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

ers, increased sweating (hyperhidrosis) is often noticed in these areas. Similarly, because of an undergrowth of skin in other parts of the body, many individuals affected with Goltz syndrome do not sweat normally (hypohidrosis) throughout the rest of their bodies.

Additionally, individuals affected with Goltz syndrome may present patches of hair loss on both their scalps and in their pubic regions. The teeth of Goltz syndrome patients are often malformed, mispositioned, or absent, and cavities are commonplace because of missing or incomplete tooth enamel.

Unusual bone formations are also associated with Goltz syndrome. Missing or extra fingers or toes, webbed fingers or toes, permanently bent fingers or toes, and fusion of bones in the fingers or toes have all been observed in Goltz syndrome. Other skeletal abnormalities such as curvature of the spine, underdevelopment or a protrusion of the lower jaw, and fused vertebrae may also be present.

Individuals diagnosed with Goltz syndrome are likely to exhibit facial asymmetry, underdeveloped ears, wide-set eyes, and a pointed chin. Hearing loss, either developed or from birth, is frequently experienced by individuals affected with Goltz syndrome due to the underdevelopment of the ears. Many eye abnormalities have been seen in those affected with Goltz syndrome. These range from missing eyes (anophthalmia) and incomplete formation of the eye (coloboma) to clouding of the cornea, drooping eyelids, and crossed eyes. The mucous membranes of the nose and throat may also be affected. Mental retardation has been observed in some, but not all, cases.

Diagnosis

Goltz syndrome is generally diagnosed by the presence of the characteristic skin abnormalities coupled with the characteristic fatty deposits in the gums, lips, armpits, vagina, or anus. It is distinguished from the other possible ectodermal dysplasias by the lack of pigmentation of the skin in some of the affected areas, the abnormal sweating experienced by those individuals affected, the lack of cysts in the eyes, and the presence of tear ducts. The papillomas in the genital areas are often misdiagnosed as genital warts, but Goltz syndrome patients will test negative for human papillomavirus (HPV), the cause of the common genital wart. Prenatal diagnosis is not yet available, but connection to the Xp22.3 locus makes genetic testing for this dominant condition potentially possible. In families with a child affected by Goltz syndrome, a skin test on the parents should be conducted to evaluate the potential risk of a second child being born affected with this syndrome.

K E Y T E R M S

Anopthalmia—A medical condition in which one eye is missing.

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

Coloboma—A birth defect in which part of the eye does not form completely.

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

Dermis—The layer of skin beneath the epidermis.

Ectodermal dysplasia—A hereditary condition that results in the malformation of the skin, teeth, and hair. It is often associated with malfunctioning or absent sweat glands and/or tear ducts.

Epidermis—The outermost layer of the skin.

Hyperhidrosis—Excessive perspiration that may be either general or localized to a specific area.

Hypohidrosis—Insufficient perspiration or absent perspiration which may be either general or localized to a specific area.

Hypoplasia—Incomplete or underdevelopment of a tissue or organ.

Oligodactyly—The absence of one or more fingers or toes.

Papilloma—Any benign localized growth of the skin and the linings of the respiratory and digestive tracts. The most common papilloma is the wart.

Treatment and management

The treatment and management of Goltz syndrome varies according to symptoms observed. Dermatological treatments such as skin creams and more targeted treatments are usually indicated. Some affected individuals will require dental work or surgery. Others will need respiratory therapies to keep the nose and throat clear. Certain skeletal deformations seen in Goltz syndrome patients may be corrected by orthopedic surgery. Because of the associated abnormal sweating patterns, those with Goltz syndrome should not be exposed to heat and should avoid heavy exercise.

Prognosis

Goltz syndrome is thought to be almost always lethal in males. Even so, a male patient as old as 68 has been

syndrome Goltz

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

495

Greig cephalopolysyndactyly

Papules, small raised sections of skin, such as that shown on this patients arm are characteristic of Goltz syndrome.

(Custom Medical Stock Photo, Inc.)

reported in the medical literature. In females, a full life expectancy is possible if medical treatment is followed.

Resources

PERIODICALS

Buchner, S., and P. Itin. “Focal Dermal Hypoplasia in a Male Patient: Report of a Case and Histologic and Immunohistochemical Studies.” Archives of Dermatology (August 1992): 1078-82.

Lee, I., et al. “Electronmicroscopic Observation of the Basement Membrane Zone in Focal Dermal Hypoplasia.” Pediatric Dermatology (January-February 1996): 5-9.

Mendez, P., M. Vega, and A. Mosqueda. “Mucosal Lesions in Focal Dermal Hypoplasia Syndrome.” Medecina Oral (April 1999): 366-71.

ORGANIZATIONS

Ectodermal Dyplasia Society. 108 Charlton Lane, Cheltenham, GlosGL53 9EA. UK http://www.ectodermaldysplasia

.org .

National Foundation for Ectodermal Dysplasias. PO Box 114, 410 E Main, Mascoutah, IL 62258-0114. [phone]. Fax: [phone]. http://www.nfed.org .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

WEBSITES

“Focal Dermal Hypoplasia.” Online Mendelian Inheritance in

Man. http://www.ncbi.nlm.nih.gov/entrez/dispomim

.cgi?id=305600 (05 February 2001).

“Focal Dermal Hypoplasia.” Reader’s Digest Health.http://rdhealth . com/kbase/nord/nord926 . htm (February 5, 2001).

Paul A. Johnson

Goltz-Gorlin syndrome see Goltz syndrome

Goniodysgenesis hypodontia, iridogoniodysgenesis with somatic anomalies see Rieger syndrome

Goodman syndrome see Carpenter syndrome

Gordon syndrome see Distal arthrogryposis syndrome

I Greig cephalopolysyndactyly

Definition

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

Description

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

Genetic profile

Greig cephalopolysyndactyly (GCPS) can be found in several generations of a family. It is an autosomal

496	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

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

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

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

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

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

Scientists have used animal models and the fruit fly Drosophila to study the function of the GLI3 gene. The normal function of the GLI3 protein is to bind to the

K E Y T E R M S

Abdominal hernia—Bulging of an organ or tissue through the muscle of the stomach wall.

Chromosome deletion—A missing sequence of DNA or part of a chromosome.

Chromosome translocation—The exchange of genetic material between chromosomes, which can lead to extra or missing genetic material.

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

Polysyndactyly—Having both extra digits (toes, fingers) as well as webbing (syndactyly) between the digits.

Post-axial polydactyly—An extra finger or toe on the outside of the hand or foot.

Pre-axial polydactyly—An extra finger or toe on the inside of the hand or foot.

Syndactyly—Webbing or fusion between the fingers or toes.

DNA helix at specific places. By doing so, it helps to regulate which genes are activated or “turned on.” Many of the mutations identified so far seem to interfere with the protein binding function. In effect, other genes that would normally be activated during development of the embryo may in fact not be turned on.

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

Demographics

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

Signs and symptoms

Most individuals with Greig cephalopolysyndactyly have a large head circumference (the distance as measured around the cranium). The forehead is high and wide, and slightly rounded in front (frontal bossing). This is due to the cranial sutures closing later than normal, causing the bones of the forehead to remain apart. The widen-

cephalopolysyndactyly Greig

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

497

Greig cephalopolysyndactyly

ing of the forehead appears to dip down into the space between the eyes, setting the eyes farther apart than normal. The bridge of the nose is broad and flat. This adds to the impression of distance between the eyes. Many times, the rest of the face will also look broad, almost box-like. The chin is small in comparison. The mouth is wide, and the corners of the mouth may be turned downward. The ears are usually normal. Individuals with GCPS can have a short neck, making it look as if the head rests on the shoulders. Intelligence is usually normal, although a few individuals have had mild learning disabilities.

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

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

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

Diagnosis

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

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

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

Treatment and management

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

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

Prognosis

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

Resources

ORGANIZATIONS

AboutFace International. 123 Edwards St., Suite 1003, Toronto,

ONT M5G 1E2. Canada

FACES: The National Craniofacial Association. PO Box 11082,

Chattanooga, TN 37401. [phone] or [phone].

[e-mail]. http://www.faces-cranio.org/ .

WEBSITES

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

Alliance of Genetic Support Groups.

http://www.geneticalliance.org.htm .

Let’s Face It. http://www.faceit.org .

Kevin M. Sweet, MS, CGC

498	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

I Griscelli syndrome

Definition

Griscelli syndrome is a rare, sometimes fatal disorder that associates partial albinism with immunodeficiency. Partial albinism is characterized by a partial lack of melanin (pigment) in the eyes, hair, and skin. The partial albinism found in patients with Griscelli syndrome is caused by an abnormal melanosome distribution. Immunodeficiency refers to an immune system in which restance to infection is lowered.

Description

In addition to having silvery hair, most people with Griscelli syndrome develop hemophagocytic syndrome, which causes some blood cells in the body to engulf and destroy other blood cells. Hemophagocytic syndrome leads to death unless the patient undergoes a bone marrow transplant.

Some people with Griscelli syndrome are severely impaired neurologically but have no apparent immune abnormalities. Neurologic problems may be spasticity (in which a patient has uncontrolled muscular contractions), rigidity (in which a patient is inflexible or stiff), and convulsions. Through 1994 only 19 patients were reported in the medical literature as having the disorder.

Genetic profile

Griscelli syndrome is an autosomal recessive disorder that sometimes occurs in children with parents who are related by blood. There is evidence that the disorder is caused by mutations in the gene that encodes myosin VA, a protein in muscle tissue. (The gene encoding myosin VA is MYO5A.) The gene associated with Griscelli syndrome has been mapped to the long end of chromosome 15 at location 15q21. A second gene, RAB27A, maps very close to the same region (15q21) as MYO5A.

Demographics

Both males and females are born with Griscelli syndrome.

Signs and symptoms

Griscelli syndrome causes pigmentary dilution of the skin and hair, and clumps of pigment in hair shafts. Griscelli syndrome also causes an accumulation of melanosomes in melanocytes.

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.

Melanin—Pigments normally produced by the body that give color to the skin and hair.

Melanocytes—A cell that can produce melanin.

Melanosomes—Granules of pigment within melanocytes that synthesize melanin.

Peptide—A molecular compound made of two or more amino acids.

Protease—An enzyme that acts as a catalyst in the breakdown of peptide bonds.

People with Griscelli syndrome may also have frequent infections in which pus is present, fever, an abnormal decrease in the number of white blood cells, and a reduction in the number of platelets in the blood.

Diagnosis

Griscelli syndrome can be diagnosed in fetuses in the womb by microscopically examining the hair shaft. After birth, patients are diagnosed with Griscelli syndrome based on the signs and symptoms.

Griscelli syndrome is similar to Chediak-Higashi syndrome. For example, both are autosomal recessive disorders in which partial albinism and immunodeficiency are associated. And patients with either disorder are likely to have frequent infections.

However, patients with Chediak-Higashi syndrome are likely to have giant granules in their leukocytes, a type of white blood cell. And leukocyte-specific protease activity is typically low in patients with Chediak-Higashi sydrome, and typically normal in patients with Griscelli syndrome.

Treatment and management

In patients who have hemophagocytic syndrome associated with Gricselli syndrome, treatment may be in the form of bone marrow transplantation.

Prognosis

The prognosis for babies with Griscelli syndrome is poor without bone marrow transplantation.

syndrome Griscelli

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

499

Griscelli syndrome

Resources

PERIODICALS

Bahadoran, P., et al. “Rab27a. A Key to Melanosome Transport in Human Melanocytes.” Journal of Cell Biology 152 (February 19, 2001): 843-50.

Durandy, A., et al.”Prenatal Diagnosis of Syndromes Associating Albinism and Immune Deficiencies (ChediakHigashi Syndrome and Variant).” Prenatal Diagnosis 13 (1993): 13-20.

Gogus, S., et al. “Griscelli Syndrome: Report of Three Cases.”

Pediatric Pathology and Laboratory Medicine 15 (1995): 309-319.

Griscelli, C., et al. “A Syndrome Associating Partial Albinism and Immunodeficiency.” American Journal of Medicine 65 (1978): 691-702.

Hurvitz, H., et al. “A Kindred with Griscelli Disease: Spectrum of Neurological Involvement.” European Journal of Pediatrics 152 (1993): 402-405.

Klein, C., et al. “Partial Albinism with Immunodeficiency (Griscelli Syndrome).” Journal of Pediatrics 125 (1994): 886-895.

Mancini, A.J., L.S. Chan, and A.S. Paller. “Partial Albinism with Immunodeficiency: Griscelli Syndrome: Report of a Case and Review of the Literature.” Journal of the American Academy of Dermatology 38 (1998): 295-300.

Menasche, G.E., et al. “Mutations in RAB27A Cause Griscelli Syndrome Associated with Haemophagocytic Syndrome.” Nature Genetics 25 (2000): 173-176.

Pastural, E., et al. “Griscelli Disease Maps to Chromosome 15q21 and Is Associated with Mutations in the Myosin-Va Gene.” Nature Genetics 16 (1997): 289-292.

Pastural, E., et al. “Two Genes Are Responsible for Griscelli Syndrome at the Same 15q21 Locus.” Genomics 63 (2000): 299-306.

ORGANIZATIONS

Genetic Alliance. 4301 Connecticut Ave.NW, #404, Washington, DC 20008-2304. (800) 336-GENE (Helpline) or [phone]. Fax: [phone] [e-mail]://www.geneticalliance.org .

WEBSITES

“Griscelli Syndrome.” Online Mendelian Inheritance in Man.

www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=214450 .

Sonya Kunkle

Gronblad-Strandberg-Touraine syndrome see Pseudoxanthoma elasticum

500	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

H

I Haim-Munk syndrome

Definition

Haim-Munk syndrome is an extremely rare genetic disorder similar to Papillon-Lefevre syndrome. Features include callous patches of skin on the palms of the hands and the soles of the feet, long pointy fingers, and degeneration of the tissues that surround and support the teeth.

Description

Haim-Munk syndrome is characterized by red, scaly thick patches of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) that are apparent at birth along with frequent pus-producing (pyogenic) skin infections, overgrowth of the fingernails and toenails (onychogryphosis), and degeneration of the gums and bone surrounding the teeth (periodontosis) beginning in childhood. The severe and ongoing periodontosis usually causes the baby teeth to fall out prematurely, and often results in the loss of the permanent adult teeth as well.

In 1965, researchers Haim and Munk reported findings similar to Papillion-Lefevre syndrome in four siblings from an inbred Jewish family that originated from Cochin, India, on the Malabar Coast and later migrated to Israel. Features that are alike in both Papillion-Lefevre syndrome and Haim-Munk syndrome include skin abnormalities and severe periodontitis. These disorders are considered alternate forms of the same genetic mutation. There are a number of additional features reported in Haim-Munk syndrome that include long, thin, pointed fingers (arachnodactyly), bone loss in the fingers or toes (acroosteolysis), abnormal changes of the nails, and a claw-like deformity of the hands.

Haim-Munk syndrome is also known as Cochin Jewish disorder or congenital keratosis palmoplantaris.

Genetic profile

Haim-Munk syndrome is a homozygous expression of an autosomal recessive trait. Among palmoplantar ker-

atoderma disorders, only Papillon-Lefevre syndrome and Haim-Munk syndrome are associated with the premature loss of teeth. It is suspected that Haim-Munk syndrome could be genetically different from common forms of palmoplantar keratoderma that are linked to the cytokeratin gene families.

Preliminary findings suggest that DNA markers other than keratin genes are responsible for the HaimMunk syndrome. In 1997, genotype data in affected individuals found that the gene mutations in Haim-Munk syndrome were not due to a gene defect in either type I or type II keratin gene clusters on chromosomes 12 and 17, markers common to other palmoplantar keratoderma conditions.

Because Papillon-Lefevre syndrome and HaimMunk syndrome present different symptoms than palmoplantar keratoderma disorders, both genetic syndromes are thought to be related to specific bacterial infections in those with palmoplantar keratoderma.

The cause of Papillon-Lefevre syndrome is a mutation in the cathepsin C gene resulting in periodontal disease and palmoplantar keratosis. Haim-Munk syndrome is thought to be a variant clinical expression of PapillonLefevre syndrome that is caused by defects in the cathepsin C gene as well.

A study in 2000 reported a mutation of cathepsin C (exon 6, 2127A*G) that changes a highly conserved amino acid in the cathepsin C peptide. This suggests that Haim-Munk syndrome and Papillon-Lefevre syndrome are alternate forms of defects in the cathepsin C gene. The study also notes that the basis for the difference in clinical expression (symptoms) of these two syndromes caused by the mutated cathepsin C gene is not known.

Demographics

The estimated occurrence of Papillion-Lefevre syndrome, of which Haim-Munk is an extremely rare variant, is considered one to two persons per million. There appears to be no variance by gender. While PapillionLefevre syndrome cases have been identified throughout

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

501

Haim-Munk syndrome

K E Y T E R M S

Acroosteolysis—Loss of bone tissue at the ends of the fingers and/or toes.

Arachnodactyly—A condition characterized by abnormally long and slender fingers and toes.

Atrophy—Wasting away of normal tissue or an organ due to degeneration of the cells.

Onychogryphosis—Overgrowth of the fingernails and toenails.

Palmoplantar keratoderma—Group of mostly hereditary disorders characterized by thickening of the corneous layer of skin (hyperkeratosis) on the palms and soles as a result of excessive keratin formation (protein in the skin, hair and nails).

Palmoplantar keratosis—A raised thickening of the outer horney layer of the skin on the palms of the hand and the soles of the feet.

Periodontitis—Inflammatory reaction of the tissues surrounding and supporting the teeth that can progress to bone destruction and abscess formation, and eventual tooth loss.

Pes planus—Flat feet.

Pyogenic—Pus forming.

the world, Haim-Munk syndrome has only been described among descendants of an inbred Jewish family originally from Cochin, India, who migrated to Israel.

Signs and symptoms

The two major manifestations of Haim-Munk syndrome are dermatological abnormalities and juvenile periodontitis.

Individuals identified with the Haim-Munk syndrome show more severe skin abnormalities than groups with Papillion-Lefevre syndrome. Extensive palmoplantar hyperkeratosis typically begins within the first two to three years of life. At birth the palms and soles are bright red in color and then progress to a calloused and scaly appearance. As the patient gets older the disease often involves thick scaly patches on the entire front and back area of the hands and feet, as well as the elbows and knees.

A typical pattern of periodontis with Haim-Munk syndrome is as follows: initially the deciduous (baby) teeth appear at the normal time but the gums proceed to swell and bleed. Usually all the deciduous teeth fall out

by age four, the mouth then heals and the secondary teeth begin to appear, severe gingival inflammation develops and the majority, or all, of the permanent teeth often fall out by age 15.

Individuals with Haim-Munk syndrome may also have some of the following signs and symptoms:

•Wasting (atrophy), or thickening, of the nails.

•A deformity of the fingers called arachnodactyly— abnormally long, thin, tapered fingers and toes.

•Lack of normal blood flow to the extremities that results in numbness and tingling in the fingers and/or toes. It also can cause loss of bone tissue at the ends of the fingers and/or toes (acroosteolysis).

•A curve of the bones in the hands causing claw-like features.

•Flat feet (pes planus).

•Recurrent pus-forming (pyogenic) skin infections.

Diagnosis

There are no published diagnostic criteria for HaimMunk syndrome. Researchers use clinical examination of inbred Jewish Cochin descendents to confirm the presence of Haim-Munk. Diagnosis of Papillon-Lefevre syndrome is confirmed by red, thick calloused skin on the palms and soles at birth and dental problems that are usually present by age five.

Affected individuals are diagnosed with Haim-Munk syndrome when all of the following features are present:

•palmoplantar keratoderma

•thick, rough, and scaly patches of skin on the forearms and legs

•severe early onset periodontitis

•arachnodactyly

•abnormal changes of the nails

Radiology is used to view the thin and tapering bone deformities in the fingers and dental problems associated with Haim-Munk syndrome.

Genetic testing can confirm the mutation of the cathepsin C gene. Genotyping for polymorphic DNA markers (D11S1887, D11S1367, and D11S1367) are used to identify the presence of the cathepsin C gene mutations associated with Haim-Munk syndrome.

Treatment and management

Treatments include extraction of the teeth and use of dental prosthesis, or dentures. Medications are also used to treat skin lesions associated with this disorder.

502	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

Prognosis

A normal life span has been reported for individuals with Haim-Munk syndrome. Loss of the baby teeth may occur by age six and loss of the permanent teeth by age 15; however, general health is not impaired and dentures are well tolerated.

Resources

BOOKS

Winter, Robin M., and Michael Baraitser. Multiple Congenital

Anomalies, A Diagnostic Compendium. London: Chapman

and Hall Medical, 1991.

PERIODICALS

Hart, T.C., et al. “Haim-Munk Syndrome and Papillion-Lefevre Syndrome Are Allelic Mutations in Cathepsin C.” Journal of Medical Genetics 37(2000): 88-94.

Hart, T.C., et al. “Localization of a Gene for Prepubertal Periodontitis to Chromosome 11q14 and Identification of a Cathepsin C Gene Mutation.” Journal of Medical Genetics 37 (2000): 95–101.

Stabholz, A., et al. “Partial Expression of the Papillon-Lefevre Syndrome in two Unrelated Families.” Journal of Clinical

Periodontology (1996): 764–69.

WEBSITES

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

Nina B. Sherak, MS, CHES

I Hair loss syndromes

Definition

Hair loss syndromes are a varied group of disorders and conditions characterized by the gradual or sudden loss of large amounts of hair—most often from the scalp, but sometimes from other areas of the body. Hair loss (or baldness) is sometimes referred to as alopecia. Madarosis is the medical term for the loss of eyelashes (ciliary madarosis) or eyebrows (superciliary madarosis).

Genetic factors are the most common cause of alopecia. Although hair loss, unlike some genetic disorders, is not a life-threatening or disabling condition, it often has painful psychological consequences. Good grooming and an attractive appearance are important factors in the contemporary job market as well as interpersonal relationships, and a full head of hair is considered a positive feature. Historically, men have tended to put less weight on their external appearance than women have, but this pattern has changed in the last two decades. Present evidence indicates that men are now as vulnerable to pressures to “look good” as women are, and that hair loss is

a frequent focus of men’s concerns about their looks. American men spend over two billion dollars each year on hair-replacement products.

Description

Hair loss syndromes can be divided into two major categories, those caused by some type of inflammation, and those caused by genetic factors, aging, or medication side effects. The noninflammatory syndromes are subdivided into two groups according to the pattern of hair loss. The inflammatory syndromes are also subdivided into two groups according to the presence or absence of tissue destruction.

Noninflammatory patterned hair loss

ANDROGENETIC ALOPECIA Androgenetic alopecia is the most common hair loss syndrome, covering about 95% of cases of hair loss. It is also referred to as andro- gen-dependent or genetic hair loss. In order to understand this form of alopecia, it is useful to begin with some basic facts about the structure and growth cycle of human hair. Hair is composed primarily of keratin, a tough protein that is also found in the fingernails, toenails, and the outermost layer of skin. Each individual hair consists of a hair follicle, which is a small sac that produces the hair shaft, and the hair shaft itself. The average adult scalp contains about 100,000 hair follicles, the number depending on the natural color of the hair. Brunettes have the highest number of scalp follicles (about 155,000), followed by blondes (140,000) and redheads (85,000). The average adult loses between 70 and 100 scalp hairs per day from ordinary combing, brushing, or shampooing. A loss of more than 150 hairs per day is abnormal.

Human hair differs from the hair of other animals in that its growth cycle is not synchronized; an examination of a group of scalp hairs from the same part of the scalp will show that they are in different phases of growth. There are three phases in the human hair growth cycle. Hairs in the anagen, or growth, stage remain in the follicle during an average period of two to eight years, and grow between a quarter-inch and a half-inch per month. About 90% of scalp hairs are in the anagen phase at any one time. At the end of the anagen phase, the hair enters a brief catagen phase lasting between two and four weeks. During this phase the follicle begins to break down. The catagen phase is followed by a telogen, or resting, phase that lasts between two and four months. Hairs in the telogen phase are shed when the growth phase of the next cycle begins and the new hair shaft pushes out the old hair. About 10% of the hairs on the scalp are normally in the telogen phase. These hairs will regrow about six months after they have been shed.

syndromes loss Hair

G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S

503

Hair loss syndromes

What happens in androgenetic baldness is that the hair growth cycle is affected by the rise in the level of androgens (male sex hormones) in the body that occurs at puberty. Women as well as men produce androgens, although in much smaller amounts. The amount of these hormones does not need to be abnormally high for androgenetic hair loss to occur. Males who have a normal level of androgens and a gene for baldness will develop male pattern hair loss, or MPHL. There are two androgens that contribute to MPHL, dihydrotestosterone (DHT) and testosterone. Testosterone is converted to DHT by an enzyme called 5-alpha-reductase. In men with genes for baldness, the hair follicles in the scalp remove testosterone from circulation and convert it to DHT. The action of DHT over time shortens the duration of the anagen phase of the hair growth cycle and decreases the proportion of the hairs in the anagen phase. As the anagen phase decreases, the hairs produced are shorter in length and thinner in diameter. As a larger percentage of the hairs are in the resting or telogen phase, more are lost during normal grooming. This process of the shortening and thinning of each hair shaft is called miniaturization. Miniaturization is accompanied by the loss of hair pigment production, so that the miniaturized hairs are also lighter in color. The light-colored fine hairs that are left at the end of the miniaturization process are called vellus hairs.

In MPHL, hair loss tends to occur in certain areas rather than being distributed evenly over the head. One common pattern is recession of the hair at the temples, with the man’s hairline moving backward over time in an “M” pattern. The hair at the crown of the head also begins to thin, and may meet the receding hairline so that the remaining hair forms the rough outline of a horseshoe.

In female pattern hair loss, or FPHL, there is an overall thinning of the hair as well as more pronounced hair loss in certain areas of the scalp, usually the crown. Women with FPHL may find that their hairlines recede a little, but rarely to the same extent as happens in men. Androgens play the same role in hair loss in women that they do in men, since the adrenal glands and ovaries secrete small amounts of androgens.

There are other important differences between FPHL and MPHL:

•FPHL generally appears at later ages, in the woman’s late twenties or early thirties, whereas MPHL can affect boys as young as 15.

•FPHL is frequently associated with hormonal changes in women, such as those that occur after childbirth; with the use of birth control pills; or after menopause.

•Women very rarely experience complete loss of hair from a specific area of their scalp due to FPHL. The

process of miniaturization in FPHL affects the hair follicles at random, so that some hairs are unaffected. These normal thick hairs are interspersed among thinner, miniaturized hairs.

TRACTION ALOPECIA Traction alopecia is a noninflammatory patterned hair loss syndrome in which the pattern of loss is related to pulling or friction on specific areas of the scalp. It is usually caused either by hair styles in which the hair is pulled into tight braids or held too tightly by rubber bands, or by frequent use of electronic headsets (e.g., Walkman radios, hands-free telephones, etc.) for long periods of time. The tension or rubbing damages the hair shafts and hinders the growth of new hair. In some cases the use of tight hair rollers at night or frequent use of blow dryers on high settings contributes to hair loss from traction alopecia.

TRICHOTILLOMANIA Trichotillomania is a psychiatric disorder that results in patterned hair loss. It is characterized by recurrent episodes of pulling or tugging at the hair in order to relieve stress or tension. The most commonly affected areas are the scalp, the eyebrows, and the eyelashes, although some patients with the disorder pull at hair elsewhere on the body. Trichotillomania can usually be differentiated from other hair loss syndromes by laboratory study of a hair sample.

Noninflammatory diffuse hair loss

TELOGEN EFFLUVIUM Telogen effluvium is a common cause of diffuse hair loss, which means that hairs are shed from all parts of the scalp, not just certain patterned areas. Effluvium is a Latin word that means “outflow,” and refers to the large amounts of hair that may be lost. Persons affected by telogen effluvium may lose as much as 30%-40% of their hair in a short period of time.

Telogen effluvium results from an abnormal alteration of the hair growth cycle, in which large numbers of hairs in the anagen phase suddenly switch into the telogen phase. Within six weeks to four months after this switch, these hairs begin to shed.

There are number of possible causes for telogen effluvium, including:

•Major surgery.

•Pregnancy and childbirth.

•Crash dieting.

•Nutritional deficiencies, including iron deficiency.

•Malabsorption syndrome.

•Infectious diseases accompanied by high fever, such as scarlet fever, early syphilis, or typhoid.

•Hypothyroidism.

504	G A L E E N C Y C L O P E D I A O F G E N E T I C D I S O R D E R S