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Acrocallosal syndrome, Schinzel type is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings may be variable, including among affected members of the same family (kindred). However, the disorder is typically characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) and moderate to severe mental retardation. In addition, many affected individuals have malformations of the skull and facial (craniofacial) region and/or distinctive abnormalities of the fingers and toes (digits). Characteristic craniofacial abnormalities may include an unusually large head (macrocephaly) with a prominent forehead, widely spaced eyes (ocular hypertelorism), downslanting eyelid folds (palpebral fissures), a small nose with a broad nasal bridge; and malformed (dysplastic) ears. Most affected individuals also have distinctive digital malformations, such as the presence of extra (supernumerary) fingers and toes (polydactyly) and webbing or fusion (syndactyly) of certain digits. Additional physical abnormalities may also be present, including growth retardation, resulting in short stature. Although autosomal recessive inheritance has been suggested, the acrocallosal syndrome often appears to occur randomly for unknown reasons (sporadically).
Causes
According to many investigators, acrocallosal syndrome, Schinzel type may be inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers of a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
Parents of some individuals with acrocallosal syndrome, Schinzel type have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for the development of the disease.
Numerous cases have also been reported in which there was no apparent family history of the disease. In such instances, researchers indicate that the disorder may result from new genetic changes (mutations) that appear to occur randomly for unknown reasons (sporadically). Since many reported cases have appeared to occur sporadically, some researchers question whether the disorder is inherited as an autosomal recessive trait, instead indicating that there may be an autosomal dominant mode of inheritance.
In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
Some investigators have suggested that acrocallosal syndrome may be a variant of Greig cephalopolysyndactyly syndrome, resulting from different changes (mutations) of the same disease gene. Greig cephalopolysyndactyly syndrome, an autosomal dominant disorder, is known to result from mutations disrupting the normal functioning of a gene known as GLI3, which is located on the short arm (p) of chromosome 7 (7p13)*. However, during the genetic analysis of individuals with the acrocallosal syndrome in one family, evidence appeared to exclude the chromosomal location involved in Greig cephalopolysyndactyly syndrome.
*Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, 7p13 refers to band 13 on the short arm of chromosome 7.
According to other researchers, trisomy 12p was confirmed in an individual with the apparent acrocallosal syndrome. Trisomy 12p is a chromosomal disorder in which a portion of the short arm of chromosome 12 appears three times rather than twice in cells of the body. (For further information, please see the “Related Disorders” section below.) Due to the “overlapping” of certain symptoms associated with the acrocallosal syndrome and trisomy 12p, some researchers have suggested that acrocallosal syndrome may result from mutations of a gene located on chromosome 12p. Further research is needed to determine the disease gene (or genes) that may play a role in causing the acrocallosal syndrome, Schinzel type.
Mutations in the KIF7 gene have been found to cause the 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 the acrocallosal syndrome.
Diagnosis
In some instances, such as in families with members previously diagnosed with the disorder, acrocallosal syndrome, Schinzel type may be suspected before birth (prenatally) based upon certain specialized tests, such as ultrasound or fetoscopy. Fetal ultrasonography is a noninvasive diagnostic procedure in which reflected sound waves create an image of the developing fetus. During fetoscopy, a flexible, ultrasound-guided, viewing instrument is introduced into the uterus through the abdominal wall to directly observe the fetus.
The diagnosis is usually made or confirmed at birth based upon a thorough clinical examination, identification of characteristic physical findings, and various specialized tests. Such testing may include x-ray studies; advanced imaging techniques, such as computed tomography (CT) scanning or magnetic resonance imaging (MRI); or other studies to help detect or characterize certain malformations that may be associated with the disorder (e.g., agenesis or hypoplasia of the corpus callosum, certain craniofacial abnormalities, polydactyly, and syndactyly, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of certain organs and tissues.
A thorough cardiac evaluation may also be recommended to detect any heart abnormalities that may be associated with the disorder. Such evaluation may include a thorough clinical examination, during which heart and lung sounds are evaluated through the use of a stethoscope, and specialized tests that enable physicians to assess the structure and function of the heart (e.g., x-ray studies, electrocardiography, echocardiography, cardiac catheterization).
Treatment
The treatment of acrocallosal syndrome, Schinzel type is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat neurological disorders (neurologists); physicians who specialize in heart disease (cardiologists); physicians who diagnose and treat disorders of the skeleton, joints, muscles, and related tissues (orthopedists); eye specialists; and/or other health care professionals.
Specific therapies for individuals with acrocallosal syndrome, Schinzel type are symptomatic and supportive. For those with hydrocephalus, early surgery may be advised to insert a tube (shunt) to drain excess cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed.
In some instances, surgery may also be recommended to help correct certain craniofacial malformations, polydactyly and syndactyly, and/or other physical abnormalities potentially associated with the disorder. In addition, for those with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.
Physicians may regularly monitor affected infants and children to help ensure prompt detection and early aggressive treatment of respiratory infections. In addition, in some instances, certain preventive measures may be recommended for those who may be prone to repeat respiratory infections. For affected infants who develop respiratory distress, treatment may include various supportive measures, including appropriate oxygen therapy.
Disease management may also include supportive therapies to help ensure proper caloric intake and nutrition in those with feeding difficulties. In some cases, treatment with certain anticonvulsant medications may also be recommended to help prevent, reduce, or control seizures.
Early intervention may be important to ensure that children with the disorder reach their potential. Special services that may be beneficial include special education, physical therapy, and/or other medical, social, or vocational services.
Genetic counseling will be of benefit to affected individuals and their families. Another treatment for this disorder is symptomatic and supportive.
References
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