Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

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Ectrodactyly-ectodermal dysplasia-clefting syndrome

Definition

Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is one of more than 100 ectodermal dysplasia syndromes. EEC syndrome is characterized by deformities of the hands and feet (ectrodactyly), abnormalities of the skin, hair, and nails (ectodermal dysplasia ), and cleft lip and/or cleft palate (clefting). Other symptoms include dental, eye, skin, and kidney abnormalities.

Description

Ectodermal dysplasias (ED) are a group of inherited disorders that result from problems in early development of the ectodermal layer in the embryo. Problems with the ectoderm cause the hair, teeth, nail, and glands to develop and function abnormally. EEC syndrome is characterized by deformities of the hands and feet (ectrodactyly) that are sometimes referred to as lobster-claw deformities, abnormalities of the skin, hair, and nails (ectodermal dysplasia), and cleft lip and/or cleft palate (clefting). Other abnormalities include absence of the teeth and other dental abnormalities, decreased ability to sweat, absence of tear ducts, photophobia (increased sensitivity to light), and kidney abnormalities. Most individuals with EEC syndrome have some of these abnormalities, but very few individuals have all of these abnormalities.

EEC syndrome is genetic disorder with autosomal dominant inheritance with incomplete penetrance and variable expression. It can be inherited from a parent, but many individuals are the first in their family to be affected. DNA testing is now available and may be used to clarify the diagnosis in an individual with characteristic symptoms of the syndrome.

The cosmetic concerns of EEC can have a tremendous impact on the quality of life of an individual with EEC syndrome. The facial and limb differences can be socially isolating and physically challenging. Children and adults with EEC may be socially ostracized due to their physical appearance. Many individuals erroneously assume that people with EEC syndrome have limited abilities. It is important to increase awareness with educational programs and to take proactive steps to foster self-esteem in children with EEC syndrome.

Genetic profile

EEC syndrome has autosomal dominant inheritance with incomplete penetrance and variable expression. It is caused by mutations in the p63 gene , which is located on the long arm of chromosome 3 (3q27). The p63 gene appears to be necessary for the normal development of the skin and limbs, although its exact function is not known as of 2005.

Mutations in the p63 gene are inherited in an autosomal dominant manner. Every individual has two p63 genes: one from their father and one from their mother. In an autosomal dominant disorder, only one gene has to have a mutation for the person to have the EEC disorder. Some individuals with EEC syndrome are born to unaffected parents. Their EEC syndrome is the result of a de novo, or new mutation. No one knows the cause of de novo mutations or why they occur so frequently in EEC syndrome. Because individuals pass half of their genes onto their children, a person with EEC syndrome has a 50% chance that their child will also inherit EEC syndrome. If two unaffected people have a child with EEC syndrome, they have about a 4% risk to have another child with EEC syndrome. This increased recurrence risk is due to the possibility of germline mosaicism. Germline mosaicism is the presence of two cell lines in the reproductive cells (eggs or sperm cells) of an individual. Thus, a parent of a child with EEC syndrome may have one normal cell line and one cell that contains the mutation for EEC syndrome.

While EEC syndrome has autosomal dominant inheritance, it also shows incomplete penetrance. Incomplete penetrance is the term that is used to describe individuals with a mutation in a gene that do not have any symptoms of a particular disease. Although this is very rare, there are some large families in which this phenomenon has been documented. Because the physical findings of EEC syndrome can be so variable, it is important to carefully examine other family members to make sure that they do not have an extremely mild case of EEC syndrome.

The findings or symptoms of EEC vary from family to family and even from person to person within the same family. For example, one sibling may have cleft lip and hand abnormalities, while another sibling may have kidney and eye abnormalities. This phenomenon is referred to as variable expression. Most ectodermal dysplasias show some degree of variable expression. This can often make it very difficult for a physician to make an exact diagnosis.

Demographics

The overall incidence of ectodermal dysplasias in the United States is seven out of 10,000 people. Because the findings of EEC syndrome overlap those seen in other ectodermal dysplasia, the exact prevalence of EEC syndrome is not known. With the advent of DNA testing, it may soon be possible to get an accurate prevalence figure for EEC syndrome, but, as of 2005, this is not yet possible.

Signs and symptoms

In order to understand the signs and symptoms of EEC syndrome it is important to understand a little about early embryonic development. Very early in pregnancy, the cells that will develop into the embryo are organized as a small round ball. These cells eventually separate into three distinct layers: the endoderm, the mesoderm, and the ectoderm. The endoderm can be thought of as the inside layer. Cells from the endoderm will eventually form into the lining of the digestive tract and the respiratory tract. The mesoderm can be thought of as the middle layer, and the cells of the mesoderm will eventually become the muscles, bones, cartilage, heart, and blood vessels. The ectoderm (involved in EEC syndrome) can be thought of as the outside layer. The cells of the ectoderm will eventually become the skin, hair, nails, brain, and nervous system. Any disruption of the development of the ectoderm will lead to disruption of the organs formed from this layer.

EEC syndrome is the result of a disruption of the ectoderm layer very early in development. This disruption causes the specific defects seen in EEC syndrome, including defects of the skin, hair, nails, and other organs. As of 2005, the exact nature of this disruption or problem in formation of the ectooderm is not known. Research in this area is ongoing.

EEC syndrome is a disorder that causes multiple congenital abnormalities. Although these anomalies appear to be diverse, they all arise from the same underlying defect, or insult, to the early embryonic ectodermal tissue. Ectodermal tissue is responsible for the formation of the limbs, nails, eyes, skin, hair, teeth, kidneys, glands, and face. All of these organs and systems are affected to some degree in EEC syndrome. Most individuals will have some of the EEC abnormalities, but it is very rare for one individual to have all of these abnormalities.

Abnormalities of the hands and feet of individuals affected with EEC may include:

ectrodactyly (lobster-claw deformity) of the hands and feet
syndactyly (webbed fingers or toes)

Abnormalities of the eyes of affected individuals may include:

nasolacrimal duct obstruction (tear duct obstruction)
excessive lacrimation (tears)
blephariphimosis/blepharospasm
corneal ulcers and scarring
telecanthus
photophobia

Skin abnormalities of individuals affected with EEC may include:

dry skin
lack of sweat pores
thin skin/generalized skin atrophy
hyperkeratosis (thickened skin)

Individuals affected with EEC may have hair abnormalities, including:

dry, brittle hair
generalized depigmentation of hair
fine hair
sparse hair, or alopecia areata

Teeth abnormalities in affected individuals may include:

abnormalities in the tooth buds, resulting in missing or abnormally shaped teeth
defective enamel
small teeth

Abnormalities of the kidneys of affected individuals may include:

dilated ureters or uretral atresia
double ureters
hydronephrosis
multiple renal cysts
renal agenesis
renal dysplasia

Gland abnormalities of individuals affected with EEC may include:

absent or hypoplastic thymus
hypopituitarism
isolated growth hormone deficiency
pituitary diabetes insipidus

Facial abnormalities of affected individuals may include:

cleft lip
cleft palate
malformed ears

Additionally, individuals affected with EEC can experience nail dystrophy.

There are two other ectodermal dysplasia syndromes that closely resemble EEC syndrome: Rapp-Hodgkin syndrome (RHS) and ankyloblepharon-ectodermal defects-cleft lip and palate (AEC) syndrome (also known as Hay Wells syndrome). These syndromes share some of the specific findings of EEC syndrome, but differ in important ways.

The Rapp-Hodgkin syndrome (RHS) is another type of ED associated with cleft lip and palate . However, RHS does not share the hand and foot defects of EEC syndrome. People with RHS do have some sweating problems, and their hair grows slowly and is coarse. Some affected individuals have persistent scalp dermatitis. As a rule, individuals with RHS have more teeth than those with EEC. General health, intelligence, and lifespan are within normal expectations.

The Hay-Wells syndrome (HWS), also known as the anklyloblepharon-ectodermal dysplasia-cleft lip and palate syndrome, is one of several syndromes that affect both the ectoderm and structures that do not derive from the ectoderm. The scalp hair is sparse and wiry, while the eyelashes are sparse or absent. The nails may be absent or malformed, and the teeth and sweat glands may also be affected. The feature that differentiates HWS from the other ectodermal dysplasias is the fusion of the upper and lower eyelids usually by narrow bands of tissue connecting the lids (anklyloblepharon). Patients may also have inflammatory dermatitis of the scalp.

Diagnosis

The diagnosis of EEC syndrome can be complex because of the overlap of symptoms with other ectodermal dysplasia syndromes. The diagnosis of EEC syndrome is usually made through a combination of clinical exam, x rays, kidney imaging tests, skin biopsy, and DNA testing.

To make the diagnosis of EEC, a physician must evaluate which ectodermally derived structures are involved and look for physical features that do not develop from the ectoderm. By looking at the specific pattern of defects, it may be possible to make a correct diagnosis, but because of the overlap between other ectodermal dysplasias, it can often be difficult to make a definitive diagnosis based only clinical exam alone. DNA testing and other tests can help aid in the diagnosis.

X rays are often helpful in establishing the diagnosis of EEC syndrome. X rays may be taken of the jaw to look for dental abnormalities, while x rays of the limbs may be done to look for subtle abnormalities that may not be seen with a clinical exam. The presence of dental abnormalities or limb abnormalities would add to the suspicion that a person had EEC syndrome.

Because individuals with EEC syndrome can have kidney abnormalities, it is important to assess their kidney structure. This can be done using an IV pyelogram or ultrasound. The presence of a kidney abnormality would lend credence to the diagnosis of EEC syndrome, but the absence of a kidney abnormality does not rule out the diagnosis as not every person with EEC syndrome has every symptom.

A skin biopsy involves removing a small amount of several layers of skin to examine them under a microscope. In EEC syndrome, the skin cells themselves may be abnormal. In addition, the sweat glands may be abnormal in number or shape.

DNA testing can also be performed on blood samples from children or adults. The presence of a mutation in the p63 gene would confirm the diagnosis of EEC syndrome. Because scientist have not yet found all of the mutations in this gene, the absence of a detectable mutation does not completely rule out the diagnosis.

The diagnosis of EEC syndrome can also be made prenatally (during pregnancy) either by ultrasound (sonogram) or by prenatal DNA testing. Sonograms use sound waves to provide an image of a fetus. The structural abnormalities of EEC syndrome, including cleft lip, kidney abnormalities, and limb abnormalities, can be detected during the second trimester of pregnancy. Because of the overlap in the some of the structural abnormalities of the ectodermal dysplasias, it can be very difficult to definitively diagnose EEC syndrome by sonogram. Other ectodermal dysplsias can look very similar to EEC syndrome on a sonogram. DNA testing can have a role in clarifying ambiguous ultrasound findings.

Prenatal testing can also be done using DNA testing. A sample of tissue from a fetus is obtained by either chorionic villi sampling (CVS) or by amniocentesis . Chorionic villi sampling is generally done between 10 and 12 weeks of pregnancy, and amniocentesis is done between 14 and 18 weeks of pregnancy. Chorionic villi sampling involves removing a small amount of tissue from the developing placenta. The tissue in the placenta contains the same DNA as the fetus. Amniocentesis involves removing a small amount of fluid from around the fetus. This fluid contains some fetal skin cells. DNA can be isolated from these skin cells. The fetal DNA is then tested to determine if it contains mutations in the p63 gene that causes EEC syndrome. Because not all of the mutations causing EEC syndrome have been found, DNA testing is not always definitive and the interpretation of the test results is best done by a genetics professional.

Treatment and management

There is no cure for EEC syndrome, but there are many treatments available to address the symptoms. These treatments include surgery, dental care, prevention of complications from hypohydrosis (abnormal sweating), and other preventative treatments.

Individuals with EEC syndrome may need surgery to correct cleft lips, cleft palates, and abnormalities with their hands and feet. Correction of cleft lip is usually done in infancy, as is surgery for cleft palate. Correction of cleft palate is important for feeding and for speech.

Surgery may be done on hand and foot abnormalities to improve the function of these limbs, to improve the appearance of these limbs, and to aid in shoe fit.

Typically patients with EEC syndrome will need extensive dental work. X rays may be taken to document the presence or absence of teeth. Abnormal teeth may be pulled or capped. Replacement dentures may be worn during childhood. After growth has ended, many individuals will receive dental implants.

Hypohydrosis, or impaired sweating, is a major complication of EEC syndrome. Without normal sweating, the body cannot regulate temperature properly. Therefore, overheating is a common problem, and can lead to seizures, coma, and death in severe cases. It is important that affected individuals with an impaired ability to sweat follow the general precautions of using air conditioning when necessary, avoiding vigorous exercise, wear light clothing, and avoid hot temperatures.

Abnormal development of the eye can result in dryness of the eye, cataracts, and vision defects. Artificial tears can be used to protect the eyes from corneal scarring, which can lead to blindness if left untreated.

Prognosis

The prognosis for most individuals with EEC syndrome is very good. Life expectancy ranges from slightly reduced to normal. The most life-threatening complications come from sweating problems. Individuals with an impaired ability to sweat are at risk to overheat, which can lead to seizures, coma, and death. The life expectancy of individuals with EEC syndrome without sweating problems is expected to be normal.

The prognosis for most people with EEC syndrome is very good. In general, they have minimal and manageable serious medical problems, normal IQ, and most achieve success and have a long life, irregardless of their disabilities. Successful social adaptation plays an important role in the ultimate success and happiness of an individual with EEC syndrome. It is very important that the career and life choices of an individual with EEC syndrome not be limited by preconceived ideas about their abilities.