Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

Ectodermal dysplasia

KEY TERMS

Amastia—A birth defect involving absent breast(s).

Dysplasia—The abnormal growth or development of a tissue or organ.

Ectoderm—The outermost of the three embryonic cell layers, which later gives rise to the skin, hair, teeth, and nails.

Ectrodactyly—A birth defect involving a split or cleft appearance of the hands and/or feet, also referred to as a “lobster-claw malformation.”

Hyperthermia—Body temperature that is much higher than normal (i.e. higher than 98.6°F).

ent genetic alterations producing identical physical features). As with many other human genetic conditions, mouse models are being used to identify candidate genes that may be responsible for these disorders.

Demographics

The exact incidence of ectodermal dysplasia conditions has not yet been studied accurately and is not known. One published report estimated the incidence of these conditions collectively as 7 per 10,000 births. The disorders have been reported in individuals and families of diverse ethnic backgrounds. One early description of an ectodermal dysplasia came from Charles Darwin, who cited a report of an affected individual from the Indian subcontinent in an 1897 publication.

Signs and symptoms

Most ectodermal dysplasia conditions cause significant dental abnormalities. In some cases, the majority of the primary (“baby”) and secondary (“adult”) teeth are missing. Teeth that are present may show a characteristic conical, pointed shape (“peg-teeth”), or have abnormal enamel that is prone to cavities.

Hair is often thin with an abnormal texture. In hypohydrotic ectodermal dysplasia, the scalp hair is thin during childhood and ultimately shows premature balding. Although body hair, eyebrows, and eyelashes are also sparse in this condition, beard and mustache hair are normal. Hair is also sparse in EEC syndrome. In tricho- dento-osseous syndrome and Hay-Wells syndrome, the hair is sparse, coarse, and wiry. Individuals with incontinentia pigmenti may have patchy, bald areas of abnormal skin on the scalp. Frequent scalp infections occur in many of the ectodermal dysplasias.

A variety of skin abnormalities may occur in ectodermal dysplasia conditions. The skin may be dry, thin, and prone to eczema, infection, cracking, bleeding, and other problems. In hypohydrotic ectodermal dysplasia, sebaceous glands (the oil glands within the skin) are absent, causing severe dryness. Increased pigmentation may occur around the eyes (in hypohydrotic dysplasia), over the joints (in hidrotic ectodermal dysplasia), or in a linear pattern over the trunk (in incontinentia pigmenti). Hyperkeratosis, or thickened skin, occurs on the palms and soles of the feet in hidrotic ectodermal dysplasia. Reddening and blistering of the skin may occur during infancy in incontintentia pigmenti. In Hay-Wells syndrome, abnormal bands of skin may occur between the upper and lower jaws and between the eyelids.

Decreased numbers of sweat glands and associated impaired sweating ability is an important feature of hypodrotic ectodermal dysplasia. This can lead to life-threat- ening hyperthermia in hot environments or with physical exertion. Sweating is normal in most other ectodermal dysplasias.

Many ectodermal dysplasias involve abnormalities of the mucous membranes. Production of tears and saliva may be deficient. In hypohydrotic ectodermal dysplasia, the mucous glands in the respiratory tract may be absent or decreased in number, leading to dryness, infections, and an unusual foul-smelling secretion known as ozena. In some cases, dryness of the pharynx and larynx may affect the quality of the voice.

Finger and toenails are abnormal in many of the ectodermal dysplasias. In EEC syndrome, the nails may be thin and brittle. Nails may be absent or abnormally formed in Hay-Wells syndrome, Rapp-Hodgkin syndrome, hidrotic ectodermal dysplasia, tooth and nail syndrome, and incontintentia pigmenti. Nails are normal in hypohydrotic ectodermal dysplasia.

Some individuals with ectodermal dysplasia, particularly those with EEC syndrome, may have hearing impairment.

Structural birth defects may occur in some ectodermal dysplasias. In EEC, Hay-Wells, and Rapp-Hodgkin syndromes, cleft lip and palate may occur. EEC is also characterized by split hand/split foot (or “lobster claw”) malformations and genitourinary anomalies. Amastia (absence of the breast) may occur in hypohydrotic ectodermal dysplasia and breasts may be underdeveloped in incontintia pigmenti and EEC syndrome. Some individuals with incontinentia pigmenti may have defects of the eye (such as congenitally crossed eyes, cataracts, or atrophy of the optic nerve) or central nervous system (such as a small head size, mental retardation, or seizures).

dysplasia Ectodermal

Ehlers-Danlos syndrome

apy. The abnormal skin banding that may occur in the mouth and between the eyelids in Hay-Wells syndrome also requires surgical correction.

Prognosis

Among males with hypohydrotic ectodermal dysplasia, unrecognized episodes of hyperthermia are a dangerous complication. The mortality rate during infancy and early childhood in affected, undiagnosed males is 20% due to neurologic damage associated with hyperthermic episodes. If affected males are diagnosed and managed appropriately, a normal life expectancy and normal intelligence can be expected.

Otherwise, the tissue abnormalities and birth defects that occur in the ectodermal dysplasias are usually not life-threatening.

These conditions typically do not cause mental retardation, although a minority of cases of incontintenti pigmenti and EEC syndrome may involve cognitive impairment.

Resources

PERIODICALS

Coskun, Yavuz, and Ziya Bayraktaroglu. “Ectodermal dysplasia.” (Pathological Case of the Month) Archives of Pediatrics & Adolescent Medicine 151, no. 7 (July 1997): 741–2.

WEBSITES

National Foundation for Ectodermal Dysplasias.www.nfed.org .

Jennifer Roggenbuck, MS, CGC

Edwards syndrome see Trisomy 18

I Ehlers-Danlos syndrome

Definition

The Ehlers-Danlos syndromes (EDS) refer to a group of inherited disorders that affect collagen structure and function. Genetic abnormalities in the manufacturing of collagen within the body affect connective tissues, causing them to be abnormally weak.

Description

Collagen is a strong, fibrous protein that lends strength and elasticity to connective tissues such as the skin, tendons, organ walls, cartilage, and blood vessels.

Each of these connective tissues requires collagen tailored to meet its specific purposes. The many roles of collagen are reflected in the number of genes dedicated to its production. There are at least 28 genes in humans that encode at least 19 different types of collagen. Abnormalaties in these genes can affect basic construction as well as the fine-tuned processing of the collagen.

Genetic profile

There are numerous types of EDS, all caused by changes in one of several genes. The manner in which EDS is inherited depends on the specific gene involved. There are three patterns of inheritance for EDS: autosomal dominant, autosomal recessive, and X-linked (extremely rare).

Chromosomes are made up of hundreds of small units known as genes, which contain the genetic material necessary for an individual to develop and function. Humans have 46 chromosomes, which are matched into 23 pairs. Because chromosomes are inherited in pairs, each individual receives two copies of each chromosome and likewise two copies of each gene.

Changes or mutations in genes can cause genetic diseases in several different ways, many of which are represented within the spectrum of EDS. In autosomal dominant EDS, only one copy of a specific gene must be changed for a person to have EDS. In autosomal recessive EDS, both copies of a specific gene must be changed for a person to have EDS. If only one copy of an autosomal recessive EDS gene is changed, the person is referred to as a carrier, meaning they do not have any of the signs or symptoms of the disease itself, but carry the possibility of passing on the changed gene to a future child. In X- linked EDS, a specific gene on the X chromosome must be changed. This affects males and females differently because males have one and females have two X chromosomes.

As of 2001 the few X-linked forms of EDS fall under the category of X-linked recessive. As with autosomal recessive, this implies that both copies of a specific gene must be changed for a person to be affected. However, because males only have one X chromosome, they are affected if an X-linked recessive EDS gene is changed on their single X chromosome. That is, they are affected even though they have only one changed copy. On the other hand, that same gene must be changed on both of the X chromosomes in a female for her to be affected.

Although there is much information regarding the changes in genes that cause EDS and their various inheritance patterns, the exact gene mutation for all types of EDS is not known.

Demographics

EDS was originally described by Dr. Van Meekeren in 1682. Dr. Ehlers and Dr. Danlos further characterized the disease in 1901 and 1908, respectively. Today, according to the Ehlers-Danlos National Foundation, one in 5,000 to one in 10,000 people are affected by some form of EDS.

Signs and symptoms

EDS is a group of genetic disorders that usually affects the skin, ligaments, joints, and blood vessels. Classification of EDS types was revised in 1997. The new classification involves categorizing the different forms of EDS into six major subtypes including classical, hypermobility, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis, and a collection of rare or poorly defined varieties. This new classification is simpler and based on descriptions of the actual symptoms.

Classical type

Under the old classification system, EDS classical type was divided into two separate types: type I and type II. The major symptoms involved in EDS classical type affect the skin and joints. The skin has a smooth, velvety texture and bruises easily. Affected individuals typically have extensive scarring, particularly at the knees, elbows, forehead, and chin. The joints are hyperextensible, so there is a tendency towards dislocation of the hip, shoulder, elbow, knee, or clavicle. Due to decreased muscle tone, affected infants may experience a delay in reaching motor milestones. Children may have a tendency to develop hernias or other organ shifts within the abdomen. Sprains and partial or complete joint dislocations are also common. Symptoms can range from mild to severe. EDS classical type is inherited in an autosomal dominant manner.

There are three major clinical diagnostic criteria for EDS classical type. These include skin hyperextensibility, unusually wide scars, and joint hypermobility. At this time there is no definitive test for the diagnosis of classical EDS. Both DNA and biochemical studies have been used to help identify affected individuals. In some cases, a skin biopsy has been found to be useful in confirming a diagnosis. Unfortunately, these tests are not sensitive enough to identify all individuals with classical EDS. If there are multiple affected individuals in a family, it may be possible to perform prenatal diagnosis using a DNA information technique known as a linkage study.

Hypermobility type

Excessively loose joints are the hallmark of this EDS type, formerly known as EDS type III. Both large joints,

KEY TERMS

Arthrochalasia—Excessive loosness of the joints.

Blood vessels—General term for arteries, veins, and capillaries, which transport blood throughout the body.

Cartilage—Supportive connective tissue that cushions bone at the joints or which connects muscle to bone.

Collagen—The main supportive protein of cartilage, connective tissue, tendon, skin, and bone.

Connective tissue—A group of tissues responsible for support throughout the body; includes cartilage, bone, fat, tissue underlying skin, and tissues that support organs, blood vessels, and nerves throughout the body.

Dermatosparaxis—Skin fragility caused by abnormal collagen.

Hernia—A rupture in the wall of a body cavity, through which an organ may protrude.

Homeopathic—A holistic and natural approach to health care.

Hyperextensibility—The ability to extend a joint beyond the normal range.

Hypermobility—Unusual flexibility of the joints, allowing them to be bent or moved beyond their normal range of motion.

Joint dislocation—The displacement of a bone.

Kyphoscoliosis—Abnormal front-to-back and side- to-side curvature of the spine.

Ligament—A type of connective tissue that connects bones or cartilage and provides support and strength to joints.

Osteoarthritis—A degenerative joint disease that causes pain and stiffness.

Scoliosis—An abnormal, side-to-side curvature of the spine.

Tendon—A strong connective tissue that connects muscle to bone.

Uterus—A muscular, hollow organ of the female reproductive tract. The uterus contains and nourishes the embryo and fetus from the time the fertilized egg is implanted until birth.

Vascular—Having to do with blood vessels.

syndrome Danlos-Ehlers

Ehlers-Danlos syndrome

such as the elbows and knees, and small joints, such as toes and fingers, are affected. Partial and total joint dislocations are common, and particularly involve the jaw, knee, and shoulder. Many individuals experience chronic limb and joint pain, although x rays of these joints appear normal. The skin may also bruise easily. Osteoarthritis is a common occurrence in adults. EDS hypermobility type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS hypermobility type. These include skin involvement (either hyperextensible skin or smooth and velvety skin) and generalized joint hypermobility. At this time there is no test for this form of EDS.

Vascular type

Formerly called EDS type IV, EDS vascular type is the most severe form. The connective tissue in the intestines, arteries, uterus, and other hollow organs may be unusually weak, leading to organ or blood vessel rupture. Such ruptures are most likely between ages 20 and 40, although they can occur any time, and may be life-threat- ening.

There is a classic facial appearance associated with EDS vascular type. Affected individuals tend to have large eyes, a thin pinched nose, thin lips, and a slim body. The skin is thin and translucent, with veins dramatically visible, particularly across the chest.

The large joints have normal stability, but small joints in the hands and feet are loose and hyperextensibile. The skin bruises easily. Other complications may include collapsed lungs, premature aging of the skin on the hands and feet, and ruptured arteries and veins. After surgery there may be poor wound healing, a complication that tends to be frequent and severe. Pregnancy also carries the risk complications. During and after pregnancy there is an increased risk of the uterus rupturing and of arterial bleeding. Due to the severe complications associated with EDS type IV, death usually occurs before the age of 50 years. A study of 419 individuals with EDS vascular type, completed in 2000, found that the median survival rate was 48 years, with a range of 6–73 years. EDS vascular type is inherited in an autosomal dominant manner.

There are four major clinical diagnostic criteria for EDS vascular type. These include thin translucent skin, arterial/intestinal/uterine fragility or rupture, extensive bruising, and characteristic facial appearance. EDS vascular type is caused by a change in the gene COL3A1, which codes for one of the collagen chains used to build Collage type III. Laboratory testing is available for this form of EDS. A skin biopsy may be used to demonstrate the structurally abnormal collagen. This type of bio-

chemical test identifies more than 95% of individuals with EDS vascular type. Laboratory testing is recommended for individuals with two or more of the major criteria.

DNA analysis may also be used to identify the change within the COL3A1 gene. This information may be helpful for genetic counseling purposes. Prenatal testing is available for pregnancies in which an affected parent has been identified and the change in their DNA is known or their biochemical abnormality has been demonstrated.

Kyphoscoliosis type

The major symptom of kyphoscoliosis type, formerly called EDS type VI, is general joint looseness. At birth, muscle tone is poor, and motor skill development is subsequently delayed. Also, infants with this type of EDS have an abnormal curvature of the spine (scoliosis). The scoliosis becomes progressively worse with age, with affected individuals usually unable to walk by age 20 years. The eyes and skin are fragile and easily damaged, and blood vessel involvement is a possibility. The bones may also be affected as demonstrated by a decrease in bone mass. Kyphoscoliosis type is inherited in an autosomal recessive manner.

There are four major clinical diagnostic criteria for EDS kyphoscoliosis type. These include generally loose joints, low muscle tone at birth, scoliosis at birth (which worsens with age), and fragility of the eyes, which may give the white area of the eye a blue tint or cause the eye to rupture. This form of EDS is caused by a change in the PLOD gene on chromosome 1, which encodes the enzyme lysyl hydroxylase. A laboratory test is available in which urinary hydroxylysyl pryridinoline is measured. This urine test is extremely senstive and specific for EDS kyphoscolios type. Laboratory testing is recommended for infants with three or more of the major diagnostic criteria.

Prenatal testing is available if a pregnancy is known to be at risk and an identified affected family member has had positive laboratory testing. An amniocentesis may be performed in which fetal cells are removed from the amniotic fluid and enzyme activity is measured.

Arthrochalasia type

Dislocation of the hip joint typically accompanies arthrochalasia type EDS, formerly called EDS type VIIB. Other joints are also unusually loose, leading to recurrent partial and total dislocations. The skin has a high degree of stretchability and bruises easily. Individuals with this type of EDS may also experience mildly diminished bone mass, scoliosis, and poor muscle tone. Arthrochalasia type is inherited in an autosomal dominant manner.

There are two major clinical diagnostic criteria for EDS arthrochalasia type. These include severe generalized joint hypermobility and bilateral hip dislocation present at birth. This form of EDS is caused by a change in either of two components of Collage type I, called proa1(I) type A and proa2 (I) type B. A skin biopsy may be performed to demonstrate an abnormality in either component. Direct DNA testing is also available.

Dermatosparaxis type

Individuals with this type of EDS, once called type VIIC, have extremely fragile skin that bruises easily but does not scar excessively. The skin is soft and may sag, leading to an aged appearance even in young adults. Individuals may also experience hernias. Dermatosparaxis type is inherited in an autosomal recessive manner.

There are two major clinical diagnostic criteria for EDS dematosparaxis type. These include severe skin fragility and sagging or aged appearing skin. This form of EDS is caused by a change in the enzyme called procollagen I N-terminal peptidase. A skin biopsy may be preformed for a definitive diagnosis of dermatosparaxis type.

Other types

There are several other forms of EDS that have not been as clearly defined as the aforementioned types. Forms of EDS within this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns within this group include X-linked recessive, autosomal dominant, and autosomal recessive.

Diagnosis

Clinical symptoms such as extreme joint looseness and unusual skin qualities, along with family history, can lead to a diagnosis of EDS. Specific tests, such as skin biopsies, are available for diagnosis of certain types of EDS, including vascular, arthrochalasia, and dermatosparaxis types. A skin biopsy involves removing a small sample of skin and examining its microscopic structure. A urine test is available for the kyphoscoliosis type.

Management of all types of EDS may include genetic counseling to help affected individuals and their families understand the disorder and its impact on other family members and future children.

If a couple has had a child diagnosed with EDS, the chance that they will have another child with the same

Hyperflexion of the joints, the ability to bend them beyond normal, is seen in most patients with Ehlers-Danlos syndrome. Overflexing of the hand is demonstrated by this patient. (Custom Medical Stock Photo, Inc.)

disorder depends on with what form of EDS the child has been diagnosed, and if either parent is affected by the same disease or not.

Individuals diagnosed with an autosomal dominant form of EDS have a 50% chance of passing the same disorder on to a child in each pregnancy. Individuals diagnosed with an autosomal recessive form of EDS have an extremely low risk of having a child with the same disorder.

X-linked recessive EDS is accompanied by a slightly more complicated pattern of inheritance. If a father with an X-linked recessive form of EDS passes a copy of his X chromosome to his children, his sons will be unaffected and his daughters will be carriers. If a mother is a carrier for an X-linked recessive form of EDS, she may have affected or unaffected sons, or carrier or unaffected daughters, depending on which X chromosome her child inherits from her and which sex chromosome is inherited from the father.

Prenatal diagnosis is available for specific forms of EDS, including kyphoscoliosis type and vascular type. However, prenatal testing is only a possibility in these types if the underlying abnormality has been found in another family member.

Treatment and management

Medical therapy relies on managing symptoms and trying to prevent further complications. There is no cure for EDS.

Braces may be prescribed to stabilize joints, although surgery is sometimes necessary to repair joint damage caused by repeated dislocations. Physical therapy teaches individuals how to strengthen muscles around joints and may help to prevent or limit damage.

syndrome Danlos-Ehlers

Ellis-van Creveld syndrome

Elective surgery is discouraged due to the high possibility of complications.

Alternative treatment

There are anecdotal reports that large daily doses (1–4 g) of vitamin C may help decrease bruising and aid in wound healing. Constitutional homeopathic treatment may be helpful in maintaining optimal health in persons with a diagnosis of EDS. Individuals with EDS should discuss these types of therapies with their doctor before beginning them on their own. Therapy that does not require medical consultation involves protecting the skin with sunscreen and avoiding activities that place stress on the joints.

Prognosis

The outlook for individuals with EDS depends on the type of EDS with which they have been diagnosed. Symptoms vary in severity, even within one subtype, and the frequency of complications changes on an individual basis. Some individuals have negligible symptoms while others are severely restricted in their daily life. Extreme joint instability and scoliosis may limit a person’s mobility. Most individuals will have a normal lifespan. However, those with blood vessel involvement, particularly those with EDS vascular type, have an increased risk of fatal complications.

EDS is a lifelong condition. Affected individuals may face social obstacles related to their disease on a daily basis. Some people with EDS have reported living with fears of significant and painful skin ruptures, of becoming pregnant (especially those with EDS vascular type), of their condition worsening, of becoming unemployed due to physical and emotional burdens, and of social stigmatization in general.

Constant bruises, skin wounds, and trips to the hospital take their toll on both affected children and their parents. Prior to diagnosis, parents of children with EDS have found themselves under suspicion of child abuse.

Some people with EDS are not diagnosed until well into adulthood and, in the case of EDS vascular type, occasionally not until after death due to complications of the disorder. Not only may the diagnosis itself be devastating to the family, but in many cases other family members find out for the first time they are at risk for being affected.

Although individuals with EDS face significant challenges, it is important to remember that each person is unique with his or her own distinguished qualities and potential. Persons with EDS go on to have families, have careers, and become accomplished citizens, surmounting the challenges of their disease.

Resources

PERIODICALS

“Clinical and Genetic Features of Ehlers-Danlos Syndrome Type IV, the Vascular Type.” The New England Journal of Medicine 342, no. 10 (2000).

“Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997.” American Journal of Medical Genetics 77 (1998): 31–37.

“Living a Restricted Life with Ehlers-Danlos Syndrome.”

International Journal of Nursing Studies 37 (2000): 111–118.

ORGANIZATIONS

Elhers-Danlos National Foundation. 6399 Wilshire Blvd., Ste 203, Los Angeles, CA 90048. (323) 651-3038. Fax: (323) 651-1366. http://www.ednf.org .

Ehlers-Danlos Support Group—UK. PO Box 335, Farnham, Surrey, GU10 1XJ. UK. 01252 690 940. http://www.atv

.ndirect.co.uk .

WEBSITES

GeneClinics. http://www.geneclinics.org .

Java O. Solis, MS

Elattoproteus syndrome see Proteus syndrome

I Ellis-van Creveld syndrome

Definition

Ellis-van Creveld syndrome is an individually recognized genetic condition characterized by short stature and malformations of the heart, limbs, nails, and teeth. The name given to this condition originates from Richard W. B. Ellis of Scotland and Simon van Creveld of the Netherlands. Each had a patient with this syndrome in his care when the two met by chance in an English train car on the way to a pediatric conference in the late 1930s.

Description

Ellis-van Creveld (EvC) syndrome primarily affects the skeletal system, but is also associated with congenital heart defects. EvC syndrome is one of the six short rib polydactyly syndromes, or SRPS. There is considerable overlap between the features of these six syndromes. Clinical, radiological, and pathological studies are being conducted to determine if there are indeed six distinct SRPS, or if each is a different mutation at the gene that also causes Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome is alternatively known as chondroectodermal dysplasia or mesoectodermal dysplasia. The name chondroectodermal dysplasia is meant to indicate a dysplasia, or abnormal growth or development, of the skeleton (chondro-) and the skin (ectodermal). The name mesoectodermal dysplasia is meant to indicate an abnormal growth or development of the skin (ectodermal) and primarily the middle portion of the bone (meso-). However, neither medically descriptive term defines the syndrome completely, and Ellis-van Creveld syndrome remains the most used name for both medical and common purposes.

Ellis-van Creveld syndrome is characterized by short arms and legs; short ribs; short fingers; polydactyly, or extra fingers or toes; and dysplastic, or abnormal, teeth and nails. Limb shortening is more noticeable in the legs than in the arms. Many older children affected by EvC syndrome develop knock-knee, or genu valgum, which may have to be corrected by orthopedic surgery. The underdeveloped ribs generally cause a condition known as pectus carinatum, in which the chest is narrow and elongated. A sixth finger on both hands occurs in all patients with EvC syndrome, while extra toes are observed in approximately 20% of the EvC syndrome population. Polydactyly in affected individuals is always symmetric. That is, if the left hand possesses a sixth finger, the right hand will also possess a sixth finger.

Dysplastic, or abnormal, teeth and nails are observed in all individuals with EvC syndrome. The most common dental anomalies are: teeth present at birth; wide spaces between permanent teeth; the late eruption of, or the complete lack of, some permanent teeth; and permanent teeth that more closely resemble baby teeth than permanent teeth. The most common nail abnormalities are absent or malformed fingernails or toenails. Thin, brittle hair is also observed in a majority of patients with EvC syndrome.

Congenital heart defects occur in approximately 5060% of affected individuals. The most common cardiac abnormality observed is a common atrium rather than the normal two-chambered atrium. This “hole in the heart” can often be surgically repaired, resulting in normal heart function.

Genetic profile

Ellis-van Creveld syndrome is an autosomal, or nonsex linked, recessive condition. The gene responsible for EvC syndrome has been identified and its locus determined on the distal short arm of chromosome 4p. In 2000, it was shown that the EvC gene is the same gene that causes Weyers acrofacial dysostosis.

KEY TERMS

Autosomal—Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Dysplasia—The abnormal growth or development of a tissue or organ.

Heterozygous—Having two different versions of the same gene.

Homozygous—Having two identical copies of a gene or chromosome.

Postaxial polydactyly—A condition in which an extra finger or toe is present outside of the normal fifth digit.

Primary atrial septation—An improper division of the atria of the heart, or a “hole in the heart,” which results in the formation of a common atrium rather than the normal two-chambered atrium.

Short rib polydactyly syndromes—A collection of genetic disorders characterized by abnormally short ribs and extra fingers or toes. Research is ongoing to determine if these disorders are the result of mutations in a common gene.

Weyers acrofacial dysostosis—The condition resulting from a mutation of the same gene that shows mutation in Ellis-van Creveld syndrome. As is usually the case when comparing expressions of the same gene mutation, the single dose Weyers acrofacial dysostosis presents milder symptoms than the double dose Ellis-van Creveld syndrome.

Certain mutations in the EvC gene cause EvC syndrome. In order for EvC syndrome to appear, the affected child must inherit a mutation of this gene from each parent. The child must receive two abnormal genes.

When the child receives only a single copy of an abnormal gene that would cause EvC syndrome, that child is affected with Weyers acrofacial dysostosis. Weyers acrofacial dysostosis is an autosomal dominant condition characterized by tooth and nail abnormalities, extra fingers and toes, and milder limb anomalies than those observed in Ellis-van Creveld syndrome. As is often the case in homozygous disorders, EvC syndrome presents much more pronounced physically observable and potentially life-threatening signs than the corresponding heterozygous condition, Weyers acrofacial dysostosis.

syndrome Creveld van-Ellis

Ellis-van Creveld syndrome

Polydactyly, having extra fingers or toes, is a common feature in patients with Ellis van Creveld syndrome.

(Greenwood Genetic Center)

Demographics

Ellis-van Creveld syndrome has an incidence of approximately one out of 150,000 live births. Ellis-van Creveld syndrome has a much higher occurrence among the Old Order Amish, an isolated and inbred religious community in Lancaster County, Pennsylvania.

As a homozygous condition, both parents of an affected child must carry the abnormal EvC gene. The parents of an affected child have a one in four chance of having additional children affected with EvC syndrome. The transmission of such homozygous genetic disorders is facilitated by the close association among potentially related individuals in a relatively small and isolated population such as that of the Amish. Also, a relatively high frequency of Ellis-van Creveld syndrome has been observed in the Aboriginal people of Western Australia. This high frequency has been attributed to a founder effect from Dutch castaways and genetic drift caused by the isolation and interbreeding of these peoples.

Signs and symptoms

Ellis-van Creveld syndrome is characterized by short limbs and short body length identifiable at birth. The average adult height range for those affected by EvC syndrome is 43–60 in (109–152 cm). The head and neck are generally unaffected other than possible abnormalities of the upper lip, and dental anomalies including delayed eruption of the permanent teeth, which are generally underdeveloped and more similar to a child’s teeth than to those of an adult. EvC syndrome is further characterized by congenital heart defects, usually a single upper chamber (atrium) rather than the normal two upper chambers. Affected individuals have short, poorly developed

ribs, which leads to a narrow chest; this is termed pectus carinatum.

Males affected by EvC syndrome may present abnormalities of the penis in which the urethral opening occurs on the underside of the penis rather than at the tip of the glans (hypospadias); they may also have one or both testicles undescended (cryptorchidism). Further skeletal anomalies associated with EvC syndrome include: low hips; a spur-like projection at the acetabula, the socket in the hipbone that accepts the head of the thighbone; a fusion of the capitate and hamate bones; two carpal bones, the fusion of which makes the formation of a fist difficult or impossible; knock-knee; clubfeet that turn down and in; and postaxial polydactyly, or extra fingers/toes that arise outside the normal fifth digit. Fingernails and toenails are generally malformed. Neurologically, mental retardation has been observed in patients with EvC syndrome, but it is not the norm. A brain abnormality of one of the normal cavities of the brain (Dandy-Walker syndrome) is also occasionally associated with EvC syndrome.

Diagnosis

Ultrasound imaging of developing fetuses can reveal the limb shortening and underdeveloped ribs that are characteristic of the short rib polydactyly syndromes (SRPS), which includes Ellis-van Creveld syndrome. An ultrasound scan is now available after the sixteenth week of gestation that may identify extra digits in the developing fetus.

Ellis-van Creveld syndrome is generally differentially diagnosed from the other SRPS by the additional presence of atrial abnormalities. However, it is often difficult to distinguish Ellis-van Creveld syndrome from two other forms of skeletal dysplasia. These are asphyxiating thoracic dysplasia (ATD), also known as Jeune syndrome; and short rib polydactyly syndrome (SRPS) type III, or Verma-Naumoff type SRPS. Individuals with Jeune syndrome often die of respiratory distress shortly after birth, whereas individuals diagnosed with EvC syndrome are more likely to die from congenital heart failure. Patients with Jeune syndrome often have extra fingers or toes; but, unlike those with EvC syndrome, this polydactyly is often not symmetric. Jeune syndrome does not present the nail and hair abnormalities seen in EvC syndrome. Older children can often be differentially diagnosed with Jeune syndrome rather than EvC syndrome if they develop kidney problems, which may also later lead to kidney failure as adults. Kidney dysfunction is not associated with Ellis-van Creveld syndrome.

Verma-Naumoff type SRPS is virtually indistinguishable from EvC syndrome prior to birth. However, individuals with Verma-Naumoff type SRPS also exhibit heart, kidney, and intestinal malformations that are not present in the Ellis-van Creveld population. VermaNaumoff type SRPS has an essentially 100% mortality rate within hours of birth, as those affected die from respiratory distress. All three of these conditions arise from autosomal recessive inheritance. As of 2001, the genetic evidence is beginning to further the hypothesis that these three conditions are the result of mutations of the same gene on chromosome 4p that has been identified as the cause of Ellis-van Creveld syndrome.

Treatment and management

Genetic counseling of individuals affected with either Ellis-van Creveld syndrome or the allelic disorder, Weyers acrofacial dysostosis, may prevent the conception of children with EvC syndrome. Congenital heart defects associated with Ellis-van Creveld syndrome may be surgically corrected. The potential outcome of such a procedure is normal heart function. Extra fingers or toes (polydactyly) can be surgically removed shortly after birth. This is more a cosmetic treatment than a necessary one in the case of fully developed extra digits. If a person affected with EvC syndrome develops genu valgum (knock-knee), he or she may require orthopedic surgery to straighten the legs at the knee. Dental treatment also has an important role in management of Ellis-van Creveld syndrome.

Many people of extremely short stature adapt their surroundings to their size. Others choose to undergo one of the bone lengthening procedures that have increasingly become available. These bone lengthening procedures are generally performed only on the limbs. They often do not offer complete relief to the patient who may also have a smaller than normal thoracic cavity caused by undersized ribs.

Prognosis

Ellis-van Creveld syndrome is generally non-lethal with approximately two-thirds of those affected surviving to adulthood. Mortality is higher when the congenital heart defects associated with EvC syndrome are also present. Approximately half of those affected with Ellisvan Creveld syndrome with heart abnormalities die in childhood due to cardiorespiratory problems associated with these congenital heart defects or associated with pressure on the chest, primarily the lungs, caused by an underdeveloped rib cage. Of these, approximately onehalf die within the first six months of life.

Resources

PERIODICALS

Polymeropoulos, M., et al. “The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.” Genomics (July 1996): 1–5.

Ruiz-Perez, V., et al. “Mutations in a new gene in Ellis-Van Creveld syndrome and Weyers acrodental dysostosis.” Nature Genetics (March 2000): 283–86.

ORGANIZATIONS

Ellis-Van Creveld Foundation. Farthingdale Farm, Hackmans Lane, Purleigh, Chelmsford, CM3 6RW. UK 01-621- 829675. http://www.cafamily.org.uk/Direct/e24.html .

Genetic Alliance. 4301 Connecticut Ave. NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or (202) 966-5557. Fax: (888) 394-3937 info @geneticalliance. http://www.geneticalliance.org .

WEBSITES

Johns Hopkins Hospital Greenberg Center for Skeletal Dysplasias. http://www.med.jhu.edu/Greenberg.Center/ evc.htm . (February 7, 2001).

OMIM—Online Mendelian Inheritance in Man. http://www

.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?225500 . (February 7, 2001).

WebMD—Ellis-van Creveld syndrome. http://webmd.lycos

.com/content/asset/adam_disease_ellis-van_creveld_ syndrome . (February 7, 2001).

Paul A. Johnson

I Emery-Dreifuss

muscular dystrophy

Definition

Emery-Dreifuss muscular dystrophy (EDMD) is a rare childhood-onset degenerative muscle disease seen almost exclusively in males. Emery-Dreifuss muscular dystrophy is characterized by a classic triad of symptoms. These include early-onset contractures, very slow progressive muscle weakness and degeneration involving the upper arms and lower legs, and cardiac (heart) muscle disease.

Description

Emery-Dreifuss muscular dystrophy affects the arms, legs, spine, face, neck, and heart. This disease is characterized by contractures of the elbows and the Achilles tendons at an early age, slowly progressive muscle wasting and weakness, and life potentially life-threat- ening heart muscle disease. Intelligence is normal, however physical problems may be severe.

dystrophy muscular Dreifuss-Emery