Hermansky-Pudlak Syndrome 

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

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]

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.

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.

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.

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.

 

Presentation

History

Past ocular history in patients with Hermansky-Pudlak syndrome (HPS)should include the following:

  • Photophobia

  • Previous eyeglasses, bifocals, eyeglasses tints, low vision aids

  • Amblyopia therapy

  • Involuntary eye movements (nystagmus)

  • Eye deviations and

  • Strabismus surgery

Past systemic history in patients with Hermansky-Pudlak syndrome should include the following:

  • Bleeding diathesis: The most important questions when evaluating a patient with oculocutaneous albinism (OCA) are as follows: Do you bruise easily? Does your child bruise easily? Ask about aspirin and its derivatives intake.

  • The review of systems should include pulmonary symptoms associated to pulmonary fibrosis, such as dyspnea upon exertion, a history of previous pulmonary function tests, and steroid therapy.

  • Evaluate symptoms associated with colitis, such as abdominal pain, diarrhea, upper and lower gastrointestinal bleeding, and previous intestinal surgery.

  • Female patients with the syndrome should be asked about menometrorrhagia, abnormal uterine bleeding, complications during labor, cesarean delivery, and/or gynecologic surgery.

  • A history of sun exposure, sunblock application, skin biopsies, and malignancies should be obtained.

The family history of patients with Hermansky-Pudlak syndrome should include the following: nationality, parental consanguinity, and incidence of HPS in other family members.

Physical

A wide ocular phenotypic variety exists in patients with Hermansky-Pudlak syndrome. Ocular findings in these patients include the following:[10, 11, 12]

  • Poor visual acuity: Best-corrected visual acuity in patients with Hermansky-Pudlak syndrome ranges from 20/60 to 20/400 in the Snellen chart.

  • Refractive errors that range from high myopia to hyperopia may be present. With the rule astigmatism is most common in patients with the syndrome.

  • Strabismus: Patients with both horizontal and vertical eye deviations have been reported. The most common types of strabismus found in patients with the syndrome are esotropia and exotropia.

  • Patients with Hermansky-Pudlak syndrome have congenital nystagmus. Periodic alternating nystagmus is most prevalent in patients with the syndrome. A variety of amplitudes and frequencies have beenreported.

  • Patients with Hermansky-Pudlak syndrome have several anterior segment abnormalities, including 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 Hermansky-Pudlak syndrome have foveal hypoplasia. Macular transparency (grading of choroidal vessels visibility) ranges from transparent to opaque. All patients have albinotic mid periphery. Vascular architecture varies.

  • Previous studies report that patients with Hermansky-Pudlak syndrome have poor binocular vision.

  • Studies show that approximately 50% of patients with Hermansky-Pudlak syndrome have color vision defects upon HRR pseudoisochromatic plates testing.

  • Visual-evoked potentials show excessive decussation of optic nerve fibers.

  • Optical coherence tomography in patients with albinism shows that patients with OCA (all types included) have thicker foveas than the general population. This may be due to absence of a foveal pit as part of foveal hypoplasia in patients with OCA. Conversely, patients with OCA have lower macular volumes than the general population. This finding is compatible with loss of retinal nuclear layers in patients with OCA.

Patients with Hermansky-Pudlak 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. The latter have brown hair and iris color.

  • Skin freckles, lentigines, actinic keratosis, and premalignant and malignant skin lesions may also be present in sun exposed areas.

Patients with Hermansky-Pudlak syndrome have several systemic findings:[13, 14, 15, 16]

  • Enamel hypoplasia

  • Since patients with Hermansky-Pudlak syndrome have bleeding tendencies, inspect lower extremities for ecchymosis.

  • Patients should have a pneumologic evaluation, since more than 50% of patients with Hermansky-Pudlak 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.[17] 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.[18]

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.[19] 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.

 

DDx

 

Workup

Laboratory Studies

Hair bulb incubation test classifies patients with OCA into tyrosinase negative or tyrosinase positive. All patients with Hermansky-Pudlak syndrome (HPS) have Ty-pos OCA. Test results should be correlated clinically because some patients may have false-negative results. This test was the standard in the 1990s. Bleeding time of patients with the syndrome varies from 6-20 minutes. Witkop and co-workers reported that 25% of patients with the syndrome have bleeding time within normal limits.[9]

Neither prothrombin time (PT) nor activated partial thromboplastin (aPTT) changes in patients with the syndrome.

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.[20]

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.[21] 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 is advisable 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.[22]

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

Medical Care

Reaching a final diagnosis is of utmost importance in the management of patients with oculocutaneous albinism (OCA). A primary physician should lead a multispecialty group in the management of patients with the syndrome. Hermansky-Pudlak 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 eyeglasses to prevent amblyopia secondary to uncorrected refractive errors (including high astigmatism).

Patients benefit from low vision evaluation and rehabilitation, especially in school-age years.

Patients with the syndrome have systemic complications associated to accumulation of autofluorescent ceroid-like 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 morbidity and early 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 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 for eye surgery as most patients need general anesthesia during procedures. The anesthesia team should be aware that patients may have post-operative pulmonary complications as part of the syndrome.

Pre-operative 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 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

Pneumologist consultation: A pneumologist may diagnose and manage pulmonary fibrosis. The pneumologist should lead pulmonary rehabilitation in patients with the syndrome.

Hematology consultation: Because patients with the syndrome have bleeding diathesis, a hematologist should evaluate, diagnose, and co-manage patients with the syndrome.

Gastroenterologic evaluation: Patients with HPS may have gastrointestinal findings associated to ceroid deposition. Some patients may have gastroduodenitis, procto-colitis, or a granulomatous (Crohn-like) colitis.[23] 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.[9] 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

Since osteoporosis has been reported in patients with OCA, patients with the syndrome may benefit from vitamin D and calcium-enriched diets as needed.

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.

Complications

Complications associated to bleeding diathesis

A hematologist should evaluate patients with Hermansky-Pudlak syndrome (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 anesthesia. Further, patients with the syndrome need careful post-operative monitoring.

 

Medication

Medication Summary

Several medications have been used to try to diminish bleeding diathesis in patients with Hermansky-Pudlak syndrome (HPS).

Hemostatic agents

Class Summary

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

Desmopressin

A synthetic analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone affecting renal water conservation. Indicated for patients with hemophilia A and mild von Willebrand disease to maintain hemostasis. If used preoperatively, administer 30 min prior to scheduled procedure.

 

Questions & Answers

Overview

What is Hermansky-Pudlak syndrome (HPS)?

What is the pathophysiology of Hermansky-Pudlak syndrome (HPS)?

What is the US prevalence of Hermansky-Pudlak syndrome (HPS)?

What is the global prevalence of Hermansky-Pudlak syndrome (HPS)?

What is the morbidity and mortality associated with Hermansky-Pudlak syndrome (HPS)?

What is the sexual predilection of Hermansky-Pudlak syndrome (HPS)?

What is the prognosis of Hermansky-Pudlak syndrome (HPS)?

What is included in patient education about Hermansky-Pudlak syndrome (HPS)?

What is included in ophthalmic patient education about Hermansky-Pudlak syndrome (HPS)?

What is included in patient education about the pulmonary complications of Hermansky-Pudlak syndrome (HPS)?

What is included in patient education about bleeding diathesis in Hermansky-Pudlak syndrome (HPS)?

What is included in dermatologic patient education about Hermansky-Pudlak syndrome (HPS)?

Presentation

Which ocular history findings are characteristic of Hermansky-Pudlak syndrome (HPS)?

What is the focus of the clinical history to evaluate for Hermansky-Pudlak syndrome (HPS)?

Which ocular findings are characteristic of Hermansky-Pudlak syndrome (HPS)?

What are the phenotypic skin findings of Hermansky-Pudlak syndrome (HPS)?

Which systemic physical findings are characteristic of Hermansky-Pudlak syndrome (HPS)?

What causes Hermansky-Pudlak syndrome (HPS)?

DDX

What are the differential diagnoses for Hermansky-Pudlak Syndrome?

Workup

What is the role of lab tests in the workup of Hermansky-Pudlak syndrome (HPS)?

What is the role of imaging studies in the workup of Hermansky-Pudlak syndrome (HPS)?

What is the role of vision testing in the workup of Hermansky-Pudlak syndrome (HPS)?

What is the role of IQ testing in the workup of Hermansky-Pudlak syndrome (HPS)?

Treatment

How is Hermansky-Pudlak syndrome (HPS) treated?

What is the role of surgery in the treatment of Hermansky-Pudlak syndrome (HPS)?

Which specialist consultations are beneficial to patients with Hermansky-Pudlak syndrome (HPS)?

Which dietary modifications are used in the treatment of Hermansky-Pudlak syndrome (HPS)?

Which activity modifications are used in the treatment of Hermansky-Pudlak syndrome (HPS)?

What are the possible complications of bleeding diathesis in Hermansky-Pudlak syndrome (HPS)?

How should the pulmonary complications of Hermansky-Pudlak syndrome (HPS) be managed?

Medications

What is the role of medications in the treatment of Hermansky-Pudlak syndrome (HPS)?

Which medications in the drug class Hemostatic agents are used in the treatment of Hermansky-Pudlak Syndrome?