eMedicine Specialties > Dermatology > Diseases of Pigmentation

Hermansky-Pudlak Syndrome

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, New York Medical College-Metropolitan Hospital; Private Practice
Coauthor(s): Ann M Johnson, MD, Pediatric Radiology Fellow, Department of Radiology, The Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Feb 14, 2008

Introduction

Background

Hermansky-Pudlak syndrome (HPS) is a rare group of autosomal recessive diseases whose manifestations include oculocutaneous albinism, bleeding, and lysosomal ceroid storage. Its etiology has been related to defects in 7 genes: HPS1, HPS2 (AP3B1) , HPS3, HPS4, HPS5, HPS6, and HPS7.

The type of albinism associated with HPS is a tyrosinase-positive form. Because patients with HPS can produce some melanin, varying amounts of pigmentation may be present; some patients have blond hair and others have brown hair. Secondary to the albinism that results from HPS, visual defects, including photophobia (light sensitivity), strabismus (crossed eyes), and nystagmus (involuntary eye movements), occur.

The bleeding problems of HPS result from platelet dysfunction and manifest with easy bruisability, nose bleeds, and extended bleeding times.

Pulmonary fibrosis, inflammatory bowel disease, and kidney disease are all symptoms linked to ceroid accumulation in the cells of these organs.

HPS was first noted in 1959 by Hermansky and Pudlak, who described 2 unrelated persons with albinism with lifelong bleeding tendencies and peculiar pigmented reticular cells in the bone marrow as well as in biopsy samples of the lymph node and the liver.

Pathophysiology

HPS results from the abnormal formation of intracellular vesicles. The impaired function of specific organelles indicates that the causative genes encode proteins operative in the formation of lysosomes and vesicles. Four such genes, HPS1, ADTB3A, HPS3, and HPS4, are associated with the 4 known subtypes of HPS: Hermansky-Pudlak syndrome type 1 (HPS-1), Hermansky-Pudlak syndrome type 2 (HPS-2), Hermansky-Pudlak syndrome type 3 (HPS-3), and Hermansky-Pudlak syndrome type 4 (HPS-4).

The HPS1 gene is located on band 10q23. The most common mutation in HPS-1 is the most common mutation in Puerto Ricans. In this variant, a 16–base pair frame shift duplication occurs at exon 15 of the HPS1 gene. In the Swiss variant, a frame shift occurs at codon 322 of the HPS1 gene. The gene products of HPS1 remain to be defined.

HPS-2 is caused by a mutation in the gene encoding the beta-3A subunit of the heterotetrameric AP3 complex (ADTB3A), which resides on chromosome 5. ADTB3A is known to assist in vesicle formation from the trans-Golgi network or late endosome.

Because the expression of the beta-3A subunit is normally ubiquitous, deficiency of the beta-3A subunit leads to a precise phenotype in cells with a large number of intracellular granules (eg, neutrophils, natural killer cells, cytotoxic T lymphocytes, platelets, melanocytes).1 The absence of AP-3 results in a low intracellular content of neutrophil elastase, with the consequence of  neutropenia. Abnormal movement of lytic granules and reduced perforin content in cytotoxic T lymphocytes and natural killer cells define their respective defects in cytolytic activity.1

The HPS3 gene is located on band 3q24. HPS3 is a biogenesis of the lysosome-related organelles complex (BLOC)–2 component.2

HPS4 involves the human homolog of the mouse light-ear gene. It is located at band 22q11.2–q12.2. Its function remains to be defined.

HPS5 (ruby-eye 2) function has been recently defined. Hermansky-Pudlak syndrome type 5 (HPS-5) results from a deficiency of the HPS-5 protein, a component of BLOC-2.3 Cells deficient in the HPS-5 protein maintain early-stage melanosome formation and Pmel-17 trafficking.3  However, tyrosinase and TYRP1 are mistrafficked and thus fail to be efficiently delivered to melanosomes of HPS-5 melanocytes.3 Syrzycka et al4 demonstrated that the pink gene encodes the Drosophila ortholog of the human HPS5 gene.

HPS6 (ruby-eye) have recently been cloned and linked to HPS.
 
A seventh type of HPS (HPS-7) has been described. HPS-7 results from mutant dysbindin, a member of BLOC-1. The sdy mutant mouse expresses no dysbindin protein, owing to a deletion in the gene DTNBP1 (encoding dysbindin); this mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex in both muscle and nonmuscle cells. Dysbindin is a component of BLOC-1, which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted, and cappuccino, which are associated with HPS in mice.5

Studies have revealed that many HPS gene products are stable components of at least 3 distinct, ubiquitously expressed protein complexes, named BLOC-1, BLOC-2, BLOC-3, and BLOC-4. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; BLOC-1, consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. In the cytosol, HPS1 (but not HPS4) is part of yet another complex, termed BLOC-5.

In some investigations, rab geranylgeranyl transferase plays a role in HPS.

Systemic manifestations of HPS involve accumulation of a ceroidlike substance in tissue lysosomes. Ceroid is the name given to the waxlike substance. This lysosomal defect has been reported in reticuloendothelial cells, bone marrow, and lung macrophages. In HPS, particularly the cases in Puerto Rico, ceroid-lipofuscin–like pigment accumulates in lysosomal structures, causing tissue damage, and, upon kidney involvement, this leads to increased urinary dolichol excretion. In addition, clinical evidence of storage disease manifesting with restrictive lung disease, granulomatous colitis, kidney failure, and cardiomyopathy is present. The Swiss variant has fewer systemic manifestations.

Platelets in patients with HPS abnormally aggregate with collagen, thrombin, epinephrine, and adenosine diphosphate (ADP). Electron microscopy shows that platelets in patients with HPS either lack dense bodies (DBs) or have smaller or fewer DBs. DBs are required for the second phase of platelet aggregation. DBs are storage sites for serotonin, calcium, and pyrophosphate.

Falcon Perez et al6 found that the Drosophila ortholog of the HPS5 subunit of BLOC-2 identically mirrors the granule group gene pink (p) that was first investigated in 1910 but had not been identified at the molecular level. The phenotype of pink mutants was worsened by alterations in AP-3 subunits or in the orthologs of VPS33A and Rab38.

The Hermansky-Pudlak HPS1/pale ear gene regulates epidermal and dermal melanocyte development.7

A germline mutation in BLOC1S3/reduced pigmentation results in a novel variation of HPS (HPS8).8

Di Pietro et al9 noted that BLOC-1 interacts with BLOC-2 and the AP-3 complex, facilitating protein trafficking on endosomes, and, when BLOC-1 is defective, HPS results.

Jung et al10 identified a homozygous deletion in the AP3B1 gene that causes HPS, type 2.

Frequency

United States

HPS may be the most frequent single-gene disorder in Puerto Rico. Some have estimated a frequency of about 1 case in 2000 population among Puerto Ricans. Others state that, in Puerto Rico, HPS has a frequency of about 1 case in 1800 population, with an estimated carrier frequency of 1 in 21.

International

HPS is common in an isolated mountain village in the Swiss Alps in the canton Valais. It has also been reported to be more common in persons of Dutch descent. Turkish and Pakistani kindreds have been reported. Cases have been reported in Japan as well.

Mortality/Morbidity

  • Most patients with HPS (about 70%) die from complications related to this syndrome. Pulmonary fibrosis leads to death in almost 50% of patients with HPS, usually in the fourth decade of life. Bleeding leads to death in about 10% of patients with HPS. Other causes of death include intestinal, liver, and kidney failure.
  • Most patients with HPS are legally blind. A lack of pigmentation in the eyes can result in photophobia (light sensitivity), strabismus (crossed eyes), and nystagmus (involuntary eye movements). Best-corrected visual acuity in patients with HPS ranges from 20/60 to 20/400.
  • Patients with HPS manifest with skin pathology related to albinism. Clinical studies report that 80% of patients with HPS have freckles or lentigines. Melanoma, solar keratoses, squamous cell carcinoma, and basal cell carcinoma have been reported.

Race

This disease is most common in Puerto Rico, but it has been reported in Switzerland, Japan, and other countries. Ashkenazi Jews with mild symptoms and mutations in the HPS3 gene have been reported.

Sex

HPS affects the sexes equally.

Age

This disease first manifests in childhood. At this time, albinism is evident. Its systemic manifestations unfold over time and are uncommon in childhood. Inflammatory bowel disease symptom onset occurs at age 12-30 years. The onset of pulmonary fibrosis begins in the third and fourth decades of life. Patients die of pulmonary fibrosis in their fourth or fifth decade of life.

Clinical

History

Because patients with HPS have platelet dysfunction, albinism, and ceroid accumulation, clinical history that relates to these complications must be investigated.

  • When the intestines are infiltrated with ceroid, patients can have diarrhea, weight loss, cramps, and possibly blood in the stool. These manifestations resemble those of inflammatory bowel disease, with the onset of symptoms occurring in patients aged 12-30 years. Most of the patients with HPS-related bowel disease are Puerto Rican. Response to medical therapy is said to be poor. One article reported 2 children, aged 7 years and 3 years, with granulomatous colitis in association with HPS.11 One of these children was Puerto Rican. Hazzan et al12 noted Crohn disease–like colitis, enterocolitis, and perianal disease in a patient with HPS, suggesting that the intestinal pathology of HPS results from the development of classic Crohn disease.
  • Ceroid can infiltrate the pulmonary system as well. When the lungs are impaired in this fashion, shortness of breath and abnormal fatigue with exertion can occur. The disease can progress to pulmonary fibrosis, with scar tissue restricting the inflation of the lungs. Patients should be asked about previous pulmonary function tests and steroid therapy. Thomas de Montpr é ville et al13 noted pulmonary fibrosis in a patient with HPS related to a defect in surfactant. This patient had undergone lung transplantation.
  • HPS impairs vision; thus, patients should be asked about photophobia, previous eyeglasses, bifocals, eyeglass tints, low-vision aids, amblyopia therapy, and strabismus surgery.
  • Patients with HPS are prone to skin cancers; thus, they should be asked about any new skin growths. A history of sun exposure, sunblock application, skin biopsy, and cancers should be obtained from patients.
  • Bleeding diathesis must be investigated. Persons with HPS may have a tendency to bruise easily or to experience frequent nosebleeds or prolonged bleeding. Epistaxis is the most frequent hemorrhagic manifestation. Patients with HPS can have unusual bleeding episodes (eg, heavy menstrual bleeding, bleeding with dental procedures). Patients should be asked about medications that affect bleeding and, thus, should be queried about the use of aspirin and aspirin derivatives. Persons should be asked if their children or parents bleed easily.
  • Women with HPS should be queried about pregnancies and pregnancy complications, menometrorrhagia, abnormal uterine bleeding, and gynecologic surgery.
  • Family history is important in understanding HPS. Patients should be asked where their families originated. Puerto Rican ancestry is important and must be investigated. Parental consanguinity and family incidence of HPS need to be reviewed with patients.
  • In 2003, Iannello et al14 described a new familial HPS clinical variant in 2 sisters, one aged 6 years and the other aged 23 years.
    • They expressed the common symptoms of HPS, but they also had diffuse interstitial pulmonary disease as well as augmented platelet aggregation. They were very susceptible to bacterial infections.
    • Interestingly, Iannello et al14 observed a urinary tract abnormality in the younger HPS sister and a porencephalic cyst in the older HPS sister. These developmental defects have been reported in persons with Cross syndrome (oculocerebral hypopigmentation syndrome), which is a syndrome that has evaded precise definition.
    • These sisters seemed to have an overlapping of the phenotypic manifestations of different rare syndromes. The presence of ceroidlike autofluorescent material in urinary sediment, combined with the histologic aspects and the autofluorescence of oral mucosa biopsy specimens, was consistent with a ceroidlike lipofuscin storage problem.
  • Enders et al15  noted lethal hemophagocytic lymphohistiocytosis in HPS type II.

Physical

Physical findings relate to albinism, which affects the skin and the eyes. Pulmonary fibrosis can also be evaluated on physical examination.

  • Skin findings
    • Patients with HPS commonly have blond hair and pale skin. Some have brown hair and brown eyes.
    • Melanocytic nevi with dysplastic features, acanthosis nigricans–like lesions in the axillae and the neck, and trichomegaly have been reported to occur.
  • Ocular findings
    • Ocular findings in patients with HPS include the following: poor visual acuity, refractive errors associated with with-the-rule astigmatism, strabismus, congenital nystagmus, prominent Schwalbe line, iris transillumination, foveal hypoplasia, and albinotic retinal mid periphery.
    • Best-corrected visual acuity in patients with HPS ranges from 20/60 to 20/400 in the Snellen chart. Refractive errors range from high myopia to hyperopia.
    • Patients with HPS have congenital nystagmus. The most common types of strabismus found in patients with this syndrome are esotropia and exotropia. Vertical deviations have been reported.
    • Patients with HPS have various anterior segment abnormalities that include the following: a prominent Schwalbe line, iris transillumination, and presenile cataracts. Iris transillumination varies from almost total transillumination (pigment found at the collarette) to minimal peripheral transillumination.
    • Patients with HPS have pale optic nerves.
    • Patients with HPS have foveal hypoplasia. Vascular architecture varies. Macular transparency (grading visibility of choroidal vessels) ranges from transparent to opaque. Patients with HPS have albinotic mid periphery.
    • Patients with HPS can have poor binocular vision.
    • Patients with this syndrome have no color vision defects on Ishihara testing.
    • Visual-evoked potentials show excessive decussation of the optic nerve fibers.
  • Pulmonary and cardiac findings
    • Because patients can manifest with impaired lung function, auscultation of patients' lungs is important.
    • Because accumulation of ceroid in the heart can cause cardiomyopathy, auscultation of the heart is important.

Causes

  • HPS is an autosomal recessive disorder. Founder effects (one or several people who originated a population) are believed to cause the clustering of the disease in such places as Puerto Rico. The origin of HPS in Puerto Rico has been traced to a region of southern Spain, and a connection to cases in Holland is possible.
  • Other researchers have identified a second example of a founder mutation causing HPS in central Puerto Rico. They estimated that the large deletion in the HPS3 gene arose from 1880-1890. At that time, the ancestors of 3 of the 6 families with HPS-3 emigrated from the town of Ciales to the towns of Aibonito, Barranquitas, and Naranjito. Each of the 3 families could also trace their ancestry to 1 individual, Calixto Rivera, who brought his relatives to Aibonito and the surrounding area to deforest his land for tobacco growing.
  • Consanguinity and geographical isolation contribute to the continued occurrence of the disease.
  • Pseudodominance has been reported in the northwestern quarter of Puerto Rico and is associated with patients with HPS who marry persons who are carriers.

More on Hermansky-Pudlak Syndrome

Overview: Hermansky-Pudlak Syndrome
Differential Diagnoses & Workup: Hermansky-Pudlak Syndrome
Treatment & Medication: Hermansky-Pudlak Syndrome
Follow-up: Hermansky-Pudlak Syndrome
Multimedia: Hermansky-Pudlak Syndrome
References
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Further Reading

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Keywords

Hermansky-Pudlack syndrome, HPS, oculocutaneous albinism, lysosomal ceroid storage

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, New York Medical College-Metropolitan Hospital; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Ann M Johnson, MD, Pediatric Radiology Fellow, Department of Radiology, The Children's Hospital of Philadelphia
Disclosure: Nothing to disclose.

Medical Editor

Smeena Khan, MD, Private Practice, Adult and Pediatric Dermatology Associates
Smeena Khan, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Jeffrey J Miller, MD, Associate Professor, Department of Dermatology, Penn State University, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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