Are You Confident of the Diagnosis?
Leukoderma or white skin has many causes. Oculocutaneous albinism in its many forms is caused by blockage of the production of melanin in both the eyes (resulting in visual abnormalities) and skin; ie, resulting in skin that is less pigmented than expected from the person’s parental skin color. There are other mechanisms by which the skin and eyes can be affected related to melanin production. Hermansky-Pudlak syndrome is one such disorder.
Melanin is an indole polymer synthesized from the amino acid tyrosine within a cytoplasmic organelle called a melanosome, which is classifed as a lysosome related organelle. The various forms of oculocutaneous albinism are caused by defects that limit or completely inhibit the production of melanin within the melanosome.
Hermansky-Pudlak syndrome is a disorder in which the abnormality is caused by a defect in the biogenesis of lysosome formation. Because melanosomes are lysosome related organelles, the genetic defects of Hermansky Pudlak affect melanogenesis in the skin. Because all cells have lysosomes, the mutations of Hermansky-Pudlak exhibit dysfunction of other organs as well. Patients with Hermansky-Pudlak syndrome have bleeding diathesis from platelet dysfunction, pulmonary fibrosis, and an intestinal disorder that resembles Crohn’s disease of the colon. A few have cardiomyopathy.
Lysosomes are complex cytoplasmic organelles with various functions. During their formation, specific proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus and then sorted and transported to designated lysosomes. The various forms of Hermansky-Pudlak all involve some dysfunction of protein sorting and/or transport of proteins from the Golgi apparatus to the melanosome, or other lysosome related organelles in platelets, lung and colon. The consequence are an albinoid (albino like) person with a bleeding diathesis and serious disorders of the lung and/or colon.
There are seven types of Hermansky-Pudlak syndrome (Table I), although some of these (types 5, 6, and 7) have been identified in few or even just one individual. The classification is based on identifcation by the specific aberrant gene and its functions. The most common type has been found in northwest villages of Puerto Rico, where the prevalence of this syndrome is about 1 in 1800 individuals. All forms of the syndrome have an autosomal recessive mode of inheritance. Of note, there are inbred mice with homologous (comparable) defects that allow for the study of the molecular and cellular basis of each of these seven types of Hermansky-Pudlak syndrome.
|Type||Clinical Features||Gene Defect||Protein Defect||Geographic Location|
|1||Serious bleeding diathesis and increased risk of pulmonary fibrosis and colitis||HPS1 (10q2.3)||BLOC-3 complex||Northwest Puerto Rico|
|2||Neutropenia and infections||AP3B1 (15q1.5)||AP-3 complex||Non Puerto Rican|
|3||Mild bleeding diathesis; normal lung and GI function||HPS3 (3q24)||BLOC-2 complex||Central Puerto Rico and Ashkenazi Jews|
|4||Relatively severe similar to HPS1||HPS4 (22q11.2-q12.2)||BLOC-3 complex||Non Puerto Rican|
|5||Mild albinism and bleeding||HPS5 (11p15-p13)||BLOC-2 complex||One Turkish child|
|6||No pulmonary or intestinal disorders but epistaxis||HPS6 (10q24.31)||BLOC-2 complex||European and Israeli Bedouins|
|7||Albinism, bleeding and pulmonary symptoms.||HPS7 (6p22.3)||Dysbindein in BLOC-1 complex||One woman|
Characteristic findings on physical examination
The typical patient with the syndrome resembles an albino with oculocutaneous albinism type 2. The amount of pigment in the skin and hair is variable. The skin is light and hair blond to tan or even reddish (Figure 1, Figure 2). Freckles and pigmented macules can be present similar to individuals with oculocutaneous albinism 2. They can exhibit markedly sun damaged skin (see Figure 1). They have all of the ocular defects common to albinism.
Patients with Hermansky-Pudlak have a bleeding diathesis related to platelet dysfunction. It is commonly manifested by bruising, epistaxis, prolonged bleeding from minor cuts and scratches or after minor surgical procedures. The platelets of these individuals lack dense granules which are a type of lysosome related organelle that contain ADP (adenosine diphosphate) and ATP ( adenosine triphosphate). Release of ADP from the dense granules causes aggregation of platlets and clotting. Patients have normal numbers of platelets which are defective. Absence of the granules can be observed by various forms of electron microscopy that also confirms the diagnosis.
In addition, some patients can have a restrictive form of pulmonary fibrosis that can cause their demise. Others have granulomatous inflammation of the distal colon that produces a Crohn’s-like disorder. Both of these disorders are thought to be caused by deposition of a protein ceroid-lipofuschin related to the lysosomal malformation. These latter two complications cause a significant mortality rate in those affected and the average life expectancy is 50 years or less.
Who is at Risk for Developing this Disease?
All forms of Hermansky-Pudlak syndrome are inherited in an autosomal recessive mode. Typically there is a family history of albino-like conditions associated with bleeding diathesis and pulmonary dysfunction and/or colitis. The largest group of affected individuals have type 1 syndrome and live in northwest Puerto Rico, where the incidence is calculated to about 1:1800 population. Type 3 Hermansky Pudlak is also found in central Puerto Rico and in a small number of Ashkenazi Jews. A few individuals living in Europe also have been found to have other types of Hermansky-Pudlak syndrome.
The occurrence and severity of pulmonary and intestinal disease varies between the various types and is most consistently found in type 1. Individuals with type 3 have the mildest form of the disorder. Typically those with type 3 exhibit normal lungs and intestinal track and only a mild bleeding diathesis.
What is the Cause of the Disease?
Melanosomes and dense granules in platelets are lysosome related organelles. Like other lysosomes and lysosome related organelles, their proper formation and function depend on specific proteins synthesized in the endoplasmic reticulum to be sorted and transported into their internal milieu.
The various forms of Hermansky-Pudlak are all manifestations of abnormalities in protein sorting and/or transport so that the lysosome-related organelles lack the protein constituents required for their function. The pulmonary and colon disorders are associated with deposition of a lipid protein complex called lipofuscin or ceroid into the tissues. The seven types are caused by mutations in seven different genes localted on different chromosomes.
Systemic Implications and Complications
Melanin formation in those with Hermansky-Pudlak is deficient during embryogenesis and like those individuals with oculocutaneous albinism, the patients have light blond, tan, or reddish hair and very light skin. Many of these individuals have severe sun damage on exposed skin (see Figure 1) and are susceptible to formation of skin cancers, especially squamous cell carcinomas. Generally these individuals are legally blind and unable to get a valid driver’s license.
The bleeding disorder is not severe but is manifested by prolonged bleeding from minor cuts, excessive menstrual bleeding, bleeding from the gums, or nose bleeds. The pulmonary symptoms and colitis appear during adulthood, age 20 to 30 years, and those with severe pulmonary disease have a shortened life expectancy, often dying before the age of 50 years.
From a dermatologic perspective, treatments of complications of the syndrome such as nonmelanoma skin cancer are treated utilizing standard surgical and topical chemotherapeutic techniques.
Optimal Therapeutic Approach for this Disease
These patients require the assistance of various physicians. From the dermatologist, they require advice about use of sunscreens , clothing, and hats for sun protection. Although sunscreens with spf (sun protective factor) of 25 or 30 is adequate for most individuals, individuals with Hermansky Pudlak or other types of albinism ought to apply sunscreens with spf of 50 or higher. Addition of UVA screens are adviseable. Frequent skin examinations are indicated and sun damage and skin cancers treated as indicated. They require ophthalmological consultation for proper eye wear to give them the best possible vision.
Generally, bleeding is not severe, but a hematologist might confirm absence of platelet dense bodies to confirm the diagnosis. For surgery and for delivery of babies, desmopressin has been used to correct the bleeding diathesis with variable success. The effects of aspirin on platelet functions are different from those associated with Hermansky-Pudlak syndrome. Nevertheless, aspirin should be avoided by those with this disorder.
A geneticist might be consulted to give the patient advice about his/her future children. Pulmonary specialist and gastroenterologists should assist in evaluating the extent and severity of the pulmonary fibrosis and the severity of the colitis. These problems tend to occur in adult life. It is adviseable to have medical evaluations during the teenage years and at intervals thereafter. Because the bleeding can be prolonged after cuts and similar wounds, the patient with this syndrome should avoid occupations or sports that expose him/her to injuries.
A multidisciplinary approach combining the expertise of dermatologists, geneticists, hematologists, opthalmologists, and gastroenterologists is warranted. Severe bleeding has been reported following delivery of a baby to a patient with this disorder. Gynecologists should be informed that the patient has this disorder and the delivery coordinated with a hematologist who can decide if platelet transfusions or administration of desmopressin are indicated.
Sun avoidance and photoprotection cannot be overemphasized. Vitamin levels should be monitored, especially if the child or adult does not have adequate sources of vitamin D-containing foods and dairy products.
Unusual Clinical Scenarios to Consider in Patient Management
Rare complications include melanoma, renal faliure, and cardiomyopathy.
What is the Evidence?
Babadoran, P, Ortonne, J, Nordlund, JJ, Boissy, R, Hearing, V. “Albinoid disorders”. The pigmentary system: physiology and pathophysiology. 2006. pp. 613-9. (This is an excellent review of various albinoid conditions including Hermansky-Pulak syndrome.)
Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, W, Ortonne, JP. “The pigmentary system: physiology and pathophysiology”. 2006. (This is the definitive reference on the basic and clinical science of skin color and its disorders.)
JP, Ortonne, Nordlund, J, Nordlund, JJ, RE, Boissey, VJ, Hearing, RA, King, WS, Oetting, JP, Ortonne. “Mechanisms that cause abnormal skin color”. 2006. pp. 521-38. (An in-depth review of the mechanisms by which skin color can be altered.)
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