AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Other Problems to be Considered

Tyrosinase-positive oculocutaneous albinism
Tyrosinase-negative oculocutaneous albinism
Ocular albinism
Chediak-Higashi syndrome

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Hair bulb incubation test classifies patients with OCA into tyrosinase negative or tyrosinase positive. All patients with HPS have Ty-pos OCA. Test results should be correlated clinically because some patients may have false-negative results.
• Bleeding time of patients with the syndrome varies from 6-20 minutes. Witkop and coworkers reported that 25% of patients with the syndrome have bleeding time within normal limits.⁴
• Platelet studies: Patients with the syndrome have normal platelets counts. However, platelets in patients with the syndrome show abnormal aggregation with collagen, thrombin, epinephrine, and ADP.
• Platelet electron microscopy remains a clinical method of HPS diagnosis. Platelets of patients with the syndrome show virtual absence of DB. The high calcium content of DB allows their visualization in unfixed, unstained whole mount preparations in the EM. DB are needed for the second phase of platelet aggregation. HPS platelets lack granulophysin/CD63, which is a DB component and lysosomal membrane marker.
• Genetic linkage analysis: Patients with OCA and bleeding tendencies may be referred for genetic linkage analysis. In this way, the mutation leading to the syndrome may be found.
• Desmopressin trial: Some patients with the syndrome have an improved platelet aggregation, upon intravenous or intramuscular desmopressin injection. Patient's response to desmopressin should be evaluated prior to elective surgical procedures.
• Pulmonary function tests: Mutations in the HPS-1 gene are associated with fatal pulmonary fibrosis. Patients with HPS should be evaluated using pulmonary function tests. Forced vital capacity (FVC), forced expiratory volume (FEV), mean total lung capacity, mean vital capacity, and mean diffusing capacity of the lung for carbon monoxide fall as interstitial lung disease progresses in patients with the syndrome.
• Bone densitometry: Previous studies have reported that patients with albinism have a decreased bone density when compared to age-corrected control subjects. Bone densitometry should be completed in patients with OCA.

Imaging Studies

• High-resolution CT (HRCT) chest scan may be requested by a pneumologist in patients with the syndrome. Brantly and coworkers report that 82% of patients with the syndrome have abnormal HRCT chest scans.⁵
• Patients with the syndrome who undergo trauma should have a CT scan to rule out intra-articular or intracranial bleeding.

Other Tests

• Low vision aids: Since patients with the syndrome have low vision, patients may benefit from a low vision aid evaluation. Instruments, such as closed circuit television (CCTV), "traveler's device," scanners, and telescopic lenses, facilitate patients' learning process.
• Intelligence tests: Since patients with the syndrome have low vision, special (for the visually handicapped) intelligence quotient tests should be used to evaluate them.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Reaching a final diagnosis is of utmost importance in the management of patients with OCA. A primary physician should lead a multispecialty group in the management of patients with the syndrome. HPS should be ruled out in all patients with Ty-pos OCA who have Puerto Rican ancestors.

• Early ophthalmic evaluation is needed in patients with a suspected OCA diagnosis. Ophthalmologists will inspect the iris for transillumination and retinal findings compatible with OCA.
• Further, patients with the syndrome may benefit from eye glasses to correct amyloidogenic refractive errors and also from low vision evaluation and rehabilitation.
• Patients with the syndrome have systemic complications associated to accumulation of autofluorescent ceroidlike pigments within macrophages in various tissues, including bone marrow, spleen, liver, colon, lymph nodes, and kidneys.
• A pneumologist should evaluate patients with the syndrome because of the high mortality associated with pulmonary fibrosis.
• Early hematology consultation should be requested when a patient with OCA has a history of easy bruising.
• A geneticist should evaluate patients with the syndrome and their families. The geneticist should lead the search for the HPS-1 gene mutation in patients with HPS. Genetic counseling may benefit patients with the syndrome.

Surgical Care

Systemic complications make surgeries more challenging in patients with the syndrome. Both the surgeon and the anesthesia team should be aware of the potential pulmonary and hematologic complications that may occur when a patient with the syndrome undergoes surgery.

• A preoperative pneumologist consultation is needed. The anesthesia team should be aware that patients may have postoperative pulmonary complications as part of the syndrome.
• Preoperative hematology consultation is advisable prior to elective ocular surgeries. Since patients with the syndrome have bleeding tendencies, intraoperative, perioperative, and postoperative hemorrhages should be prevented and treated. If platelet aggregation improves with desmopressin, it may be administered in the preoperative period. However, sometimes plasmapheresis is needed in the perioperative period.
• Ophthalmologists should try to avoid retrobulbar blocks in patients with the syndrome. Whenever possible, patients with HPS may benefit from general endotracheal anesthesia. Phacoemulsification may help prevent intraoperative and postoperative bleeding in patients with the syndrome. Prolonged bleeding has been reported following strabismus surgery in patients with the syndrome.

Consultations

• Hematology consultation: Because patients with the syndrome have bleeding diathesis, a hematologist should evaluate, diagnose, and co-manage patients with the syndrome.
• Pneumologist consultation: A pneumologist may diagnose and manage pulmonary fibrosis. The pneumologist should lead pulmonary rehabilitation in patients with the syndrome.
• Gastroenterologic evaluation: Patients with HPS may have gastrointestinal findings associated to ceroid deposition. Some patients may have a granulomatous (Crohn-like) colitis. Upper and lower gastrointestinal bleeding has been reported in patients with both HPS type 1 and HPS type 3. A gastroenterologist should treat patients who have gastrointestinal complications as part of the syndrome.
• Dermatology consultation: Patients with the syndrome are at an increased risk of skin malignancies. A dermatologist should periodically evaluate patients with HPS.
• Gynecologic evaluation: A gynecologist should evaluate patients with HPS. Witkop and coworkers reported menometrorrhagia in 60% of female patients with the syndrome.⁴ Up to 46% of patients underwent gynecologic surgical procedures as part of treatment of abnormally abundant menstrual bleeding. No maternal mortalities have been reported in female patients with the syndrome.
• Rheumatologic evaluation: Previous studies have reported osteopenia in patients with albinism. Patients with HPS should have bone densitometry studies. Treatment of osteopenia may benefit patients with the syndrome.

Diet

Osteoporosis has been reported in patients with OCA. Patients with the syndrome may benefit from vitamin D and calcium-enriched diets.

Activity

• Patients with the syndrome are at increased risk of skin malignancies. Therefore, patients with HPS should avoid sun exposure. Further, sunglasses with ultraviolet ray protection may benefit patients with the syndrome.
• To prevent bleeding following trauma, patients with HPS should avoid contact sports.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Several medications have been used to try to diminish bleeding diathesis in patients with the syndrome.

Drug Category: Hemostatic agents

Are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Complications

• Complications associated to bleeding diathesis
• • A hematologist should evaluate patients with HPS since bleeding may complicate ocular surgery.
  • Retrobulbar anesthesia in patients with HPS may lead to lid ecchymosis and/or retrobulbar hemorrhage.
  • Hyphema may occur following anterior segment procedures.
  • Vitreous hemorrhage has been reported during vitreoretinal surgery in patients with the syndrome.
  • Patients with HPS may have prolonged bleeding following strabismus surgery. Patients with the syndrome who respond to desmopressin should use it in the perioperative period.
• Complications associated to ceroid deposition
• • Patients with HPS should obtain a preoperative pulmonary evaluation. The anesthesia team should be aware of bleeding tendencies and potential pulmonary complications as part of the syndrome.
  • Patients with HPS may have pulmonary complications following general endotracheal anesthesia. Further, patients with the syndrome need careful postoperative monitoring.

Prognosis

• Visual prognosis: Most patients with HPS are legally blind. Vision aids may benefit these patients. Presenile cataracts may further reduce vision in patients with the syndrome.
• Multiple blood transfusions increase the risk of blood-borne infections in patients with HPS.
• 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.
• Witkop and coworkers reported that 76% of patients with the syndrome die of causes directly related to the syndrome.⁴ 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.

Patient Education

• Ophthalmic education
• • Health professionals need to educate family members about photophobia, low vision, nystagmus, and strabismus in patients with the syndrome.
  • Opticians 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.
• 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.
• 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).
• 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.
• A social worker may educate patients with the syndrome about the benefits and resources available to citizens with disabilities and special needs.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Bruises.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Diagnosis: In a managed care system, a primary physician needs to lead multiple subspecialists to reach a HPS diagnosis. Having a definite diagnosis may save the patient's life. HPS must be ruled out in every patient who has Ty-pos OCA and was born in Puerto Rico or has Puerto Rican ancestors. Because the syndrome has been reported in other nations, every patient with OCA should be asked about bleeding tendencies.
• Ophthalmologic care: Ophthalmologists need to become familiar with state and federal laws protecting patients with legal blindness. A patient with HPS has statutory blindness if best-corrected central visual acuity is 20/200 or less. Due to legal blindness, patients with the syndrome may benefit from special education, medical, and social benefits granted by the Disability Act. Eyeglasses and low vision aids may benefit patients with the syndrome. Further, in some states, patients with OCA may drive using telescopic lenses.
• Dermatologic care: Since patients with the syndrome are at risk of skin malignancies, dermatologic follow-up care is needed. In some states, patients with skin diseases (eg, OCA) are allowed to enhance visibility tints in car windows. Physicians need to be aware of the local and federal laws regarding these issues.

Special Concerns

• Obstetric care: Since patients with the syndrome have bleeding tendencies, they are at increased risk during labor, cesarean delivery, and perinatal period. A hematology consultation is needed for patients with HPS.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

To all my patients with Hermansky-Pudlak syndrome and their family members: I thank you for allowing me to participate in your multisystemic health care.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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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].
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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].
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Article Last Updated: Feb 20, 2008