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, acrocallosal syndrome often appears to occur randomly for unknown reasons (sporadically).
In individuals with acrocallosal syndrome, Schinzel type, the range and severity of associated findings may be extremely variable. However, in all reported cases to date, the disorder has been characterized by underdevelopment (hypoplasia) or absence (agenesis) of the thick band of nerve fibers joining the two hemispheres of the brain (corpus callosum) as well as moderate to severe mental retardation. In some cases, brain malformations may be associated with additional complications, such as sudden episodes of uncontrolled electrical activity in the brain (seizures) or hydrocephalus, a condition in which impaired flow or absorption of the fluid that circulates through cavities (ventricles) of the brain and the spinal canal (cerebrospinal fluid [CSF]) potentially leads to increasing fluid pressure in the brain. Individuals with acrocallosal syndrome may also have abnormally diminished muscle tone (hypotonia) and experience severe psychomotor retardation–or marked delays in the development of certain physical, mental, or behavioral skills that are typically acquired at particular stages (i.e, “developmental milestones”). Over 50 percent of affected individuals also have abnormal growth delays, often resulting in short stature.
Acrocallosal syndrome, Schinzel type is also often associated with distinctive malformations of the skull and facial (craniofacial) region. Such abnormalities often include an unusually large head (macrocephaly) with a high, broad, bulging forehead; a prominent back region of the head (occiput); and underdeveloped midfacial regions (midface hypoplasia). In addition, the “soft spot” at the front of the skull (anterior fontanelle) may be abnormally large in some affected infants or children. (The “soft spots” or fontanelles [anterior and posterior fontanelles] are the membrane-covered gaps between bones of the skull at birth.) Individuals with acrocallosal syndrome may also have a small, short nose; a broad nasal bridge; upwardly turned nostrils (anteverted nares); and malformed (dysplastic) ears that may be abnormally rotated toward the back of the head (posteriorly rotated). In some instances, additional craniofacial abnormalities may also be present, such as protruding lips, an abnormal groove in the upper lip (cleft lip), and/or incomplete closure of the roof of the mouth (cleft palate).
Individuals with acrocallosal syndrome may also have abnormalities affecting the eyes. These may include widely spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); vertical skin folds (epicanthal folds) that may cover the eyes’ inner corners; and drooping of the upper eyelids (ptosis). In some instances, additional eye (ocular) defects may be present, such as internal deviation of one eye toward the other (convergent strabismus or esotropia); abnormalities of the colored (pigmented) layers of the retinas or the nerve-rich, innermost membranes of the eyes (i.e., decreased retinal pigmentation); and/or degeneration of the nerves that transmit impulses from the retinas to the brain (optic atrophy). In such cases, the degree of visual impairment depends upon the severity and/or combination of eye abnormalities present.
Acrocallosal syndrome, Schinzel type is also typically characterized by distinctive malformations of the fingers and toes (digits). For example, in many affected individuals, there may be duplication or the presence of extra (supernumerary) great toes (halluces) and, in some cases, partial duplication of the thumbs (preaxial polydactyly) with abnormal division of the bones at the ends of the thumbs (bifid terminal phalanges). There may also be duplication of certain digits toward the “pinky” side of the hands and the “small toe” side of the feet (i.e., postaxial polydactyly). Additional digital abnormalities often include webbing or fusion (syndactyly) of certain fingers or toes, particularly of the first to the third toes, and underdevelopment or fusion of affected nails.
In some cases, additional physical abnormalities may also be associated with the disorder. Some affected infants may have structural heart malformations at birth (congenital heart defects). These typically include an abnormal opening in the fibrous partition (septum) that separates the upper or lower chambers of the heart (atrial or ventricular septal defects) or abnormalities of the heart valve (i.e., pulmonary valve) that enables blood to flow from the lower right chamber (ventricle) of the heart to the lungs while preventing the backflow of blood into the right ventricle. In addition, in some affected individuals, there may be protrusion of part of the intestines into muscles of the groin (inguinal hernia) or through a weakness in the abdominal wall around the navel (umbilical hernia). Others may have an epigastric hernia or protrusion of an internal organ through the membrane in the middle region of the abdomen above the navel. Some affected males may also have genital abnormalities, such as undescended testes (cryptorchidism), abnormal placement of the urinary opening (hypospadias), and/or an unusually small penis (micropenis).
In some infants with acrocallosal syndrome, the period shortly after birth (neonatal period) may be complicated by seizure episodes, feeding difficulties, and an increased risk of respiratory infections. In some cases, respiratory infections as well as breathing difficulties (dyspnea), lack of sufficient oxygen supply to bodily tissues (hypoxia), and other associated abnormalities (i.e., respiratory distress) may lead to potentially life-threatening complications.
As mentioned previously, reports in the medical literature suggest that the symptoms and findings associated with acrocallosal syndrome, Schinzel type may vary greatly in range and severity from case to case. For example, some investigators have reported “incomplete” forms of the disorder in which duplication of the great toes (preaxial polydactyly) or certain characteristic craniofacial features were not present. In other reported cases, the siblings of some individuals with the disorder have been affected by anencephaly, a congenital abnormality characterized by absence of the top of the skull (skullcap or calvaria) and major portions of the brain (e.g., cerebral hemispheres). Some researchers suggest that anencephaly may represent a severe manifestation of the spectrum of brain malformations potentially associated with acrocallosal syndrome.
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 for 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 for 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 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 genetic analysis of individuals with 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 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 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 acrocallosal syndrome, Schinzel type.
Acrocallosal syndrome, Schinzel type appears to affect males and females in relatively equal numbers. The disorder was originally reported in 1979 (A. Schinzel). Over 25 cases have been recorded in the medical literature.
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 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).
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 repeated 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 for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic disorders in the future.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 200900; Last Edit: 6/11/1999.