Greig Cephalopolysyndactyly Syndrome

 Greig Cephalopolysyndactyly Syndrome

OVERVIEW

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; metopic synostosis; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most individuals, GCPS is inherited in an autosomal dominant pattern.

SYMPTOMS

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 have 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, the more likely the individual will show these uncommon symptoms, because larger deletions can affect other genes in addition to GLI3.

CAUSES

GCPS is caused by abnormal variants in the GLI3 gene. Most of the variants in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, affected individuals have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3, and neighboring genes are diagnosed with the “Greig cephalopolysyndactyly contiguous gene syndrome.” A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific variant type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.

GCPS is inherited in an autosomal dominant pattern. 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. Disorders inherited in a dominant pattern 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.

AFFECTED POPULATIONS

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.

DISORDERS WITH SIMILAR SYMPTOMS

Symptoms of the following disorders can be similar to those of Greig cephalopolysyndactyly syndrome. Comparisons may be useful for a differential diagnosis.

Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by multiple craniofacial abnormalities, including an enlarged head (macrocephaly), a protruding forehead (frontal bossing), and/or widely spaced eyes (ocular hypertelorism). Additional symptoms can include absence (agenesis) of the nerve fibers that connects the two halves of the brain (corpus callosum), intellectual disability, and digital abnormalities including extra fingers and toes (polydactyly). In the past, many researchers suspected that ACLS and GCPS may have represented variable expressions of the same disorder. Some individuals with ACLS have abnormal variants of the GLI3 gene or abnormal variants of the KIF7 gene. ACLS is typically inherited in an autosomal recessive pattern. (For more information on this disorder, choose “crocallosal” as your search term in the Rare Disease Database.)

Oro-facial-digital syndrome is a group of rare genetic disorders in which there have been many types identified. Symptoms common to many types include split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad-based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), extra fingers and toes (polydactyly), shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oro-Facial-Digital” as your search term in the Rare Disease Database.)

Pfeiffer syndrome (acrocephalosyndactyly type V) is generally accepted to be the same condition as Noack syndrome (acrocephalopolysyndactyly type I). It is a rare genetic disorder characterized by craniofacial abnormalities, digital malformations, and/or additional physical abnormalities. Affected individuals may exhibit several bone abnormalities of the face and head (craniofacial dysostosis), including a short, pointed head (acrobrachycephaly) and widely spaced eyes (ocular hypertelorism). Several abnormalities of the jaws and teeth may also be present, including an underdeveloped upper jawbone (maxillary hypoplasia), highly arched palate, prominent lower jaw (prognathism), and improper alignment of the teeth (malocclusion) when the jaws close. Individuals with Pfeiffer syndrome may also have webbed fingers and/or toes (syndactyly); abnormally short, broad thumbs and big toes; and/or malformed, misshapen, and/or absent bones (i.e., proximal and terminal phalanges) within the thumbs and/or great toes. Additional physical abnormalities may be present in some patients. Pfeiffer syndrome is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Pfeiffer” as your search term in the Rare Disease Database.)

DIAGNOSIS

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 by observing extra fingers or toes (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. 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 the GLI3 gene. If the individual has a history of recurrent pregnancy losses, consideration should be given to chromosome (cytogenetic) testing. A balanced chromosome translocation that interrupts the GLI3 gene can cause pregnancy losses due to an unbalanced chromosome translocation in offspring

STANDARD THERAPIES

Treatment

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 is recommended for affected individuals and their families.

Type of Doctor Department : orthopedic