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At a glance

Autosomal recessive inherited, tyrosinase-positive oculocutaneous albinism with bleeding diathesis secondary to a platelet storage pool deficiency, and occasionally restrictive lung disease and cardiomyopathy.

Synonym

Oculocutaneous Albinism-Hemorrhagic Diathesis Syndrome.

History

Described in 1959 by F. Hermansky and P. Pudlak, two Czech internists.

Incidence

The highest incidence is found in the Puerto Rican population (1:1,800). A high incidence of a milder variant of HPS has also been described in an isolated high mountain village in the southern Swiss Alps. The estimated incidence in the general population is in the range of 1:500,000 to 1:1,000,000 live births.

Genetic inheritance

Ten different types of Hermansky-Pudlak Syndrome can be distinguished genetically and to some degree, also clinically. The most common and most severe form of this autosomal recessive disorder (HPS Type I) is caused by mutations in the HPS1-gene located on chromosome 10q24.2. It accounts for approximately 75% of all HPS cases from Puerto Rico and 45% of cases in the general population. Mutations in the HPS-3 gene located on chromosome 3q24 are responsible for the remaining quarter of HPS cases in Puerto Rico and for about 20% of cases in the general population. The other gene mutations (HPS-2, HPS-4 to HPS-10) account for only a small number of cases.

The HPS1-gene is involved in the generation of the lysosome-related organelles (LRO) complex-3 (BLOC-3) protein, which is a component of several cytoplasmic organelles, the granular fraction of melanocytes, and platelet-dense bodies. In particular, BLOC-3 helps regulating the transport of proteins to LROs during their formation. LROs are very similar to lysosomes, which digest and recycle cell components. However, LROs perform specialized functions and thus are found only in certain cell types.

Pathophysiology

In HPS, the platelet count is normal or even elevated, but the platelets are dysfunctional due to decreased formation or absence of platelet-dense bodies. These intracellular platelet organelles are rich in serotonin, calcium, phosphate, ATP, and ADP and release their content upon platelet activation and play a crucial role in the second wave of platelet aggregation during clot formation. Because of the lack of dense bodies, this step is compromised, which results in bleeding diathesis. The accumulation of ceroid lipofuscin pigment (a wax-like substance) in lysosomal organelles in body tissues can cause cell damage. The highest concentration of ceroid lipofuscin is found in the kidneys, lung alveolar macrophages, bone marrow, spleen, liver, and large intestine. Moderate amounts occur in the heart, lymph nodes, and other tissues.

Diagnosis

Standard blood tests (including complete blood count, coagulation factor activites, prothrombin time, and activated partial thromboplastin time) fail to identify the platelet defect in HPS. However, electron microscopic examination of the platelets reveals their lack of dense bodies, which is characteristic ...

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