GCPS, a rare genetic disorder that is present at birth (congenital), is characterized by abnormalities of the fingers and toes (digits) and the head and facial (craniofacial) area. The range and severity of symptoms vary from individual to individual, with the facial characteristics, in particular, being quite subtle in some individuals.
Infants with this disorder exhibit various digital malformations, including extra (supernumerary) fingers and/or toes (polydactyly); webbing or fusion of the fingers and/or toes (cutaneous or osseous syndactyly); abnormally wide thumbs and/or great toes (halluces); and/or split (bifid) end bones of the thumbs and/or halluces (terminal phalanges). Affected infants with supernumerary digits will usually display the additional digit(s) toward the “pinky finger” side of the hand (postaxial polydactyly) and the “big toe” side of the foot (preaxial polydactyly). The extra digit can be a complete digit or a non-functional incomplete digit. The degree of digital fusion may also vary from the skin only joining part of the distance to the fingertip to the skin being joined all the way to the tip of the finger. In some cases, only the soft tissue is fused, but in others, the bone or boney cartilage may be fused.
Affected infants can also have craniofacial malformations including an abnormally large head (macrocephaly); a high, prominent or protruding forehead (frontal bossing); high anterior hairline; a broad nasal bridge; and/or widely spaced eyes (ocular hypertelorism). In some cases, the fibrous joints (sutures) between certain bones in the skull may be abnormally wide and may close unusually late in development; on the other hand, in rare individuals, certain cranial sutures may close prematurely (craniosynostosis). Such irregular closure of the sutures may cause the head to appear unusually shaped (scaphocephaly, trigonencephaly, or plagiocephaly).
In many individuals with GCPS, additional abnormalities may be present. These may include permanently flexed fingers (camptodactyly), dislocation of the hip, protrusion of a portion of the large intestine through an abnormal opening in the muscular wall that lines the lower abdominal cavity (inguinal hernia), and/or other physical abnormalities. Rarely (less than 10% of affected individuals), it can include developmental delays, intellectual disability, seizure, build-up of fluid inside the skull (hydrocephalus), and abnormalities affecting the nerve fibers (corpus callosum) that connect the two cerebral hemispheres of the brain may be present. In most individuals with the severe form of the disorder, it is caused by a deletion of the entire GLI3 gene. The larger the deletion encompassing GLI3 gene is (greater than 300 kb), the more likely the individual will show these uncommon symptoms.
GCPS is inherited as an autosomal dominant trait. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy regardless of the gender of the child.
In some individuals, the disorder is due to spontaneous (de novo) genetic changes (mutations) that occur in the germ cell. In such situations, the disorder is not inherited from the parents.
The gene that is altered in patients with GCPS is the GLI3 gene, located on the short arm (p) of chromosome 7 (7p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 7p13″ refers to band 13 on the short arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Mutations disrupting the normal function (expression) of the GLI3 gene are the cause of the disorder. Most of the mutations or alterations in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, patients have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3 and neighboring genes are called the “Greig cephalopolysyndactyly contiguous gene syndrome.” A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific mutation type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.
GCPS affects males and females in equal numbers. There have been over 200 patients with this disorder reported in the medical literature. However, because some affected individuals may exhibit few and/or mild symptoms, they may never be diagnosed with the disorder. Therefore, it is difficult to determine the true frequency of GCPS in the general population.
GCPS is usually diagnosed at birth based upon a thorough clinical evaluation; identification of characteristic physical findings; and specialized imaging procedures, including X-rays and computed tomography (CT) scanning. In pregnancies at 50% risk, GCPS may be detected before birth (prenatally) by observing the presence of extra digits (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus. There are other prenatal testing methods available, such as analyzing the fetal cells.
X-rays and CT scanning may be used to detect and reveal the extent of bone fusion in severe occurrences of osseous syndactyly. In some individuals with GCPS, X-ray studies may also reveal advanced bone age.
Macrocephaly is defined as a head circumference greater than the 97th centile compared to appropriate age and sex standards. In addition, if the distance between the pupils is greater than the 97th centile compared to appropriate age and sex standards, then the individual has widely spaced eyes that can be considered as GCPS feature.
Two conditions must be considered prior to diagnostic testing: the presence of developmental delay or intellectual disability and history of recurrent pregnancy losses in the parent of the individual. Once the clinical features consistent with GCPS are confirmed (through X-rays and CT scans), individuals without significant developmental delay or intellectual disability should have genetic testing through sequence analysis (a method that detects benign deletion). If the individual does have developmental delay or intellectual disability, he or she should have either comparative genomic hybridization or SNP-array to detect possible copy number changes in GLI3.
The treatment of GCPS is directed toward the specific symptoms apparent in each individual. Treatment may require the efforts of a team of specialists who may need to systematically and comprehensively plan an affected child’s treatment. Such specialists may include pediatricians, specialists who diagnose and treat skeletal disorders (orthopedists), orthopedic and plastic surgeons, physical and occupational therapists, and/or other health care professionals.
Craniofacial reconstructive surgery for GCPS is not common since the widely spaced eyes and macrocephaly are not sufficiently severe enough to warrant surgery. Surgery for extra digit at the thumb/big toe is normally prioritized over the extra digit near the pinky because of the importance of grasping and balancing.
Specific therapies for the treatment of this disorder are symptomatic and supportive. In some patients, surgery may be performed to correct digital and/or craniofacial abnormalities. Genetic counseling will be of benefit for affected individuals and their families.
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