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

•Medications. A number of medications are known to cause telogen effluvium, including beta blockers; oral contraceptives; retinoids; nonsteroidal anti-inflamma- tory agents (NSAIDs), such as indomethacin (Indocin) and ibuprofen (Advil); aspirin and other salicylates; lithium; anticoagulants (blood thinners); and anticonvulsants (medications for seizures).

Telogen effluvium usually stops after a few months and new hair grows in. The first regrowth may be finer than usual but the follicles will eventually produce hair of normal thickness.

ANAGEN EFFLUVIUM Anagen effluvium is a type of diffuse hair loss resulting from a sudden interruption of the growth phase. Unlike the time lag that characterizes telogen effluvium, hair loss in anagen effluvium occurs at once. The most common cause of anagen effluvium is chemotherapy, including treatment with methotrexate, bleomycin, vinblastine, vincristine, cyclophosphamide, doxorubicin, daunorubicin, and cytarabine. This form of hair loss, however, can also be caused by poisoning with arsenic, thallium, bismuth, or borax.

Anagen effluvium usually stops as soon as the chemical cause is removed, but it may take several months for hair to regrow completely.

Inflammatory nonscarring hair loss

ALOPECIA AREATA Alopecia areata is a nonscarring recurrent form of hair loss characterized by smooth round or oval patches of bare skin. There may be some mild itching but no visible skin eruptions. Alopecia areata is usually considered an idiopathic disorder, which means its cause is unknown. Some researchers, however, consider it an autoimmune disorder. It is often triggered by stress or anxiety. Alopecia areata usually affects only the scalp, the eyebrows, and (in men) the beard, but may cause hair loss over the entire scalp (alopecia totalis) or even the entire body (alopecia universalis). The loss of hairs from the eyebrows and eyelashes that may be associated with alopecia totalis is called madarosis.

PSORIASIS Psoriasis is a chronic inflammatory skin disease that frequently affects the elbows and knees as well as the scalp. On the scalp, psoriasis is marked by the appearance of red plaques or patches with silvery scales. These patches may also be found behind the ears. Psoriasis can cause massive but temporary hair loss.

Inflammatory scarring hair loss

In hair loss syndromes marked by tissue scarring, the hair loss is permanent and irreversible. These syndromes should be diagnosed as quickly as possible to minimize the extent of damaged tissue.

LUPUS ERYTHEMATOSUS Lupus erythematosus is an autoimmune disorder than can affect a number of different organ systems. About 85% of lupus patients are women between 20 and 40 years of age. More than 10% of women with lupus develop a form of the disorder known as chronic discoid or chronic cutaneous lupus erythematosus. Chronic discoid lupus can occur on the scalp as well as the face, and is marked by dark red patches or plaques between 0.5 in (1.3 cm) and 0.75 in (1.9 cm) in diameter. The plaques are covered by dry, horny scales that plug the hair follicles and cause permanent hair loss.

LICHEN PLANOPILARIS Lichen planopilaris is a form of lichen planus, an idiopathic recurrent skin disorder that usually affects the wrists, legs, and mucous membranes. It is characterized by itching pinkish-red or purplish patches or pimples on the scalp. Like lupus, lichen planopilaris can cause lasting hair loss.

BACTERIAL OR FUNGAL INFECTIONS Scarring alopecia can be caused by dermatophytes, which are fungi that live on the skin and hair. These fungi include

Trichophyton rubrum, Trichophyton tonsurans, and

Microsporum audouinii. The dermatophytes infect the skin of the scalp and move down the hair shaft into the follicle, which may be permanently destroyed.

SCLERODERMA Scleroderma is a chronic disorder in which the patient’s skin and connective tissue become progressively thicker and more rigid. Its cause is not known. As the patient’s scalp thickens, the hair is gradually but permanently lost.

INJURIES Scarring alopecia can also result from burns, trauma to the scalp, or radiation treatment.

Genetic profile

Male pattern hair loss (MPHL)

Male pattern hair loss (MPHL) is a polygenic disorder, which means that its appearance is directed by more than one gene. It may be inherited from either the father’s or mother’s side. The belief that MPHL is inherited only through the mother is a myth. Genes for baldness are, however, dominant, which means that 50% of the children of a balding parent of either sex will inherit the baldness genes. Genetic factors appear to influence the age at onset of MPHL; the extent and speed of hair loss; and the pattern of hair loss. MPHL may begin at any time after the levels of androgens in a boy’s blood begin to rise during puberty.

It is important to note that genes for baldness depend on normal levels of androgen in the body to produce androgenetic hair loss. Men who were castrated prior to puberty, or have abnormally low levels of androgen for other reasons, do not go bald even if they have a gene for baldness.

syndromes loss Hair

Hair loss syndromes

male/female ratio is 1:1 in children, but is about 1:4 in college students. The disorder may be underdiagnosed in males because their hair loss is attributed to MPHL.

Signs and symptoms

The signs and symptoms of each hair loss syndrome are included in its description.

Diagnosis

The differential diagnosis of hair loss is usually made on the basis of the patient’s history, visual examination of the scalp, and the results of laboratory tests. The more common forms of alopecia can be diagnosed by a family physician, but those that are related to skin disorders may require referral to a dermatologist. There are four key questions that the doctor will ask in evaluating hair loss:

•How long has the patient been losing hair?

•Is there a pattern to the remaining hair?

•Is the hair loss associated with redness, itching, or pain?

•Are there any patches of broken skin, pimples, plaques, or other signs of infection in the affected areas?

Patient history

The patient’s medical history may contain information about previous episodes of hair loss; eating and nutritional habits; use of prescription medications; surgery or chemotherapy; occupational exposure to arsenic, thallium, or bismuth; recent illnesses with high fevers; recent periods of severe emotional stress or anxiety; or other factors that may influence hair loss. In addition, the doctor will ask about grooming habits, including the use of dyes, home permanents, hair straighteners, hair sprays, and similar products as well as blow dryers, rollers, and other hair styling equipment.

Laboratory tests

Laboratory tests are performed on samples of the hair itself as part of the differential diagnosis. Microscopic study of a hair sample will indicate, for example, damage to the hair shaft, broken hairs, and changes in the shape of the hair. For example, broken hairs may suggest traction alopecia or trichotillomania. In trichotillomania, there will also be an unusually high number of hairs in the catagen phase. Anagen effluvium produces hairs with tapered or pointed ends, sometimes called “pencil-point” hairs. In telogen effluvium, the hairs have white bulbs at the end and can often be removed from the head by very gentle pulling. In alopecia areata, the area of hair loss is bordered by telltale “exclamation point” hairs.

Alopecia, an inherited hair loss syndrome, results in balding. (Custom Medical Stock Photo, Inc.)

Hair samples can also be subjected to chemical analysis if heavy metal poisoning is suspected. Arsenic and thallium are absorbed by the hair shaft and can be detected by appropriate tests.

Skin biopsies are most useful in diagnosis when an infection or other inflammatory condition is suspected as the cause of the hair loss. While scarring can often be seen during a visual examination of the scalp, a biopsy may be the only way to tell if the hair follicles have been destroyed, as well as to differentiate among lupus, dermatophyte infection, alopecia areata, and scleroderma. Biopsies may also be useful in determining the presence of traction alopecia or trichotillomania. In these conditions, pieces of hair shaft are sometimes found in the surrounding skin. Some hair follicles may show signs of injury and are interspersed among normal follicles.

Treatment and management

The treatment of hair loss syndromes is determined by their causes.

Medications

TOPICAL APPLICATIONS Topical applications for hair loss syndromes fall into two major categories—those that stimulate the growth of new hair and those that reduce inflammation. The most frequently prescribed topical medication for male pattern hair loss is minoxidil, which was originally developed to lower high blood pressure. It was approved by the FDA for the treatment of androgenetic hair loss in 1988. Minoxidil, sold under the trade name Rogaine, is applied twice a day as a 2% or 5% solution. Rogaine is also sometimes prescribed for female pattern hair loss and alopecia areata. Its chief drawback

syndromes loss Hair

Hair loss syndromes

is its high cost—it costs between $650 and $700 a year to use Rogaine twice a day.

Alopecia areata may be treated with topical corticosteroids, or with injections of triamcinolone acetonide (Kenalog) in the affected areas every three or four weeks. Topical corticosteroids are also used to treat chronic discoid lupus, lichen planopilaris, and psoriasis. Tar shampoos are frequently recommended along with topical steroids to treat psoriasis of the scalp.

ORAL MEDICATIONS One oral medication, finasteride, has been approved by the FDA since 1997 for the treatment of male pattern hair loss. Finasteride, sold under the trade names Propecia or Proscar, works by interfering with the body’s production of 5-alpha-reduc- tase, the enzyme that converts testosterone to DHT. It is considered the most effective nonsurgical treatment of MPHL. The usual daily dose of finasteride is 1 mg. Unlike minoxidil, finasteride does not appear to be effective in postmenopausal women. It has not been tested on women of childbearing age because its androgen content could cause birth defects in male children.

Oral antifungal medications are considered better than topical preparations for treating dermatophyte infections of the scalp because topical products do not penetrate around the hair follicle. The mostly commonly prescribed oral antifungal drugs are griseofulvin (Grisactin, Fulvicin), ketoconazole (Nizoral), and fluconazole (Diflucan).

Clomipramine (Anafranil), which is a tricyclic antidepressant, or fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI), have been used in the treatment of trichotillomania.

Surgery

As of 2001, surgical transplantation is considered the most effective treatment of MPHL, but is not recommended for alopecia areata. Punch grafts or larger skin flaps bearing the patient’s own hair are transferred from areas of the head with normal hair growth to the balding areas. Hair transplantation is expensive but is usually permanent. It appears to work best on patients with dark or curly hair.

Scalp reduction is another surgical technique used in treating MPHL, in which bald areas at the top of the scalp are removed. It works best for patients with relatively little hair loss.

Non-surgical hair additions

These devices consist of human hair, synthetic fibers, or combinations of both. They are added to existing hair or attached to the scalp with adhesives to cover

areas of hair loss. They include hair weaves, hair pieces, hair extensions, toupees, partial hair prostheses, and similar devices. Non-surgical hair additions are less expensive than surgery but still cost between $750 and $2500, depending on materials and design. They can be used in combination with hair replacement surgery.

Psychotherapy

Cognitive-behavioral therapy is considered the most effective form of psychotherapy in treating trichotillomania. Individual psychodynamic psychotherapy is often helpful for persons who are emotionally upset by hair loss, particularly those whose employment depends on their appearance.

Prognosis

The prognoses of hair loss syndromes vary according to their causes. Hair loss caused by inflammatory scarring has the worst prognosis, as syndromes or injuries that form scar tissue destroy the hair follicles, preventing regrowth. The prognosis for alopecia areata is less favorable if the disorder affects large areas of the scalp, begins in adolescence, or has existed for a year or longer before the patient seeks treatment. Alopecia areata that begins in adult life and is limited to a few small areas of the scalp often goes away by itself in a few months, although the condition can recur. Diffuse hair loss related to anagen or telogen effluvium has a good prognosis; although complete regrowth may take some months, the hair does come back once the cause is identified and removed.

The prognosis for androgenetic alopecia varies. Rogaine does not work equally well for all men with MHPL. Those who benefit most from treatment with Rogaine have been bald for less than ten years; have a bald spot on the crown of the head that is smaller than 4 inches across; and still have vellus hairs in their balding areas. In addition, hair that grows in as a result of Rogaine will fall out once the patient stops using it. Finasteride is becoming the first-line non-surgical treatment for MPHL because it prevents hair loss as well as aiding regrowth; one study indicates that finasteride prevents further loss of hair in 90% of men even five years after they take it, and assists regrowth in 65% of men even two years later.

Resources

BOOKS

“Alopecia.” The Merck Manual of Diagnosis and Therapy.

Edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

Helm, Thomas N., MD. “Hair Disorders.” Conn’s Current Therapy. Edited by Robert E. Rakel, MD. Philadelphia: W. B. Saunders Company, 2000.

ORGANIZATIONS

American Academy of Dermatology. PO Box 4014, 930 N. Meacham Rd., Schaumburg, IL 60168-4014. (847) 3300230. Fax: (847) 330-0050. http://www.aad.org .

American Hair Loss Council. (888) 873-9719.http://www.ahlc.org .

American Society for Dermatologic Surgery. 1567 Maple Ave., Evanston, IL 60201. (708) 869-3954.

Dept. of Health and Human Services. Public Health Service, FDA, 5600 Fishers Lane, Rockville, MD 20857.

National Alopecia Areata Foundation (NAAF). PO Box 150760, San Rafael, CA 94915-0760. (415) 456-4644.

WEBSITES

American Hair Loss Council. http://www.ahlc.org .

Food and Drug Administration consumer affairs. http://vm. cfsan.fda.gov/~dms/cos .

International Society of Hair Restoration Surgery. http:// www.ishrs.org .

Rebecca J. Frey, PhD

I Hallermann-Streiff syndrome

Definition

Hallermann-Streiff syndrome is a rare genetic condition which causes characteristic facial features, visual abnormalities, tooth problems, short stature, and occasionally mental impairment.

Description

Hallermann-Streiff syndrome is also known as Francois dyscephaly syndrome, Hallermann-Streiff- Francois syndrome, oculomandibulodyscephaly with hypotrichosis, and oculomandibulofacial syndrome. The distinctive facial features of Hallermann-Streiff syndrome include a very small head that is unusually wide with a prominent forehead, a small underdeveloped jaw, an unusually small mouth, and/or a characteristic beakshaped nose. Small eyes, clouding of the lens of the eyes (cataracts) and other eye problems often leading to blindness are common. Problems with the teeth, skin, hair, and short stature are also common. Most individuals are of normal intelligence but mental impairment has been reported in some. Most cases of Hallermann-Streiff syn-

drome occur randomly for unknown reasons and may be the result of mutations, or changes to the genetic material.

Genetic profile

Hallermann-Streiff syndrome is a genetic condition. Genes are units of hereditary material which are passed to a child by his or her parents. The information contained in genes is responsible for the growth and development of all the cells and tissues of the body. Most genes occur in pairs: one copy of each pair is inherited from the mother through the egg cell and one copy of each pair is inherited from the father through the sperm cell. If there is a gene alteration (mutation), this may interfere with normal growth and development. The specific gene responsible for Hallermann-Streiff syndrome has not yet been identified.

Most cases of Hallermann-Streiff syndrome occur randomly in families with no other affected individuals. In this situation, the gene alteration is a spontaneous mutation. This means that some unknown event has caused the gene (which functions normally in the parent) to change in either the father’s sperm or the mother’s egg from which the affected individual was conceived. A person who has Hallermann-Streiff syndrome due to a spontaneous mutation can pass on this mutated gene to offspring who will also be affected. The chance for someone with Hallermann-Streiff syndrome to have a child with the same condition is 50% in each pregnancy. There is also a 50% chance to have a child who is not affected with Hallermann-Streiff syndrome.

There are some reports in the literature which indicate that Hallermann-Streiff syndrome is inherited as a recessive condition. Recessive conditions occur when both copies of a gene pair are changed. The affected individual inherits one mutated gene from each parent. The parents of the affected individual are carriers for one changed copy of the gene pair but are not affected themselves. Carrier couples have a 25% chance in each pregnancy to have a child affected with the condition. Diagnosed individuals are at risk to have an affected child only if their partner is also affected or is a carrier. There is no clear agreement on whether HallermannStreiff syndrome can be inherited as a recessive condition. Some have argued that the families reported to have recessive Hallermann-Streiff syndrome in fact do not have this condition but some other condition with features very similar to Hallermann-Streiff syndrome.

Demographics

Hallermann-Streiff syndrome affects both males and females in all ethnic groups. There have been over 150 cases reported in the literature.

syndrome Streiff-Hallermann

Hallermann-Streiff syndrome

K E Y T E R M S

Anesthetic—Drug used to temporarily cause loss of sensation in an area of the body. An anesthetic may either be general, associated with a loss of consciousness, or local, affecting one area only without loss of consciousness. Anesthetics are administered either via inhalation or needle injection.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Trachea—Long tube connecting from the larynx down into the lungs, responsible for passing air.

Tracheostomy—An opening surgically created in the trachea (windpipe) through the neck to improve breathing.

Ultrasound—An imaging technique that uses sound waves to help visualize internal structures in the body.

Signs and symptoms

Hallermann-Streiff syndrome affects the face, skull, hair, skin, eyes, teeth, and overall growth and development.

Face and skull

The facial features of individuals with HallermannStreiff syndrome are distinctive. The face is small with a thin, tapering, pinched nose, and small chin. The head is small and unusually wide with a prominent forehead, a small underdeveloped jaw, and a small mouth. Characteristic changes in the bones of the skull and the long bones of the arms and legs can usually be seen on x ray. The hair is usually sparse, particularly that of the scalp, brows, and lashes. Often there is no hair around the front and sides of the head. The skin of the scalp is thin and taut, and scalp veins are prominent.

Potential complications in Hallermann-Streiff syndrome are related to the narrow upper airway associated with the shape of the skull, particularly the small chin, mouth, and nose. The narrow air passages may result in feeding difficulties and mild aspiration of food. This can lead to severe complications including early lung infection and breathing difficulties. The lung infection can be life-threatening. Some individuals may experience a temporary stop in breathing during sleep because of an obstruction caused by the shape of the skull (obstructive

sleep apnea). Individuals with Hallermann-Streiff syndrome are also at increased risk of breathing difficulties when given a general anesthetic before surgery.

Eyes

Individuals with Hallermann-Streiff syndrome may be born with clouding of the lenses of the eyes (congenital cataracts). Congenital cataracts are the most common eye disorder and are usually the reason for a visit to the eye specialist in early life. The cataracts have been reported to spontaneously disappear in some cases. The second most common eye problem is that the eyes are unusually small. Other eye problems may include rapid, involuntary eye movements, crossing of the eyes, and/or decreased visual clarity, and in some cases, blindness.

Teeth

Dental problems are very common. They may include the presence of teeth at birth and the presence of extra teeth. Underdevelopment of tooth enamel and cavities are also common. As well, there may be absence, malformation, and/or improper alignment of certain teeth.

Growth and development

Most individuals with Hallermann-Streiff syndrome are born at term but about one-third are born premature and/or have a low birth weight. Short stature is seen in about half of the individuals with Hallermann-Streiff syndrome. The average final height for females is about 60 in (152 cm) and for males it is about 61 in (155 cm).

Most individuals are of normal intelligence; however, it is estimated that 15-30% of individuals with Hallermann-Streiff syndrome show some degree of mental impairment or slow development. Hyperactivity and seizures have been reported in a small number of individuals.

Other

A small number of individuals with HallermannStreiff syndrome have heart defects (such as a hole in the heart). There has also been a report of an individual with a weakened immune system.

Diagnosis

The diagnosis of Hallermann-Streiff syndrome is based on the presence of certain features including the characteristic facial, eye, dental, hair, and skin findings. The main features indicative of Hallermann-Streiff syndrome include a small, wide head with a prominent forehead, the characteristic small jaw and mouth with a pinched nose, cataracts, small eyes, dental abnormalities,

sparse or absent hair, thin skin, and short stature. X rays of the bones of the body may be helpful in establishing a diagnosis of Hallermann-Streiff syndrome because there are characteristic changes evident in the bones of individuals with this condition. There is no laboratory test which can be done to confirm the diagnosis. Genetic testing to identify the specific genetic alteration causing the condition is not available since the gene for Hallermann-Streiff syndrome has not been identified. Testing for Hallermann-Streiff syndrome in an unborn baby has not been done. It may be possible to detect the abnormal head shape and small chin on ultrasound (sound wave picture) of the developing baby but this has not been documented in the literature.

Treatment and management

There is no cure for Hallermann-Streiff syndrome. In general, an individual with Hallermann-Streiff syndrome requires a team of specialized doctors for treating the various problems which can occur. Assessments by a dentist, dental surgeon, and oral-facial surgeon may also be necessary to evaluate the teeth and difficulties caused by the small chin and mouth. An assessment for possible airway problems is essential. Any individual with HallermannStreiff syndrome who shows signs of day time sleepiness or snoring should be referred to a sleep center for proper diagnosis and treatment of possible obstructive sleep apnea. Treatment for this condition may include surgical procedures such as making a hole in the trachea through the neck to relieve whatever is obstructing the breathing (tracheotomy). Other surgical treatments may include advancing the chin, reducing the size of the tongue, and/or removing the tonsils. Non-surgical treatments may include medications, providing the individual with an oxygen mask, and modifying his or her sleeping position.

An individual with Hallermann-Streiff syndrome should be examined by an eye specialist (ophthalmologist) for signs and symptoms of eye problems. Surgery for some types of eye problems (cataracts, crossed eyes) may be necessary. Individuals who are blind or at risk to lose their eyesight may benefit from being referred to an association for the blind for guidance and counseling.

An examination by a heart specialist (cardiologist) for possible heart problems and by an immune specialist (immunologist) for possible decreased immune function is also recommended. Some types of heart problems may be treated with medications or may require surgical correction.

For individuals with developmental delay or mental impairment, treatment may include special education, speech therapy, occupational therapy, and physical therapy. Drugs may be used to treat hyperactivity, seizures, and other problems.

Some individuals with Hallermann-Streiff syndrome may seek cosmetic surgery for the various effects the syndrome has on the face and skull. Counseling by psychologists may also help individuals with HallermannStreiff syndrome cope with the psychological impact of having a facial difference.

Individuals with Hallermann-Streiff syndrome and their families may also benefit from genetic counseling for information on the condition and recurrence risks for future pregnancies.

Prognosis

Individuals diagnosed with Hallermann-Streiff syndrome typically have normal intelligence and life-spans when complications of this disorder are properly managed. A major difficulty for individuals with HallermannStreiff syndrome is that the visual problems can often lead to blindness, despite surgery. Lung infections can be life-threatening to these patients and must be treated immediately. Breathing problems are another serious complication resulting from the abnormal skull formation that narrows the upper airway. Although uncommon, developmental delay and mental impairment have been reported in a minority of individuals affected with Hallermann-Streiff syndrome. These individuals with significant mental impairment may require life-long supervision.

Resources

PERIODICALS

Cohen, M. M. “Hallermann-Streiff Syndrome: A Review.”

American Journal of Medical Genetics 41 (1991): 488-499. David, L. R., et al. “Hallermann-Streiff Syndrome: Experience with 15 Patients and Review of the Literature.” Journal of

Craniofacial Surgery 2 (March 1999): 160-8.

ORGANIZATIONS

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 3322373. faces@faces-cranio.org. http://www.faces-cranio

.org/ .

National Eye Institute. 31 Center Dr., Bldg. 31, Room 6A32, MSC 2510, Bethesda, MD 20892-2510. http://www.nei

.nih.gov .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

“Hallermann-Streiff Syndrome.” Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/entrez/dispomim

.cgi?id=234100 (March 9, 2001).

Nada Quercia, Msc, CGC

syndrome Streiff-Hallermann

Hand-foot-uterus syndrome

I Hand-foot-uterus syndrome

Definition

Hand-foot-uterus (HFU) syndrome is characterized by abnormalities of the hand, foot, urinary tract, and reproductive tract.

Description

HFU is a rare genetic condition. Its hallmarks include incurving of the fingers (clinodactyly) and shortened and relocated thumbs. There are also wristand ankle-bone fusions, very small feet, short great toes, uri- nary-tract abnormalities, duplications of the reproductive tract in women, urethral openings on the underside of the penis in men, and curved penis. HFU was first described in 1970. Based on the findings of genital abnormalities in affected males, a 1975 study suggested that the more accurate name of the syndrome would be hand-foot-gen- ital (HFG) syndrome.

Genetic profile

The genetic associations of hand-foot-uterus syndrome are not fully understood. A study in 1997 found mutations (changes) in a gene called HOXA13, located on chromosome #7, which appears to bring about HFU. It seems that most cases of HFU are caused by a mutation in HOXA13, but other genes may be involved.

Demographics

The ethnic origins of individuals affected by HFU are varied. The syndrome also does not appear to be more common in any specific country.

Signs and symptoms

Signs of HFU syndrome are seen in the hands, feet, urinary tract, and reproductive tract. Individuals in the same family may have different effects of varied severity; this is called intrafamilial variability.

Diagnosis

Diagnosis of HFU is usually made from physical examination by a medical geneticist. Studying x rays of the hands, feet, and reproductive tract also aids in diagnosing the syndrome. Although the HOXA13 gene has clearly been associated with the disease, diagnostic genetic testing in affected individuals or in fetuses is not available in 2001.

Treatment and management

There is no specific therapy that removes, cures, or repairs all effects of hand-foot-uterus syndrome.

K E Y T E R M S

Hypospadias—An abnormality of the penis in which the urethral opening is located on the underside of the penis rather than at its tip.

Management of HFU mainly involves the treatment of specific effects. In people with moderate to severe genital, hand, or urinary-tract abnormalities, surgery may be needed.

Prognosis

Since HFU results in a variety of physical signs and symptoms, the prognosis for each affected individual varies. Most people with mild or moderate hand, genital, or foot abnormalities lead normal lives.

Individuals with severe urinaryand/or reproductivetract abnormalities may require many surgeries. Their prognoses depend on the severity of the abnormalities and survival of the surgeries. Some people with severe reproductive-tract abnormalities may have difficulty having children.

Resources

BOOKS

Children with Hand Differences: A Guide for Families. Center for Limb Differences. Grand Rapids, Michigan: Area Child Amputee Center Publications.

ORGANIZATIONS

Cherub Association of Families & Friends of Limb Disorder Children. 8401 Powers Rd., Batavia, NY 14020. (716) 762-9997.

WEBSITES

Hensle, Terry W., Steven Y. Tennenbaum, and Elizabeth A. Reiley. “Hypospadias: What Every Parent Should Know.”http://207.10.206.114/pediatric/hypospadias.html (1997).

OMIM—Online Mendelian Inheritance of Man.

http://www3.ncbi.nlm.nih.gov/Omim/ . Reach. http://www.reach.org.uk .

Dawn A. Jacob, MS, CGC

HANE see Heredity angioneurotic edema

Happy puppet syndrome see Angelman syndrome

HARD E, Warburg syndrome see

Walker-Warburg syndrome

I Harlequin fetus

Definition

The term harlequin fetus is used to describe an extremely severe form of skin disease in which affected infants have thick, plate-like scales all over their bodies. This abnormality is present from birth. It leads to disfiguration of the facial features and limited movement of the arms, legs, fingers, and toes. Most affected infants die during the first several weeks of life, although longerterm survivors have been reported.

Description

Harlequin fetus represents the most severe presentation of inherited ichthyosis. The word ichthyosis, which is derived from the Greek word for fish, is a descriptive term used for a group of inherited disorders in which the skin is markedly thickened, ridged, and cracked. The term “harlequin ichthyosis” is therefore used interchangeably with “harlequin fetus.” Other synonyms over time have included fetal ichthyosis, ichthyosis intrauterina, keratosis diffusa fetalis, congenital diffuse maligna keratoma, and malignant keratosis.

The ichthyoses as a group are due to a variety of underlying metabolic abnormalities. However, the net effect of each abnormality is the same: keratinization, or differentiation of the cells which make up the skin, does not occur normally. The ichthyoses are separated based on their clinical features and the age at which symptoms appear.

Ichthyosis of the newborn refers to those disorders that present either at birth or shortly thereafter. Each newborn ichthyosis may be due to a different genetic abnormality, even when there is some similarity between clinical features. The harlequin fetus, however, is such a distinct and striking disorder that it is rarely confused with other types of ichthyosis. Affected infants have thick, armor-like skin with deep cracks running in different directions all over their bodies. This gives the appearance of diamond-shaped plaques. The word “harlequin” is often used to describe a variegated pattern, or a combination of patches on a solid background of a contrasting color. The severe skin abnormality leads to an open, fishmouth appearance as well as a turning outward of the eyelids. Abnormalities of the internal organs are uncommon but have been reported in some individuals. Death often occurs early due to severe skin infection.

Genetic profile

Harlequin fetus (HF) is inherited as an autosomal recessive condition. As such, a child must inherit two

K E Y T E R M S

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Fetoscopy—A technique by which a developing fetus can be viewed directly using a thin, flexible optical device (fetoscope) inserted into the mother’s uterus.

Trimester—A three-month period. Human pregnancies are normally divided into three trimesters: first (conception to week 12), second (week 13 to week 24), and third (week 25 until delivery).

copies of the HF gene in order to be affected. The presence of one HF gene and one normal gene is consistent with being a gene carrier. Carriers are normal but face a risk of having an affected child with another HF carrier. This risk is 25%, or a one in four chance, that two carriers will each pass on an HF gene to his or her offspring. This risk applies to each pregnancy two carriers have together. Conversely, there is also a 75% chance that two carriers would have an unaffected child.

A gene for harlequin fetus has not yet been identified. It has been speculated that this condition actually represents a varied group of genetic abnormalities, all of which cause a similar clinical picture. This is possible given the number of steps involved in keratinization. If so, it is likely that a different abnormal gene is present in different families.

Demographics

According to the Foundation for Ichthyosis and Related Skin Types (F.I.R.S.T.), harlequin fetus is a very rare form of congenital ichthyosis. There is limited data available to provide a specific incidence figure. However, F.I.R.S.T. provides one estimate as approximately one in every 200,000 individuals. Like other autosomal recessive conditions, HF has been observed more often among the children of consanguineous, or related, couples, such as first cousins, etc. Biologically related individuals are much more likely to carry the same recessive gene and, hence, have offspring with autosomal recessive disorders. Children with HF have, however, also been born to unrelated parents.

fetus Harlequin

Harlequin fetus

Ectropion

Eclabium

Hyperkeratotic plates with deep fissures

Harlequin fetus is a severe and usually fatal form of ichthyosis. This rare skin disorder results in thick, scaly skin; turning out of the eyelids (ectropion) and the lips (eclabium); and deep skin fissures. (Gale Group)

Signs and symptoms

Infants affected with harlequin ichthyosis have a striking and unique appearance at birth. Their skin is unusually thick, off-white in color, with deep, moist cracks running in different directions. The facial appearance is distorted with marked ectropion, or turning outward (eversion) of the eyelids. The lips also appear to be turned outward. This is referred to as eclabium. The external ears are absent or flattened against the side of the head. The hands and feet are also grayish-white in color. The fingers and toes appear malformed, in part due to the thick scale that surrounds them but probably also due to interference with blood flow to the digits from the constrictions. Nails and body hair may be missing. There is limited mobility of arms and legs.

A consistent pattern of associated internal abnormalities has not been identified in infants with HF. However, abnormalities of the central nervous system, kidneys, and lungs have been described in some affected individuals. Short stature has been observed in those infants who have survived the newborn period.

Diagnosis

A diagnosis of HF is possible based on clinical examination after birth. However, in order to confirm a diagnosis of this particular type of ichthyosis, a skin biopsy is strongly recommended. A sample of skin is submitted for electron microscopy. This specific type of technical examination can identify the characteristic changes within the epidermal cells associated with hyperkeratosis, or overgrowth of the stratum corneum. The cells of the stratum corneum contain protein, keratin, and act as a protective barrier along the surface of the body. The process by which new epidermal cells are formed and gradually changed into the cells of the stratum corneum is referred to as keratinization. It is controlled by a number of different metabolic pathways, and an abnormality at any point can theoretically lead to conditions such as ichthyosis or other serious skin abnormalities.

Prenatal diagnosis of harlequin ichthyosis has been accomplished by biopsy of the fetal skin and microscopic analysis of cells from a sample of amniotic fluid. This is usually accomplished by a combination of fetoscopy and amniocentesis. The cellular changes associated with hyperkeratosis begin during the latter part of the second trimester of pregnancy. Prenatal diagnosis of HF has been achieved usually around 21-23 weeks gestation. In 1999, a Japanese group was able to successfully diagnosis HF at the earlier gestational age of 19 weeks in an at-risk family.

Realistically, prenatal diagnosis for HF is available only to those couples that have already had at least one affected child. Based on that family history, the parents will be carriers of a gene for HF and thus at 25% risk of having another affected child. Since a gene for HF has not been identified, carrier testing in the general population is not possible. Also, prenatal ultrasound alone will not detect many of the features associated with HF, particularly in a low-risk patient population.

Treatment and management

Infants with HF have a tendency to be born prematurely. Thus, if a prenatal diagnosis of HF has been made, and the family wishes to continue the pregnancy, the woman and her doctor can devise a plan for more intensive monitoring of the remainder of her pregnancy.

Immediate care of a newborn with HF must focus on the following: temperature control, as well as prevention of dehydration, malnutrition, and infection. Infants who are born prematurely may also have breathing problems requiring placement of a breathing tube.

In 1998, guidelines were published for the care of any newborn with a severe form of congenital ichthyosis, including HF: