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

taken early and completed without delay. This minimizes psychological trauma.

In males with hypospadias, one surgery is usually sufficient to repair the defect. With more complicated hypospadias (more than one abnormally situated urethral opening), multiple surgeries may be required. In females with hypospadias, surgical repair is technically more complicated but can usually be completed in a brief interval of time.

Repairing an epispadias is more difficult. In males, this may involve other structures in the penis. Males should not be circumcised since the foreskin is often needed for the repair. Unfortunately, choices may be required that affect the ability to inseminate a female partner. Reproduction requires that the urethral meatus be close to the tip of the penis. Cosmetic appearance and urinary continence are usually the primary goals. Surgery for these defects is successful 70 to 80% of the time. Modern treatment of complete male epispadias allows for an excellent genital appearance and achievement of urinary continence.

In females, repair of epispadias may require multiple surgical procedures. Urinary continence and cosmetic appearance are the usual primary considerations. Urinary continence is usually achieved although cosmetic appearance may be somewhat compromised. Fertility is not usually affected. Repair rates that are similar or better than those for males can usually be achieved for females.

Hypospadias in both males and females is more of a nuisance and hindrance to reproduction than a threat to health. If surgery is not an option, the condition may be allowed to persist. This usually leads to an increased risk of infections in the lower urinary tract.

Prognosis

With adequate surgical repair, most males with simple hypospadias can lead normal lives with a penis that appears and functions in a normal manner. This includes fathering children. Females with simple hypospadias also have normal lives, including conceiving and bearing children.

The prognosis for epispadias depends on the extent of the defect. Most males with relatively minor epispadias lead normal lives, including fathering children. As the extent of the defect increases, surgical reconstruction is generally acceptable. However, many of these men are unable to conceive children. Most epispadias in females can be surgically repaired. The chances of residual disfigurement increase as the extent of the epispadias increases. Fertility in females is not generally affected by epispadias.

Resources

BOOKS

Duckett, John W. “Hypospadias.” Campbell’s Urology. Edited by Patrick C. Walsh, et al. Philadelphia: W. B. Saunders, 1998, pp. 2093-2116.

Gearhart, John P. and Robert D. Jeffs. “Exstrophy-epispadias complex and bladder anomalies.” Campbell’s Urology. Edited by Patrick C. Walsh, et al. Philadelphia: W. B. Saunders, 1998, pp. 1977-1982.

Nelson, Waldo E., et al., ed. “Anomalies of the bladder.” Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 2000, pp. 1639-1642.

Nelson, Waldo E., et al., ed. “Anomalies of the penis and urethra.” Nelson Textbook of Pediatrics. Philadelphia: W. B. Saunders, 2000, pp. 1645-1650.

PERIODICALS

Kajbafzadeh, A. M., P. G. Duffy, and P. G. Ransley. “The evolution of penile reconstruction in epispadias repair: A report of 180 cases.” Journal of Urology (1995), 154 (2 Pt 2): 858-61.

Shapiro, E. H. Lepor, and R. D. Jeffs. “The inheritance of the exstrophy-epispadias complex.” Journal of Urology (1984) 132(2): 308-10.

ORGANIZATIONS

Association for the Bladder Exstrophy Community. PO Box 1472, Wake Forest, NC 27588-1472. (919) 624-9447.http://www.bladderexstrophy.com/support.htm .

Hypospadias Association of America. 4950 S. Yosemite Street, Box F2-156, Greenwood Village, CO 80111. hypospadiasassn@yahoo.com. http://www.hypospadias.net .

Support for Parents with Hypospadias Boys. http://clubs

.yahoo.com/clubs/mumswithhypospadiaskids . University of California–San Francisco. http://itsa.ucsf.edu/

~uroweb/Uro/hypospadias/index.html .

WEBSITES

“Epispadias.” Johns Hopkins University Pediatric Urology Center. Johns Hopkins Exstrophy Database. http://www

.med.jhu.edu/pediurol/pediatric/exstrophy/database/ web4d.html .

Hatch, David A., MD. “Abnormal Development of the Penis and Male Urethra.” Genitourinary Development.

http://www.meddean.luc.edu/lumen/MedEd/urology/ abnpendv.htm .

“Hypospadias.” Atlas of Congenital Deformities of the External Genitalia. http://www.atlasperovic.com/contents/9.htm .

“Hypospadias.” Columbia Presbyterian Hospital.

http://cpmcnet.cpmc.columbia.edu/dept/urology/ pediatric/hypospadias.html .

“Hypospadias.” University of Michigan. http://www.urology

.med.umich.edu/clinic/pediatric/hypospadias.html .

Society for Pediatric Urology. http://www.spu.org/ .

The Penis.com.

http://www.the-penis.com/hypospadias.html .

L. Fleming Fallon, Jr., MD, DrPH

epispadias and Hypospadias

I Ichthyosis

Definition

Derived from the Greek word meaning fish disease, ichthyosis is a congenital (meaning present at birth) dermatological (skin) disease that is represented by thick, scaly skin.

Description

The ichthyoses are a group of genetic skin diseases caused by an abnormality in skin growth that results in drying and scaling. There are at least 20 types of ichthyosis. Ichthyosis can be more or less severe, sometimes accumulating thick scales and cracks that are painful and bleed. Ichthyosis is not contagious because it is inherited.

Genetic profile

Depending on the specific type of ichthyosis, the inheritance can be autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, or sporadic. Autosomal recessive means that the altered gene for the disease or trait is located on one of the first 22 pairs of chromosomes, which are also called “autosomes.” Males and females are equally likely to have an autosomal recessive disease or trait. Recessive means that two copies of the altered gene are necessary to express the condition. Therefore, a child inherits one copy of the altered gene from each parent, who are called carriers (because they have only one copy of the altered gene). Since carriers do not express the altered gene, parents usually do not know they carry the altered gene that causes ichthyosis until they have an affected child. Carrier parents have a 1-in-4 chance (or 25%) with each pregnancy, to have a child with ichthyosis.

Autosomal dominant inheritance also means that both males and females are equally likely to have the disease but only one copy of the altered gene is necessary to

have the condition. An individual with ichthyosis has a 50/50 chance to pass the condition to his or her child.

The last pair of human chromosomes, either two X (female) or one X and one Y (male) determines gender. X- linked means the altered gene causing the disease or trait is located on the X chromosome. Females have two X chromosomes while males have one X chromosome. The term “recessive” usually infers that two copies of a gene—one on each of the chromosome pair—are necessary to cause a disease or express a particular trait. X-linked recessive diseases are most often seen in males, however, because they have a single X chromosome, and no “back-up.” So, if a male inherits a particular gene on the X, he expresses the altered gene, even though he has only a single copy of it. Females, on the other hand, have two X chromosomes, and therefore can carry a gene on one of their X chromosomes yet not express any symptoms. (Their second X, or “backup,” functions normally). Usually a mother carries the altered gene for X-linked recessive ichthyosis unknowingly, and has a 50/50 chance with each pregnancy to transmit the altered gene. If the child is a male, he will have ichthyosis, while if the child is a female, she will be a carrier for ichthyosis like her mother.

X-linked dominant inheritance means that only one gene from the X chromosome is necessary to produce the condition. Mothers with the altered gene are affected, and have a 50/50 chance to pass the condition to any child, who will also have ichthyosis. In somes cases, X-linked dominant inheritance is lethal in males, which means that male fetuses with X-linked dominant ichthyosis are miscarried. This is true for a rare disorder called ConradiHunerman, in which ichthyosis is just one feature.

New mutations—alterations in the DNA of a gene— can cause disease. In these cases, neither parent has the disease-causing mutation. This may occur because the mutation in the gene happened for the first time only in the egg or sperm for that particular pregnancy. New mutations are thought to happen by chance and are therefore referred to as “sporadic,” meaning that they occur occasionally and are not predictable.

Ichthyosis

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.

Amniotic fluid—The fluid which surrounds a developing baby during pregnancy.

Autosomal dominant—A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Dermatologist—A physician that specializes in disorders of the skin.

Emollient—Petroleum or lanolin based skin lubricants.

Keratin—A tough, nonwater-soluble protein found in the nails, hair, and the outermost layer of skin. Human hair is made up largely of keratin.

Keratinocytes—Skin cells.

Keratolytic—An agent that dissolves or breaks down the outer layer of skin (keratins).

Retinoids—A derivative of synthetic vitamin A.

Sporadic—Isolated or appearing occasionally with no apparent pattern.

X-linked dominant inheritance—The inheritance of a trait by the presence of a single gene on the X chromosome in a male or female, passed from an affected female who has the gene on one of her X chromosomes.

X-linked recessive inheritance—The inheritance of a trait by the presence of a single gene on the X chromosome in a male, passed from his mother who has the gene on one of her X chromosomes. She is referred to as an unaffected carrier.

Demographics

The most common form of ichthyosis is called ichthyosis vulgaris (vulgar is Latin for common), and occurs in approximately one person in every 250 and is inherited in an autosomal dominant manner. The most rare types of ichthyosis occur in fewer than one person in

one million and are inherited in an autosomal recessive manner. Ichthyosis occurs regardless of the part of the world the child is from, or the ethnic background of the parents.

Signs and symptoms

The skin is made up of several layers, supported underneath by a layer of fat that is thicker or thinner depending on location. The lower layers contain blood vessels, the middle layers contain actively growing cells, and the upper layer consists of dead cells that serve as a barrier to the outside world. This barrier is nearly waterproof and highly resistant to infection. Scattered throughout the middle layers are hair follicles, oil and sweat glands, and nerve endings. The upper layer is constantly flaking off and being replaced from beneath by new tissue. In ichthyosis, the skin’s natural shedding process is slowed or inhibited, and in some types, skin cells are produced too rapidly.

The abnormality in skin growth and hydration called ichthyosis may present with symptoms at birth or in early childhood. Ichthyosis can itch relentlessly, leading to such complications of scratching as lichen simplex (dermatitis characterized by raw patches of skin). Either the cracking or the scratching can introduce infection, bringing with it discomfort and complications.

Diagnosis

A dermatologist will often make the diagnosis of ichthyosis, based on a clinical exam. However, a skin biopsy, or DNA study (from a small blood sample) is necessary to confirm the diagnosis. Evaluation for associated problems is done by a complete physical medical examination.

For some types of ichythyosis, the abnormal gene has been identified and prenatal testing is available. At present this is true for the autosomal recessive congenital ichythoses, which includes: lamellar ichthyosis (LI), autosomal recessive lamellar ichthyosis (ARLI), congenital ichthyosiform erythroderm (CIE), and non-bullous congenital ichthyosiform erythroderma (NBCIE).

There are four different genes that have been located for the autosomal recessive congenital ichthyoses, however, testing is available for only one gene called transg- lutaminase-1 (TGM1) located on chromosome 14. Once a couple has had a child with ichthyosis, and they have had the genetic cause identified by DNA studies (performed from a small blood sample), prenatal testing for future pregnancies may be considered. (Note that prenatal testing may not be possible if both mutations cannot be identified.) Prenatal diagnosis is available via either

chorionic villus sampling (CVS) or amniocentesis. CVS is a biopsy of the placenta performed in the first trimester of pregnancy under ultrasound guidance. Ultrasound is the use of sound waves to visualize the developing fetus. The genetic makeup of the placenta is identical to the fetus and therefore the TGM1 gene can be studied from this tissue. There is approximately a 1 in 100 chance for miscarriage with CVS. Amniocentesis is a procedure done under ultrasound guidance in which a long thin needle is inserted through the mother’s abdomen into the uterus, to withdraw a couple of tablespoons of amniotic fluid (fluid surrounding the developing baby) to study. The TGM1 gene can be studied using cells from the amniotic fluid. Other genetic tests, such as a chromosome analysis, may also be performed through either CVS or amniocentesis.

Treatment and management

Most treatments for ichthyosis are topical, which means they are applied directly to the skin, not taken internally. Some forms of ichthyosis requires two forms of treatment—a reduction in the amount of scale buildup and moisturizing of the underlying skin. Several agents are available for each purpose. Reduction in the amount of scale is achieved by keratolytics. Among this class of drugs are urea, lactic acid, and salicylic acid. Petrolatum, 60% propylene glycol, and glycerin are successful moisturizing agents, as are many commercially-available products. Increased humidity of the ambient air is also helpful in preventing skin dryness.

Because the skin acts as a barrier to the outside environment, medicines have a hard time penetrating, especially through the thick skin of the palms of the hands and the soles of the feet. This resistance is diminished greatly by maceration (softening the skin). Soaking hands in water macerates skin so that it looks like prune skin. Occlusion (covering) with rubber gloves or plastic wrap will also macerate skin. Applying medicines and then covering the skin with an occlusive dressing will facilitate entrance of the medicine and greatly magnify its effect.

Secondary treatments are necessary to control pruritus (itching) and infection. Commercial products containing camphor, menthol, eucalyptus oil, aloe, and similar substances are very effective as antipruritics. If the skin cracks deeply enough, a pathway for infection is created. Topical antibiotics like bacitracin are effective in prevention and in the early stages of these skin infections. Cleansing with hydrogen peroxide inhibits infection as well.

Finally, there are topical and internal derivatives of vitamin A called retinoids that improve skin growth and

are used for severe cases of acne, ichthyosis, and other skin conditions.

Prognosis

This condition requires continuous care throughout a lifetime. Properly treated, in most cases it is a cosmetic problem. There are a small number of lethal forms, such as harlequin fetus.

Resources

BOOKS

Baden, Howard P. “Ichthyosiform Dermatoses.” In Dermatology in General Medicine. Edited by Thomas B. Fitzpatrick, et al. New York: McGraw-Hill, 1993, pp. 531-544.

Parker, Frank. “Skin Diseases of General Importance.” In Cecil Textbook of Medicine. Edited by J. Claude Bennett and Fred Plum. Philadelphia: W. B. Saunders, 1996, p. 2204.

Sybert, Virginia P. Genetic Skin Disorders. Oxford Monographs on Medical Genetics. No. 33. New York: Oxford University Press, 1997.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. http://www.geneticalliance.org .

Foundation for Ichthyosis and Related Skin Types. 650 N. Cannon Ave., Suite 17, Landsdale, PA 19446. (215) 631-1411 or (800) 545-3286. Fax: (215) 631-1413.http://www.scalyskin.org .

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 .

National Registry for Ichthyosis and Related Disorders. University of Washington Dermatology Department, Box 356524, 1959 N.E. Pacific, Rm. BB1353, Seattle, WA 98195-6524. (800) 595-1265 or (206) 616-3179.http://www.skinregistry.org .

WEBSITES

The Alliance of Genetic Support Groups, Inc.www.geneticalliance.org .

Foundation for Ichthyosis and Related Skin Types (FIRST).www.scaleskin.org .

Immune Deficiency Foundation.www.primaryimmune.org .

National Organization for Rare Disorders (NORD).www.rarediseases.org .

The National Registry for Ichthyosis and Related Skin Types.http://depts.washington.edu/ichreg/ichthyosis.registry .

Catherine L. Tesla, MS, CGC

Ichthyosis bullosa of siemens see Ichthyosis

Ichthyosis

Incontinentia pigmenti

Ichthyosis congenita see Ichthyosis

Ichthyosis-spastic neurologic disorderoligophrenia syndrome see Sjögren

Larsson syndrome

Idiopathic basal ganglia calcification (IBGC) see Fahr disease

I Incontinentia pigmenti

Definition

Incontinentia pigmenti (IP) is an X-linked dominant disorder affecting primarily the skin, hair, teeth and nails (all components of the epidermis). This disease may have been initially described by Garrod in 1906. It was completely characterized by Bloch and Sulzberger in 1928. For this reason, incontinentia pigmenti has also been referred to as Bloch-Sulzberger syndrome.

Description

Incontinentia pigmenti has been traditionally classified into two types: type I and type II. Much debate has occurred over whether or not type I, or sporadic, incontinentia pigmenti is actually the same disease as type II, or familial, male-lethal type, incontinentia pigmenti. The debate on this issue continues in the medical literature in early 2001. The growing consensus is that sporadic (type I) incontinentia pigmenti is not, in fact, the same disease as familial, male-lethal (type II) incontinentia pigmenti. Type II (familial, male-lethal) incontinentia pigmenti is considered to be the “classic” case of incontinentia pigmenti that matches the disease characterized by Bloch and Sulzberger in 1928.

Genetic profile

The locus of the gene mutation responsible for incontinentia pigmenti type II has been mapped to the long end of the X chromosome at gene location Xq28. The affected gene is known as the NEMO gene.

A chromosome is a long chain of deoxyribonucleic acid (DNA), a double-stranded molecule composed of individual units called nucleotides. The two strands that make up a single DNA molecule are held together by a matching (base pairing) of the nucleotides on one strand with the nucleotides on the other strand. Each set of a nucleotide on one strand paired with its nucleotide on the other strand is called a base pair.

A gene is a particular segment of a particular chromosome. Within the segment containing a particular gene there are two types of areas: introns and exons. Introns are sections of the particular chromosomal segment that do not actively participate in the functioning of the gene. Exons are those sections that do actively participate in gene function. A typical gene consists of several areas of exons divided by several areas of introns.

The NEMO gene was completely sequenced by the International Incontinentia Pigmenti Consortium in 2000. The NEMO gene consists of approximately 23,000 base pairs that compose 10 exons. The first exon of this gene, which is the exon that tells this gene to “turn on,” has been found to have three variants; these are designated: 1a, 1b, and 1c.

The NEMO gene is known to partially overlap with the gene responsible for the production of glucose-6- phosphate dehydrogenase (G6PD). Mutations in the G6PD gene cause an under-production of red blood cells (anemia) that results in an insufficient amount of oxygen being delivered to the tissues and organs. Anemia resulting from mutations in the G6PD gene is observed with higher frequencies in Africans, Mediterraneans, and Asians.

The locus of the gene mutation responsible for type I incontinentia pigmenti has been mapped to band Xp11, on the short arm of the X chromosome. Individuals affected with this disorder show many of the signs of incontinentia pigmenti type II, but it is not an inherited condition. Type I incontinentia pigmenti is only exhibited as a sporadic and de novo trait. This means that when an affected individual has the symptoms of type I IP, that individual did not inherit this condition from his or her parents; rather the condition was caused by a mutation that occurred after conception.

Demographics

Incontinentia pigmenti is observed with higher frequencies in Africans, Mediterraneans, and Asians than in other portions of the population. This was originally thought to be due to the greater ability to observe the skin-related symptoms in these individuals. But, with the additional evidence that the NEMO gene and the G6PD gene overlap and that anemia resulting from mutations in the G6PD gene also disproportionately affects these populations, this anecdotal explanation has to be discarded.

More than 95% of all patients diagnosed with IP are female. The occurrence in males is probably due to a spontaneous (de novo) mutation in the NEMO gene that is not as severe as the typical mutation leading to IP or the misdiagnosis of type I IP. Approximately 70% of all IP affected individuals have been found to have the same

mutation in the NEMO gene. In these families, 100% lethality prior to birth is observed in males.

Signs and symptoms

Familial, male-lethal (type II) IP is characterized by progressive rashes of the skin. These have been classified into four stages: the red (erythematic) and blister-like (vesicular) stage; the wart-like (verrucous) stage; the darkened skin (hyperpigmented) stage; and the scarred (atrophic) stage.

The first, or erythematic vesicular, stage consists of patches of red skin containing blisters and/or boils. This condition usually appears in affected individuals at or near birth and is generally localized to the scalp, the arms, and the legs. This stage generally lasts from a few weeks to a few months and may recur within the first few months of life. It rarely recurs after the age of 6 months. This condition is often misdiagnosed as chicken pox, herpes, impetigo, or scabies. Each of these alternative diseases is potentially life-threatening in an infant, so most IP affected infants are treated for one of these diseases before the appropriate diagnosis of incontinentia pigmenti can be made.

The second, or verrucous, stage of IP is characterized by skin lesions that look like adolescent acne (pustules). Upon healing, these pustules generally leave darkened skin. This stage almost exclusively affects the arms and legs, but it may be observed elsewhere. The verrucous stage may occur at birth, which may indicate that the erythematic vesicular stage occurred prior to birth. But, more generally, the second stage of IP skin disorder is observed after the first stage has completed. The verrucous stage tends to persist for months. Rarely it may last for an entire year.

The third, or hyperpigmented, stage is characterized by “marbled skin,” in which darkened areas of skin seem to make swirling patterns across the normal and less pigmented skin. This third stage generally occurs between six and 12 months of life. In 5-10% of affected individuals, this third stage is present at birth. These areas of hyperpigmentation tend to fade with age such that they are barely visible in adults affected with type II IP.

Areas of scarred skin caused by the first two stages characterize the fourth, or atrophic, stage. These scars are often noticeable before the third stage has begun to fade. Adolescents and adults affected with type II IP will generally have pale, hairless patches or streaks, most visibly on the scalp or calves, that are associated with this fourth stage. In many adults affected with IP, the skin abnormalities may have faded to such a significant degree that they are no longer noticeable to the casual observer. Many type II IP affected individuals have a loss or lack of hair

K E Y T E R M S

Chromosome—A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

de novo mutation—Genetic mutations that are seen for the first time in the affected person, not inherited from the parents.

Exon—The expressed portion of a gene. The exons of genes are those portions that actually chemically code for the protein or polypeptide that the gene is responsible for producing.

Hyperpigmentation—An abnormal condition characterized by an excess of melanin in localized areas of the skin, which produces areas that are much darker than the surrounding unaffected skin.

Intron—That portion of the DNA sequence of a gene that is not directly involved in the formation of the chemical that the gene codes for.

Pustule—A pus-filled lesion of the skin that resembles the “pimples” of adolescent acne.

Type I incontinentia pigmenti—Sporadic IP. This disorder is caused by mutations in the gene at Xp11. These mutations are not inherited from the parents, they are de novo mutations. This type of IP probably represents a different disease than type II IP.

Type II incontinentia pigmenti—Familial, malelethal type IP. This type of IP is the “classic” case of IP. It is caused by mutations in the NEMO gene located at Xq28. Inheritance is sex-linked recessive.

on the crown of the head (alopecia). This is suspected to be caused by the underlying skin atrophies of IP.

More than 80% of individuals affected with type II IP have abnormalities of the teeth which include missing teeth, late eruption of both the baby teeth and the adult teeth, unusually pegged or cone-shaped teeth, and deficiencies in the enamel. A smaller percentage (approximately 40%) of affected individuals have irregular formations of the finger and toe nails including missing nails, thickened nails, and ridged or pitted nails. In a small number of cases, the skin lesions associated with the first two stages of skin abnormalities may be present

pigmenti Incontinentia

underneath a nail. In these cases, it is possible for this lesion to develop into a benign tumor that may cause abnormal bone development in the affected finger or toe.

Approximately 30% of all individuals affected with IP experience visual problems. Less than ten percent of type II IP affected individuals have vision problems related to an abnormal growth of blood vessels in the retina which may, if untreated, lead to a detachment of the retina possibly resulting in blindness. These symptoms generally are seen before the affected individual reaches the age of five. Other vision problems that have been observed in type II IP affected individuals include crossed eyes or “wall eyes” resulting from an improper alignment of the eyes (strabismus); partial or complete opaqueness in one or both lens (cataract); and, occasionally abnormally small eyes (microphthalmia). Because of these vision problems, some individuals affected with IP are blind at birth or will go blind if corrective treatment is not sought.

The incidence of breast development anomalies in type II IP affected girls is quite common. It is estimated to be more than ten times that of the general population. These anomalies range from the presence of an extra nipple to the complete absence of breasts.

Approximately 25% of all IP affected individuals have disorders of the central nervous system. These include mental retardation, slow motor development, epilepsy, an abnormally small brain (microcephaly) and increased muscle tone in both legs (spastic diplegia) or in all four limbs (spastic tetraplegia) similar to that seen in the classic case of cerebral palsy.

Diagnosis

The genetic mutation responsible for type I incontinentia pigmenti has been fully mapped and sequenced;

therefore, it is possible to perform a genetic test for the existence of this disease. However, most cases are still diagnosed on a clinical basis.

Clinical diagnosis of type I IP is based primarily on the skin abnormalities seen at birth. These skin problems may still be misdiagnosed as chicken pox or herpes. This misdiagnosis is easily corrected when the affected individual begins to develop the later stages of the skin anomalies. All suspected male infants should have a chromosome test performed to confirm diagnosis.

In older patients with scarred skin, a skin biopsy that shows “loose” melanin (the pigment that produces color in the skin) confirms a diagnosis of IP.

When the skin appears normal, a diagnosis of IP is indicated when an individual shows one or more of the physical symptoms characteristic of IP: teeth abnormalities, missing patches of hair (alopecia), and/or overgrowth and scarring of the retinal blood vessels; and, that individual is female, has two or more IP affected daughters, is the daughter or sister of an affected woman, or has experienced the miscarriage of two or more male fetuses.

The presence of seizures within the first weeks of life indicate central nervous system involvement in the IP affected individual and indicate an extremely high likelihood of subsequent developmental delay.

Treatment and management

Usually no treatment for the skin conditions associated with IP is necessary other than the control of secondary infection that may occur.

In a female newborn where IP is suspected, an eye exam to look for retinal abnormalities, or any of the other possible eye disorders associated with IP, should be conducted within the first few days after birth. Older affected

individuals should have regular eye exams to ensure that retinal abnormalities do not develop. Laser treatments and freezing treatments (cryopexie) are often required to prevent retinal detachment.

Dental treatment is often necessary to repair damaged enamel or for cosmetic reasons in the cases of missing teeth or abnormally shaped teeth.

In cases where there is involvement of the central nervous system, the necessary treatments are on a symptomatic basis. These may include early and continuing intervention programs for developmental delays, anticonvulsants to control seizures, muscle relaxants to control spasticity, and/or surgery to release the permanent muscle, tendon, and ligament tightening (contracture) at the joints that is characteristic of longer term spasticity.

Prognosis

Incontinentia pigmenti is generally fatal in males prior to birth. Females, and the few surviving males, who are affected with IP can expect a normal lifespan if treatment is undertaken to repair or manage any of the associated symptoms.

Resources

PERIODICALS

“Gene discovery should help diagnose incontinentia pigmenti.”

Baylor College of Medicine Press Release (May 24, 2000). Smahl, A., et al. “Genomic rearrangement in NEMO impairs NF-kB activation and is a cause of incontinentia pig-

menti.” Nature (May 25, 2000): 466-72.

ORGANIZATIONS

National Incontinentia Pigmenti Foundation. 30 East 72nd St., New York, NY 10021. (212) 452-1231. Fax: (212) 4521406. http://imgen.bcm.tmc.edu/NIPF .

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

McKusick, Victor A. “#308300 Incontinentia Pigmenti; IP.” [September 16, 1998]. OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbin-post/ Omim/dispmim?308300 .

“Nutrition: Incontinentia Pigmenti.” [June 16, 1998].

Vanderbilt Medical Center Pediatric Digital Interactive

Library. http://www.mc.vanderbilt.edu/peds/pidl/nutrit/ incont.htm .

Paul A. Johnson

Infantile autism see Autism

I Infantile refsum disease

Definition

Infantile refsum disease (IRD) is an inherited disorder characterized by the reduction or absence of cellular peroxisomes and by the accumulation of various unmetabolized substances in the blood and bodily tissues. The disorder arises in infancy and results in visual and hearing impairments, decreased muscle tone, poor growth, mental retardation, decreased coordination, liver damage, and abnormal development of facial structures. There is no cure for the disorder, and treatment is limited to the relief of symptoms.

Description

Living bodies are built up of millions of individual cells specifically adapted to carry out particular functions. Within cells are even smaller structures, called organelles, which perform different jobs and enable the cell to serve its ultimate purpose. One type of organelle is the peroxisome, whose function is to break down waste materials or to process materials that, if allowed to accumulate, would prove toxic to the cells.

Peroxisomes break down various materials through the use of enzymes (proteins that assist in biochemical reactions), and 80 different peroxisomal enzymes have been identified. These enzymes are made by the cell and transported into the peroxisome by a complex process, requiring at least 15 other proteins. In some cases, an absence or deficiency of these proteins results in a failure to transport enzymes into peroxisomes, leaving the cell unable to metabolize various substances. These substances build up in the blood stream and deposit in various tissues, causing damage.

Infantile refsum disease (IRD) results from an abnormality in the transport of enzymes into the peroxisome, manifesting as absent or reduced functioning peroxisomes. As a consequence of peroxisome deficiency, various substances accumulate in the bloodstream, including phytanic acid, pipecolic acid, hydroxycholestanoic acids, glyoxylate, and substances called very-long-chain fatty acids (VLCFA). Mutations in at least two different genes that encode proteins that participate in the transport of enzymes to the peroxisome have been identified in IRD.

IRD is thought to be the mildest form of leukodystrophy, a group of genetic disorders including

Zellweger syndrome and neonatal adrenoleukodystrophy, that damage the fatty sheaths surrounding nerves. In the past, IRD was thought to be a variant of adult refsum disease (also called classical refsum disease) because

disease refsum Infantile

Infantile refsum disease

K E Y T E R M S

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Carrier—A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Cerebellar ataxia—Unsteadiness and lack of coordination caused by a progressive degeneration of the part of the brain known as the cerebellum.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Mutation—A change in the genetic material that may alter a trait or characteristic of an individual or manifest as disease.

Organelle—Small, sub-cellular structures that carry out different functions necessary for cellular survival and proper cellular functioning.

Peripheral neuropathy—Any disease of the nerves outside of the spinal cord, usually resulting in weakness and/or numbness.

Peroxisome—A cellular organelle containing different enzymes responsible for the breakdown of waste or other products.

Retinitis pigmentosa—Progressive deterioration of the retina, often leading to vision loss and blindness.

both disorders demonstrate high levels of phytanic acid due to a peroxisomal abnormality. However, later studies demonstrated that the peroxisomal abnormality in IRD is global, affecting many different enzymes, as opposed to the abnormality in adult refsum disease, where only one specific peroxisomal enzyme is abnormal. Indeed, people with IRD show the accumulation of many substances in their bloodstream in addition to phytanic acid and experience different and more severe symptoms than those experienced by people with adult refsum disease. Currently, the two diseases are regarded as separate and distinct entities with different genetic, biochemical, and clinical profiles.

Genetic profile

IRD is a genetic condition and is inherited or passed on in a family. The genetic abnormality for the disorder

is inherited as an autosomal recessive trait, meaning that two mutant genes are needed to display the disease. A person who carries one mutant gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to their children. A child must inherit the same abnormal gene from each parent to display the disease.

IRD is caused by an abnormality in proteins that assist in the transport of enzymes into the peroxisome. Mutations in the genes for at least two different peroxisomal transport proteins have been identified. The first gene is designated PEX1 (mapped to human chromosome 7, locus 7q21-q22) and encodes for a protein called peroxisome biogenesis factor-1. The second gene is designated PEX2 (mapped to human chromosome 8, locus 8q21.1) and encodes for a protein called peroxisomal membrane protein-3.

Demographics

The combined incidence of all leukodystrophy disorders is estimated to be between 1 in 25,000 and 1 in 50,000. It is unclear whether these disorders are distributed equally among different geographical areas and ethnic groups. Because of some overlap with other leukodystrophy disorders, the incidence and prevalence of IRD in the general population is not clear.

Signs and symptoms

Symptoms associated with IRD arise at birth or very early infancy and affect many different organ systems and tissues, resulting in severe disease. Babies with IRD show decreased muscle tone and a failure to grow at appropriate rates. Characteristic facial features are often present, including prominent forehead and folds at the inner aspect of the eye, flat face and bridge of the nose, and low-set ears. While affected children are able to walk, the gait may be irregular due to abnormalities in muscle coordination.

High levels of unmetabolized substances can deposit in the fatty sheaths surrounding nerves, causing damage and resulting in peripheral neuropathy. Peripheral neuropathy is the term for dysfunction of the nerves outside of the spinal cord, causing loss of sensation, muscle weakness, pain, and loss of reflexes. Nerves leading to the ears can be affected, resulting in hearing loss or deafness. IRD also results in cerebellar ataxia, an abnormality in a specific part of the brain (the cerebellum), resulting in loss of coordination and unsteadiness. In contrast to adult refsum disease, people with IRD have extensive impairments in cognitive function resulting in severe mental retardation.

IRD often affects the eyes, causing retinitis pigmentosa, a degeneration of the retina resulting in poor nighttime vision, followed by loss of peripheral vision and eventually loss of central vision late in the course of the disease. Nystagmus (uncontrollable movements of the eye) may also be present due to related nervous system damage. Other manifestations of IRD include enlargement of the liver, poor digestion, and abnormally low blood cholesterol. Early osteoporosis (decalcifications of the bone) may also develop, leading to bone fractures or compression of the spinal bones.

Diagnosis

IRD is diagnosed though a combination of consistent medical history, physical exam findings, and laboratory and genetic testing. Typically, parents bring newborns to their physicians because of the signs of low muscle tone. Other times, the characteristic facial abnormalities or a failure to grow at appropriate rates is noted. These findings raise suspicion for a genetic syndrome or metabolic disorder, and further tests are conducted.

Laboratory tests reveal several abnormalities. Blood samples from patients with IRD show accumulation of various substances including phytanic acid, pipecolic acid, hydroxycholestanoic acids, glyoxylate, and VLCFA. Other measurements demonstrate low levels of plasmalogen, a substance normally produced by action of the peroxisomal enzymes. Immunoblot tests that measure levels of specific proteins will show deficiencies in many peroxisomal enzymes. Additional studies will reveal abnormal electrical responses from the retina and various nerve groups.

Finally, genetic testing can be preformed. When a diagnosis of IRD is made in a child, genetic testing of the PEX1 and PEX2 genes can be offered to determine if a specific gene change can be identified. If a specific change is identified, carrier testing can be offered to relatives. In families where the parents have been identified to be carriers of the abnormal gene, diagnosis of IRD before birth is possible. Prenatal diagnosis is performed on cells obtained by amniocentesis (withdrawal of the fluid surrounding a fetus in the womb using a needle) at about 16-18 weeks of pregnancy or by chorionic villus sampling (CVS) where cells are obtained from the chorionic villi (a part of the placenta) at 10-12 weeks of pregnancy.

Treatment and management

There is no cure or standard course of treatment for IRD. Currently, treatment of patients has generally involved only supportive care and symptomatic therapy.

Several studies suggest that a diet that is free of phytanic acid can limit symptoms of IRD, but this is not nearly effective as in adult refsum disease. A useful adjunct to dietary treatment is plasmapheresis. Plasmapheresis is a procedure by which determined amounts of plasma (the fluid component of blood that contains the unmetabolized substances) is removed from the blood and replaced with fluids or plasma that are free of accumulated substances. While treatment strategies may mitigate some of the symptoms experienced by the patient with IRD, they do not slow the progression of the disorder.

Experimental studies are underway to investigate whether several different agents can be of additional use. Patients with IRD have reduced levels of docosahexaenoic acid and arachidonic acid that can be corrected with the administration of oral supplements. There are some reports of improvement in symptoms with these therapies, and trials to formally investigate these claims are now in progress. Other scientific laboratories are investigating the usefulness of agents that stabilize peroxisomes in the treatment of IRD, but the experiments are still in their early stages.

Patients with IRD should be seen regularly by a multidisciplinary team of health care providers, including a pediatrician, neurologist, ophthalmologist, cardiologist, medical geneticist specializing in metabolic disease, nutritionist, and physical/occupational therapist. Genetic counseling can help people with IRD, those who are carriers of the abnormal gene, or those who have a relative with the disorder, learn more about the disease, inheritance, testing, and options available to them so they can make informed decisions appropriate to their families.

Prognosis

For patients with IRD, some success has been achieved with multidisciplinary early intervention, including physical and occupational therapy, hearing aids, alternative communication, nutrition, and support for the parents. Although most patients continue to function in the profoundly or severely retarded range, some make significant gains in self-help skills, and a small percentage may reach stable condition in their teens. Despite these few successes, the prognosis for individuals with IRD is poor; death generally occurs in the second decade of life.

Resources

BOOKS

“Peroxisomal Disorders” In Nelson Textbook of Pediatrics. Edited by R. E. Behrman. Philadelphia: W.B. Saunders, 2000, pp. 318-384.

disease refsum Infantile