Hermansky-Pudlak Syndrome

Updated: Dec 11, 2019
  • Author: Natalio J Izquierdo, MD; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Background

In 1959, Hermansky and Pudlak described two patients with oculocutaneous albinism (OCA) who had bleeding diathesis. Both patients had pulmonary disease. Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of autosomal recessive disorders characterized by tyrosinase-positive oculocutaneous albinism (Ty-pos OCA), bleeding tendencies, and systemic complications associated to lysosomal dysfunction. Individuals with HPS may have pulmonary fibrosis [1] and granulomatous colitis. Several types of HPS are described. In Puerto Rico, both type 1 (HPS type 1) and type 3 (HPS type 3) have been described. [2, 3, 4, 5, 6]

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Pathophysiology

Patients with the syndrome have Ty-pos OCA. As the name implies, both the visual and skin systems are affected. However, patients with the syndrome have a wide variety of phenotypic appearance. Patients with HPS have legal blindness, nystagmus, strabismus, iris transillumination, foveal hypoplasia, and albinotic retinal mid-periphery. Skin biopsies reveal a normal number of melanocytes. Melanosomes are reduced in both melanocytes and keratinocytes.

Patients with HPS have a bleeding tendency associated to poor platelet aggregation. Platelets in patients with the syndrome have abnormal aggregation with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP). Electron microscopy (EM) shows that platelets in patients with the syndrome have a smaller quantity of dense bodies (DB). DB are needed for the second phase of platelet aggregation. They are storage sites for serotonin, calcium, and pyrophosphate. DB are visualized in unfixed, unstained, whole mount EM preparations due to their calcium content or by staining platelets with lead citrate and uranyl acetate.

Defects in organelles from the lysosomal system may lead to HPS. The biogenesis of lysosome-related organelles complex (BLOC) type 1 and 3 are required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet-dense granules. Endomembrane organelle maturation requires cargo delivery via fusion with membrane transport intermediates and recycling of fusion factors to their sites of origin. Melanosomes and other lysosome-related organelles obtain cargoes from early endosomes, but the fusion machinery involved and its recycling pathways are unknown. Dennis et al suggest that vesicle-associated membrane protein (VAMP7) mediates fusion of BLOC-1–dependent transport carriers with melanosomes and that soluble attachment protein receptor (SNARE) recycling from melanosomes is a critical BLOC-3–dependent step. These findings explain the hypopigmentation phenotypes associated with BLOC-1 and BLOC-3 deficiency in patients with the HPS variants. [7]

Systemic complications in HPS are associated to accumulation of a ceroid-like substance in lysosomes of a variety of tissues. Ceroid deposition in patients with HPS has been associated with pulmonary fibrosis, granulomatous enteropathic disease, and renal failure. This lysosomal defect has been reported in reticuloendothelial cells, bone marrow, and lung macrophages.

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Epidemiology

Frequency

United States

The various types of HPS are rare genetic diseases worldwide.

In Puerto Rico, 5 out of 6 patients with OCA have HPS type 1. For this reason, in Puerto Rico, a patient with OCA has the HPS until proven otherwise. If a patient in the continental United States has OCA and Puerto Rican family members, the HPS must be ruled out.

HPS type 1 is the most common single gene disorder in Puerto Rico. It is most prevalent in the northwestern quadrant of the island. Epidemiologic studies report that in this region, 1 out of 1,800 persons has the syndrome. In this area, approximately 1 out of 21 persons carries the gene encoding for HPS type 1. On the other hand, HPS type 3 is more prevalent in the central mountainous region of the Caribbean island.

International

The syndrome has been described in non-Puerto Rican patients of Hispanic descent in the United States. [8] Patients with the various types of the HPS have been reported in other nations, including Holland, the United Kingdom, and Mexico. Further, it has been reported among Jews.

Mortality/Morbidity

Clinical studies show that over 70% of patients with HPS die of causes directly related to the syndrome. Systemic complications of the syndrome lead to an average patient survival age of 30-50 years. Death usually results from complications, such as pulmonary fibrosis in more than 50% of patients with the syndrome; hemorrhagic episodes in over 15% of patients with the syndrome; and granulomatous colitis in 15% of patients with the syndrome.

Clinical studies have reported that most patients with the syndrome are legally blind. Best-corrected visual acuity in patients with the syndrome ranges from 20/60 to 20/400.

Patients with HPS have skin diseases. Clinical studies report that 80% of patients with HPS have freckles or lentigines. Solar keratoses, squamous cell, and basal cell carcinoma have been reported.

Sex

No sexual predilection exists, as the syndrome has an autosomal recessive inheritance pattern.

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Prognosis

Visual prognosis: Most patients with HPS are legally blind. Low vision aids may benefit these patients. Presenile cataracts may further reduce vision in patients with the syndrome.

Pulmonary fibrosis is the most common cause of morbidity and mortality in patients with the syndrome. Pulmonary complications shorten the life span in patients with HPS.

Multiple blood transfusions increase the risk of blood-borne infections in patients with HPS.

Witkop and co-workers reported that 76% of patients with the syndrome die of causes directly related to the syndrome. [9]  The leading cause of death was pulmonary fibrosis in 50% of patients. Up to 13% of patients died from hemorrhagic episodes. Another 13% of patients with the syndrome died from sequelae of granulomatous enteropathic disease.

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Patient Education

A social worker may educate patients with HPS about the benefits and resources available to citizens with disabilities and special needs.

Ophthalmic education

Health professionals need to educate both patients with the syndrome and family members about photophobia, low vision, nystagmus, and strabismus.

Health professionals may educate patients with HPS about the benefits of protective sunglasses. Sunglasses decrease photophobia in patients with the syndrome. Sunglasses with ultraviolet protection diminish the deleterious effect of ultraviolet rays on the eye. Further, blue blockers, yellow tint, or polarized glasses may decrease photophobia in patients with HPS.

Low vision aids benefit patients with the syndrome. Parents should learn about telescopic lenses, high-contrast school materials, and font magnifiers.

Pulmonary fibrosis

Patients with HPS should be educated about the pulmonary complications of the syndrome. Education should stress the importance of adherence to medical care. Some patients with the syndrome may need cardiopulmonary rehabilitation.

Bleeding diathesis

Parents of patients with the syndrome should be warned about the potential complications associated to bleeding diathesis. Patients with HPS should avoid using medications containing aspirin and its derivatives. Further, education should emphasize trauma prevention (eg, avoiding contact sports).

Skin care

Early skin care education should be provided to parents and patients with HPS. Health professionals should educate them about skin lesions. Education should emphasize potential skin malignancies associated to sunlight exposure. Further, parents of patients with the syndrome should learn about skin care products and sun protection factors.

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