Greig cephalopolysyndactyly

Definition

Greig cephalopolysyndactyly is a very rare autosomal dominant disorder. The syndrome is characterized by physical abnormalities of the head, face, fingers and toes. Distinct features include extra fingers and/or toes; a large and unusual shape of the skull; a high, prominent forehead; and widely spaced eyes. The range and severity of symptoms may vary greatly between individuals. Some individuals with Greig cephalopolysyndactyly require medical or surgical intervention to manage these problems. The syndrome is familial and in most cases is transmitted as an autosomal dominant trait.

Description

The disorder is named for D. M. Greig (pronounced Gregg), a Scottish physician, who first described the features of this syndrome in 1926. He saw a mother and her daughter who had a peculiar shape of the skull (cephalus) and polysyndactyly of the hands and feet. Polysyndactyly means both extra digits (toes, fingers) as well as webbing (syndactyly) between the digits. Dr. Greig described them as having a high forehead and widely spaced eyes. Thus, the syndrome was termed Greig cephalopolysyndactyly.

Genetic profile

Greig cephalopolysyndactyly (GCPS) can be found in several generations of a family. It is an autosomal dominant disorder and can be inherited, and passed on, by men as well as women. Almost all genes come in pairs. Cells work best when both copies of the gene pairs are intact and do not have mutations. One copy of each pair of genes is inherited from the father, and the other copy of each pair of genes is inherited from the mother. Therefore, if a parent carries a gene mutation for GCPS, each of his/her children has a 50% (one in two) chance of inheriting the gene mutation. Each child also has a 50% chance of inheriting the working copy of the gene, in which case they would not have GCPS.

The search to find the causative gene took a number of years. The first clue came in 1989, when an 11-month old infant was found to have a deletion of genetic material on chromosome 7. The infant had a large head and polysyndactyly of the hands and feet. Other reports soon followed, with small deletions and translocations of chromosome 7. Then, in 1991, investigators began to study a gene called GLI-3 as the candidate gene. This gene was found in the region of chromosome 7p13, which was missing in these individuals. The GLI-3 gene was also suspect because of previous studies done in mice.

The mouse gene GLI-3 normally functions in the design of the skeleton and limbs in the embryo. The GLI-3 gene also works in the developing brain. Mice lacking both copies of the gene die before birth. Many have severe birth defects of the brain, skeleton and central nervous system. However, mice with just one non-working copy of the GLI-3 gene do not die. They have minor birth defects, most notably extra digits, often of the hind feet. The mice also have a duplicated bone in their front feet, and an enlarged bone in the front portion of the skull. This combination of birth defects is unusual, but common to both Xt mice and individuals with Greig cephalopolysyndactyly.

With this in mind, the GLI3 gene was scanned for alterations (mutations) in individuals with GCPS. Of interest, both small and large mutations were found throughout the coding gene regions of the gene. As none of these mutations was found in unaffected individuals, this proved that the GLI3 gene was the cause of the condition.

In addition to GSPC, Pallister-Hall syndrome and post-axial polydactyly type A (PAP-A), two other disorders of human development, are caused by alterations in the GLI3 gene. The common feature of each disorder is polydactyly of the hands and feet. However, individuals with Pallister-Hall syndrome have additional growth problems and severe mental retardation. Extra fingers and toes are the primary feature of PAP-A, and thus, the most mild in expression of the three conditions.

Scientists have used animal models and the fruit fly Drosophila to study the function of the GLI3 gene. The normal function of the GLI3 protein is to bind to the DNA helix at specific places. By doing so, it helps to regulate which genes are activated or "turned on." Many of the mutations identified so far seem to interfere with the protein binding function. In effect, other genes that would normally be activated during development of the embryo may in fact not be turned on.

It is known that the limbs (arms, legs, fingers, toes) develop between the fourth and eighth week of pregnancy. The limb defects seen in GCPS must occur during this crucial period of development.

Demographics

Greig cephalopolysyndactyly affects both males and females equally. It most likely occurs in every race and ethnic group. In all, less than 100 individuals have been described worldwide. Therefore, it is a very rare condition.

Signs and symptoms

Most individuals with Greig cephalopolysyndactyly have a large head circumference (the distance as measured around the cranium). The forehead is high and wide, and slightly rounded in front (frontal bossing). This is due to the cranial sutures closing later than normal, causing the bones of the forehead to remain apart. The widening of the forehead appears to dip down into the space between the eyes, setting the eyes farther apart than normal. The bridge of the nose is broad and flat. This adds to the impression of distance between the eyes. Many times, the rest of the face will also look broad, almost box-like. The chin is small in comparison. The mouth is wide, and the corners of the mouth may be turned downward. The ears are usually normal. Individuals with GCPS can have a short neck, making it look as if the head rests on the shoulders. Intelligence is usually normal, although a few individuals have had mild learning disabilities.

The hands are quite distinctive in appearance. Most individuals with GCPS have extra fingers on each hand. The extra finger is rarely on the thumb side (pre-axial polydactyly). It is most often on the pinky finger side (post-axial polydactyly). Some individuals have an extra finger on each side of the hand, and thus, the possibility of 14 fingers. However, the extra finger may or may not include bone, and could just be a skin tag. The thumbs are frequently quite wide in appearance. Sometimes the bones of the thumb are duplicated or split at the tip. There may also be duplication or fusion in some of the bones that make up the hand, which can be seen on x ray. Their hands are still quite functional, although surgery may be necessary.

Many of these patients will have extra toes. What is unusual is that the extra toe is most often on the great toe side, opposite to what is found in the hands. The toes may also be short. Syndactyly (extensive webbing of the skin) is a constant finding in these patients. The webbing is usually between the toes, but may involve the hands. The webbing can vary from being mild, to complete joining of the digits, with skin up to the nail. Sometimes, just a few of the digits are fused together; in others, all of the toes are webbed. The webbing may also be present alone, without extra toes, although this is uncommon. The syndactyly may also occur on just one foot, and can be quite variable. Foot mobility and walking is usually not a problem.

There are other occasional problems seen in GCPS. These include craniosynostosis (premature fusion of the skull bones), mild mental retardation, hernia of the abdominal (stomach) muscles, and lesser birth defects of the urinary tract system, such as hypospadias.

Diagnosis

Each individual with Greig cephalopolysyndactyly is affected somewhat differently. The features are usually quite variable, even within the same family. The facial features can be mild, with most individuals only having a high and broad forehead.

Therefore, the polysyndactyly of the hands and feet remains the most distinctive feature of the syndrome. With the use of x rays, changes in the bones of the hands and feet can be seen. The diagnosis of GCPS is suspected when the physician identifies the extra digits on the outside of the hands and on the inside of the foot, along with the broad forehead. This is usually seen at birth.

The availability of direct gene testing allows for a definitive diagnosis for these patients. Using a blood sample, a direct gene test looking for alterations (mutations) in the GLI3 gene can be done. An identifiable gene mutation would confirm the diagnosis in sporadic (noninherited) patients as well.

Treatment and management

Very often, the physical characteristics of the face do not require surgical treatment. Sometimes, the facial appearance even improves as the child grows. However, if the cranial sutures in the forehead close either very early or very late, there may be fairly severe disfigurement to the face. This would require surgery from a specialized craniofacial medical team. Craniofacial surgery rearranges or reconstructs the bones of the face to correct the abnormal fusion of the cranial bones.

Some degree of surgery will also be needed for the polydactyly of the hands and feet. The extra digits that are just skin tags (no bone within) are tied off at the base, and allowed to self-amputate. This is usually done at birth. For those digits that include bone, most surgeons would save the digit that would have the best use. The other digit (or digits) would then be surgically removed, usually around one year of age. Surgery is often done to release the webbing of the fingers and toes, and can be quite extensive.

Prognosis

Most individuals with Greig cephalopolysyndactyly appear to have a normal life span.

Resources

ORGANIZATIONS

AboutFace International. 123 Edwards St., Suite 1003, Toronto, ONT M5G 1E2. Canada

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 332-2373. [email protected]. <http://www.faces-cranio.org/>.

WEBSITES

About Face. <http://www.aboutface2000.org>.

Alliance of Genetic Support Groups. <http://www.geneticalliance.org.htm>.

Let's Face It. <http://www.faceit.org>.

Kevin M. Sweet, MS, CGC