Hermansky-Pudlak syndrome

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Hermansky-Pudlak syndrome

Definition

Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder of melanin production. Melanin is the pigment that gives color to the skin, hair, and eyes. A lack or decrease of pigment in the skin and eyes is called oculocutaneous albinism . HPS is a specific type of oculocutaneous albinism that also includes a bleeding tendency and the storage of ceroid, the byproduct of cell membrane breakdown, in the body's cells.

Description

In 1959, Drs. F. Hermansky and P. Pudlak reported two unrelated people with oculocutaneous albinism who had lifelong bleeding problems. The female died at age 33, and at that time large amounts of pigment were discovered in the walls of her small blood vessels.

Genetic profile

HPS is an autosomal recessive disorder. This means that the disease manifests itself when a person has inherited one nonworking copy of the HPS gene from each parent. Parents who carry the gene for HPS are healthy and have typical skin pigmentation. However, each time they have a child, the chance for the child to have HPS is 25%, or 1 in 4. Unless someone in the family has HPS, most couples are unaware of their risk.

Researchers mapped the HPS1 gene to the long arm of chromosome 10 in 1995, and later identified its exact location in 1996. The protein produced by the HPS gene helps organelles (specialized parts) of the cell's cytoplasm (portion of the cell between the membrane and nucleus) to develop and function normally.

In 1999, another group of researchers identified a mutation, or gene change, in the AP3B1 gene located on chromosome 5 as another cause of HPS. This gene makes AP3, a molecule that helps to sort proteins within the body's cells.

Demographics

In northwest Puerto Rico, HPS is a common inherited disorder. More than 300 persons are affected. The carrier rate is about one in 21. Intermarriage accounts for the high frequency. Researchers have traced the origin of HPS to southern Spain. Cases have also been reported in the Dutch, Swiss, and Japanese. Both sexes are equally affected. However, females will have more lung symptoms than males.

Signs and symptoms

People with HPS have a broad range of skin color from tan to white, reflecting the partial absence of pigmentation. Hair color ranges from brown to white, also reflecting how much pigmentation is present.

Poor vision and eye abnormalities are common in people with HPS. Visual acuity can approach 20/200. Nystagmus, an irregular rapid back and forth movement of the eyes, is also common. The eyes can have an improper muscle balance called strabismus. Sensitivity to bright light and glare, known as photophobia, is a frequent complaint of people with HPS. These visual problems all result from abnormal development of the eye due to the lack of pigment. Just as skin and hair color vary, so will eye color. Red, brown, hazel, and violet eyes have been reported.

A bleeding tendency distinguishes HPS from other types of albinism. People with HPS will bruise easily and bleed for an extended time after dental extractions and surgical procedures. Platelets are the disc-shaped structures in the blood that cause clotting. In people with HPS, the platelets are missing certain internal components that cause them to clump together during the clotting process.

The third finding of HPS is the accumulation of ceroid in certain cells of the body such as bone marrowand the lung. As ceroid collects in the lungs, it makes the affected individual prone to respiratory infections and progressive lung disease that restricts breathing. Some people also complain of colitis (an inflammation of the colon) and diarrhea (loose, watery stools).

Diagnosis

Diagnosis of HPS can be made by specialized platelet testing and molecular testing for the known gene mutations. Very few laboratories are equipped to perform these tests. A person who is suspected to have HPS should consult with a geneticist or genetic counselor to arrange for the appropriate tests. Molecular testing is available for Puerto Rican families who usually have a specific detectable gene alteration, which is a duplication of a small segment of the gene.

Analysis of the person's platelets will determine if they are lacking the critical internal parts, called dense bodies, that help to clot blood. If dense bodies are not present, then HPS is the diagnosis.

For affected people of Puerto Rican ancestry, one unique gene mutation is present. Several other mutations can also be detected, but the lack of a gene mutation does not mean a person does not have HPS, since all mutations have not been identified.

For some families with an affected child, prenatal diagnosis may be possible for future pregnancies. Parents should consult with a genetics specialist when planning a pregnancy.

Treatment and management

For the individual with HPS, vision problems are always present. Many people will meet the legal definition of blindness, but still have enough vision for reading and other activities. Other affected people may be farsighted or near-sighted.

An ophthalmologist, a specialist for the eyes, will help those individuals who have strabismus, a muscle imbalance in the eyes. They can have corrective surgery that will not only improve their physical appearance but also expand their visual field. Surgery, however, cannot restore pigment to the eyes nor correct the optic nerve pathways leading from the brain to the eyes.

Many optical aids can help a person with HPS function better in daily life. Aids like hand-held magnifiers, strong reading glasses, and glasses that have small telescopes fitted in the lens called bioptics can make hobbies, jobs, and other activities easier.

Protection from excessive sunlight is crucial for people with HPS. Sunscreens of the highest rating should be used to decrease the chance for fatal skin cancers. By wearing clothing that blocks as much sunlight as possible, people with HPS can enjoy outdoor activities. A dermatologist, a specialist in skin disorders, can examine the affected person if any changes in skin color or appearance occur. Annual skin check-ups are important.

As people with HPS reach their 30s, they begin to have lung disease. The first sign is difficulty in breathing, followed by a cough that does not bring up sputum, a mixture of saliva and mucus, from the lungs. Gradually, the lungs develop a tough, fibrous tissue that further limits breathing. The inability to breathe is the most common cause of death for people with HPS.

Prolonged bleeding after tooth extraction, nosebleed, or surgery occurs regularly in people with HPS. Before any surgery, treatment with desmopressin, a drug that stimulates clotting activity, can be effective. Also, individuals with HPS should avoid aspirin, because it makes blood less likely to clot.

Prognosis

Many people with HPS may have concerns about their physical appearance and decreased vision. Education about the disorder is important to prevent isolation and stigmatization. Once the visual difficulties are addressed, people with albinism can participate in most activities.

Although many preventive efforts can improve the quality of life for a person with HPS, the progressive lung disease cannot be halted. The inability to breathe generally becomes fatal when the affected person is 40–50 years old.

Resources

BOOKS

Kanski, Jack J. Clinical Ophthalmology: A Systematic Approach. Woburn, MA: Butterworth-Heinemann Medical, 1999.

Landau, Elaine. Living with Albinism (First Book). New York, NY: Franklin Watts, 1998.

PERIODICALS

Dell'Angelica, E.C., et al. "Altered Trafficking of Lysosomal Proteins in Hermansky-Pudlak Syndrome Due to Mutations in the Beta-3A Subunit of the AP-3 Adaptor." Molec. Cell 3 (1999): 11-21.

Depinho, R.A., and K.L. Kaplan. "The Hermansky-Pudlak Syndrome, Report of Three Cases and Review of Pathophysiology and Management Considerations." Medicine 64 (1985): 192-202.

Gahl, W.A., et al. "Genetic Defects and Clinical Characteristics of Patients with a Form of Oculocutaneous Albinism (Hermansky-Pudlak Syndrome)." New England Journal of Medicine 338 (1998): 1258-1264.

Sandberg-Gertzen, H., R. Eid, and G. Jarnerot. "Hermansky-Pudlak Syndrome with Colitis and Pulmonary Fibrosis." Scandinavian Journal of Gastroentology 34 (1999): 1055-1056.

Wijermans, P. W., and D. B. van Dorp. "Hermansky-Pudlak Syndrome, Correction of Bleeding Time by 1-Desamino-8D-Arginine Vasopressin." American Journal of Hematology 30 (1989): 154-157.

Wildenberg, S. C., W. S. Oetting, and C. Almodovar. "Gene Causing Hermansky-Pudlak Syndrome in a Puerto Rican Population Maps to Chromosome 10q2." Human Genetics 57 (1995): 755-765.

ORGANIZATIONS

Hermansky-Pudlak Syndrome Network. 39 Riveria Court, Malverne, NY 11565-1602. (800) 789-9477 or (516) 599-2077. <http://www.medhelp.org/web/hpsn.htm>.

National Organization for Albinism and Hypopigmentation. 1530 Locust St. #29, Philadelphia, PA 19102-4415. (215) 545-2322 or (800) 473-2310. <http://www.albinism.org/infobulletins/hermansky-pudlak-syndrome.html>.