eMedicine Specialties > Ophthalmology > Extraocular Muscles

Hermansky-Pudlak Syndrome

Author: Natalio J Izquierdo, MD, Associate Professor, Department of Ophthalmology, Medical Sciences Campus, University of Puerto Rico
Coauthor(s): William Townsend, MD, Professor and Director, Department of Pediatric Surgery, Section of Ophthalmology, University Pediatric Hospital, Puerto Rico Medical Center
Contributor Information and Disclosures

Updated: Feb 20, 2008

Introduction

Background

In 1959, Hermansky and Pudlak described 2 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 tendency diathesis, and systemic complications associated to lysosomal dysfunction, such as pulmonary fibrosis. There are several types of HPS. In Puerto Rico, both type one (HPS type 1) and type three (HPS type 3) have been described.

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.

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

Frequency

United States

The various types of HPS are rare genetic diseases worldwide. However, HPS type 1 is the most common single gene disorder in Puerto Rico, being most prevalent in the northwestern quadrant of the island. Epidemiologic studies report that in this region, 1 out of 1,800 persons have the syndrome. In this area, approximately 1 out of 21 persons carry the gene encoding for HPS. On the other hand, HPS type 3 is more prevalent in the central mountainous region of the island.

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

International

Patients with 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.

  • 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.

Clinical

History

Past ocular history in patients with the syndrome should include the following: photophobia, previous eyeglasses, bifocals, eyeglasses tints, low vision aids, amblyopia therapy, eye deviations, and strabismus surgery.

  • Bleeding diathesis: The most important questions when evaluating a patient with OCA are as follows: Do you bruise easily? Does your child bruise easily? Ask about aspirin and derivatives intake.
  • The review of systems should include pulmonary symptoms associated to pulmonary fibrosis, a history of previous pulmonary function tests, and steroid therapy.
  • Evaluate symptoms associated with colitis, such as abdominal pain, diarrhea, lower gastrointestinal bleeding, and previous intestinal surgery.
  • Female patients with the syndrome should be asked about menometrorrhagia, abnormal uterine bleeding, and gynecologic surgery.
  • A history of sun exposure, sunblock application, skin biopsies, and malignancies should be obtained in patients with the syndrome.
  • The family history of patients with the syndrome should include the following: nationality, parental consanguinity, and incidence of HPS in other family members.

Physical

Ocular findings in patients with the syndrome 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 midperiphery. A wide ocular phenotypic variety exists in patients with the syndrome.

  • Best-corrected visual acuity in patients with the syndrome ranges from 20/60 to 20/400 in the Snellen chart. Refractive errors range from high myopia to hyperopia. With the rule astigmatism is common.
  • Patients with the syndrome have congenital nystagmus. The most common types of strabismus found in patients with the syndrome are esotropia and exotropia. Vertical deviations have been reported.
  • Patients with the syndrome 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 (mostly in patients with HPS type 3).
  • Patients with the syndrome have pale optic nerves. All patients have foveal hypoplasia. Vascular architecture varies. Macular transparency (grading of choroidal vessels visibility) ranges from transparent to opaque. All patients have albinotic midperiphery.
  • Previous studies report that patients with the syndrome have poor binocular vision.
  • Studies show that approximately 50% of patients with the syndrome have color vision defects upon HRR pseudoisochromatic plates testing.
  • Visual-evoked potentials show excessive decussation of optic nerve fibers.
  • Patients with the syndrome have a wide variety of phenotypic skin findings. Hair color varies from light blonde to dark brown. Hair and skin pigmentation is darker in patients with HPS type 3. Patients with the syndrome may have skin freckles, lentigines, actinic keratosis, and premalignant and malignant skin lesions.
  • Patients with the syndrome have enamel hypoplasia.
  • Since patients with the syndrome have bleeding tendencies, inspect extremities for ecchymosis.
  • Patients should have a pneumologic evaluation, since more than 50% of patients with the syndrome have pulmonary fibrosis. Auscultate patients for wheezing.

Causes

HPS is a group of autosomal recessive disorders. Therefore, consanguinity and geographical isolation increases the risk of affected offspring. Pseudodominance has been reported in the northwestern quarter of Puerto Rico, because of patients with the syndrome who marry carriers of the HPS genes in geographically isolated regions.

  • Seven genes may lead to HPS in humans. Fukai and coworkers identified an HPS gene, located in chromosome region 10q23.1-23.3 by using a positional cloning approach.1 Genetic analysis of Puerto Rican patients identified a 16-base pair duplication/frameshift within exon 15. This results in a frameshift at codon Pro 496. This gene is called the HPS-1 gene.
  • Puerto Rican patients with HPS type 3 have all been homozygous for a 3,904-bp deletion in the HPS-3 gene, as described by Anikster and coworkers.2
  • However, further studies have shown evidence for locus heterogeneity in Puerto Ricans with the syndrome. Bailin and coworkers suggest that mutations in the adaptor-related code complex (termed AP-3) subunits may lead to some forms of HPS.3 The AP-3 complex facilitates transport of vesicles from the trans-Golgi network and endosomal compartments. AP-3 interacts with tyrosine signals on proteins of lysosomes and other intracellular organelles.

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
References
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References

  1. Fukai K, Oh J, Frenk E, Almodovar C, Spritz RA. Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23.1-q23.3. Hum Mol Genet. Sep 1995;4(9):1665-9. [Medline].

  2. Anikster Y, Huizing M, White J, Shevchenko YO, Fitzpatrick DL, Touchman JW, et al. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nat Genet. Aug 2001;28(4):376-80. [Medline].

  3. Bailin T, Oh J, Feng GH, Fukai K, Spritz RA. Organization and nucleotide sequence of the human Hermansky-Pudlak syndrome (HPS) gene. J Invest Dermatol. Jun 1997;108(6):923-7. [Medline].

  4. Witkop CJ, Nunez Babcock M, Rao GH, Gaudier F, Summers CG, Shanahan F, et al. Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol Asoc Med P R. Aug 1990;82(8):333-9. [Medline].

  5. Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest. Jan 2000;117(1):129-36. [Medline].

  6. DellAngelica EC, Shotelersuk V, Aguilar RC, Gahl WA, Bonifacino JS. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell. Jan 1999;3(1):11-21. [Medline].

  7. Gradstein L, FitzGibbon EJ, Tsilou ET, Rubin BI, Huizing M, Gahl WA. Eye movement abnormalities in hermansky-pudlak syndrome. J AAPOS. Aug 2005;9(4):369-78. [Medline].

  8. Hazelwood S, Shotelersuk V, Wildenberg SC, Chen D, Iwata F, Kaiser-Kupfer MI, et al. Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome. Am J Hum Genet. Nov 1997;61(5):1088-94. [Medline].

  9. Iwata F, Reed GF, Caruso RC, Kuehl EM, Gahl WA, Kaiser-Kupfer MI. Correlation of visual acuity and ocular pigmentation with the 16-bp duplication in the HPS-1 gene of Hermansky-Pudlak syndrome, a form of albinism. Ophthalmology. Apr 2000;107(4):783-9. [Medline].

  10. Izquierdo NJ, Townsend W, Hussels IE. Ocular findings in the Hermansky-Pudlak syndrome. Trans Am Ophthalmol Soc. 1995;93:191-200; discussion 200-2. [Medline].

  11. Oh J, Bailin T, Fukai K. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet. Nov 1996;14(3):300-6. [Medline].

  12. Reynolds SP, Davies BH, Gibbs AR. Diffuse pulmonary fibrosis and the Hermansky-Pudlak syndrome: clinical course and postmortem findings. Thorax. Jun 1994;49(6):617-8. [Medline].

  13. Schachne JP, Glaser N, Lee SH, Kress Y, Fisher M. Hermansky-Pudlak syndrome: case report and clinicopathologic review. J Am Acad Dermatol. May 1990;22(5 Pt 2):926-32. [Medline].

  14. Schinella RA, Greco MA, Cobert BL, Denmark LW, Cox RP. Hermansky-Pudlak syndrome with granulomatous colitis. Ann Intern Med. Jan 1980;92(1):20-3. [Medline].

  15. Simon JW, Adams RJ, Calhoun JH, Shapiro SS, Ingerman CM. Ophthalmic manifestations of the Hermansky-Pudlak syndrome (oculocutaneous albinism and hemorrhagic diathesis). Am J Ophthalmol. Jan 1982;93(1):71-7. [Medline].

  16. Summers CG, Knobloch WH, Witkop CJ Jr, King RA. Hermansky-Pudlak syndrome. Ophthalmic findings. Ophthalmology. Apr 1988;95(4):545-54. [Medline].

  17. Tang J, Tsilou E, Caruso RC, Rubin B, Gahl WA. Bilateral staphylomas in a patient with Hermansky-Pudlak syndrome. Retina. Jan 2005;25(1):99-100. [Medline].

  18. Toro J, Turner M, Gahl WA. Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol. Jul 1999;135(7):774-80. [Medline].

  19. Van Dorp DB, Wijermans PW, Meire F, Vrensen G. The Hermansky-Pudlak syndrome. Variable reaction to 1-desamino-8D-arginine vasopressin for correction of the bleeding time. Ophthalmic Paediatr Genet. Sep 1990;11(3):237-44. [Medline].

  20. Walker M, Payne J, Wagner B, Vora A. Hermansky-Pudlak syndrome. Br J Haematol. Sep 2007;138(6):671. [Medline].

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Further Reading

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Keywords

HPS, oculocutaneous albinism, OCA, tyrosinase-positive oculocutaneous albinism, Ty-pos OCA, blindness, nystagmus, strabismus, iris transillumination, foveal hypoplasia, albinotic retinal midperiphery

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Contributor Information and Disclosures

Author

Natalio J Izquierdo, MD, Associate Professor, Department of Ophthalmology, Medical Sciences Campus, University of Puerto Rico
Natalio J Izquierdo, MD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, International Society for Genetic Eye Diseases and Retinoblastoma, Pan-American Association of Ophthalmology, and Sociedad Puertorriquena de Oftalmologia
Disclosure: Nothing to disclose.

Coauthor(s)

William Townsend, MD, Professor and Director, Department of Pediatric Surgery, Section of Ophthalmology, University Pediatric Hospital, Puerto Rico Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Andrew W Lawton, MD, Medical Director of Neuro-Ophthalmology Service, Section of Ophthalmology, Baptist Eye Center, Baptist Health Medical Center
Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Managing Editor

Brian R Younge, MD, Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

 
 
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