinstein–Taybi syndrome (RTS) is a rare genetic condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. Other features of the disorder vary among affect ...

Cockayne syndrome Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosen ...

Aicardi syndrome Aicardi syndrome is a rare genetic malformation syndrome characterized by the partial or complete absence of a key structure in the brain called the corpus callosum, the presence of retinal lacunes, and epileptic seizures in the form of infanti ...

Neu–Laxova syndrome Neu–Laxova syndrome (NLS, also known as Neu syndrome; Neu-Povysilová syndrome; or 3-phosphoglycerate dehydrogenase deficiency, neonate form) is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and m ...

, Young–Madders syndrome, oto-palato-digital syndrome type 2, Toriello–Carey syndrome, and Da Silva syndromes. ACLS may be differentiated from Greig cephalopolysyndactyly syndrome by the presence of intracranial cysts. ACLS may be suspected antenatally if a previous child is affected, as any subsequent child has a 25% chance of having ACLS.

Obstetric ultrasonography Obstetric ultrasonography, or prenatal ultrasound, is the use of medical ultrasonography in pregnancy, in which sound waves are used to create real-time visual images of the developing embryo or fetus in the uterus (womb). The procedure is a stan ...

magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

can reveal polydactyly and/or cerebral malformations from the 20th week of gestation.

Chorionic villus sampling Chorionic villus sampling (CVS), sometimes called "chorionic ''villous'' sampling" (as "villous" is the adjectival form of the word "villus"), is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It ent ...

and molecular genetic testing can be performed to confirm whether mutations in disease-associated genes are present. ACLS is an extremely rare disorder, with 34 cases described in the literature as of 2005.

Management

Management of ACLS consists mainly of monitoring by a pediatric neuropsychiatrist and supportive therapies or accommodations such as

occupational therapy Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...

and

special education Special education (known as special-needs education, aided education, exceptional education, alternative provision, exceptional student education, special ed., SDC, or SPED) is the practice of educating students in a way that accommodates th ...

plans. Surgery may be considered in early childhood to remove extra digits in case of polydactyly or resolve orofacial defects such as cleft palate. If present,

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s and renal parenchymal hypertension may be treated with

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

s and

antihypertensive drug Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that r ...

s, respectively. Patients may be offered genetic and vocational counselling when appropriate.

Prognosis

Lifespan may range from stillbirth to normal expectancy depending on severity of hypotonia and onset of

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

. Severe hypotonia can lead to fatal

infant respiratory distress syndrome Infantile respiratory distress syndrome (IRDS), also called respiratory distress syndrome of newborn, or increasingly surfactant deficiency disorder (SDD), and previously called hyaline membrane disease (HMD), is a syndrome in premature infants c ...

or apnea within the first days or weeks of life. Conversely, in mild cases, subjects live relatively normal lives with some developmental delays and mild to moderate

References

External links

* {{Transcription factor/coregulator deficiencies Autosomal recessive disorders Rare genetic syndromes Ciliopathy Syndromes with dysmelia Syndromes with intellectual disability Corpus callosum Syndromes with cleft lip and/or palate Syndromes with craniofacial abnormalities