Hermansky-Pudlak syndrome

INTRODUCTION — Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement specific to certain types [1-3]. Eleven types of HPS associated with mutations in 11 different genes have been recognized (table 1). These mutations each cause altered biogenesis of lysosomes and lysosome-related organelles and defective intracellular protein trafficking.

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of HPS. Oculocutaneous albinism and Chediak-Higashi syndrome, another type of syndromic oculocutaneous albinism associated with severe immunodeficiency, are discussed separately. (See "Oculocutaneous albinism" and "Chediak-Higashi syndrome".)

EPIDEMIOLOGY — Hermansky-Pudlak syndrome (HPS) is rare, with a prevalence of 1 to 9 in 1,000,000 individuals worldwide [4], but is more common in certain populations. As an example, the prevalence is 1 in 1800 individuals in Northwest Puerto Rico, where approximately 1 in 21 individuals are carriers of the mutation [5,6]. Most HPS type 1-affected individuals in Puerto Rico have the same founder 16-base-pair duplication in exon 15 of HPS1 [6,7].

PATHOGENESIS — Hermansky-Pudlak syndrome (HPS) is caused by homozygous or compound heterozygous mutations in 1 of 11 genes that encode components in one of four HPS protein-associated complexes: adapter protein 3 (AP-3) and biogenesis of lysosome-related organelles complex 1, 2, and 3 (BLOC-1, BLOC-2, and BLOC-3). All four complexes support intracellular biogenesis, trafficking, and homeostasis of lysosome or lysosome-related organelles (LROS) (table 1) [1,8,9]. LROS include melanosomes, platelet dense bodies (also called delta granules), Weibel-Palade bodies in vascular endothelium, lamellar bodies of alveolar type II pneumocytes, and granule proteins of cytotoxic and suppressor T cells and natural killer (NK) cells [8,10,11].

The hypopigmentation in HPS is secondary to impaired melanosome formation, trafficking, or transfer to keratinocytes, while the melanin biosynthesis in melanocytes is unaffected [8]. Immature and abnormal melanosomes cause reduced pigmentation of hair, skin, and eyes. In contrast, oculocutaneous albinism is caused by mutations in genes encoding proteins involved in the melanin biosynthesis pathway. (See "Oculocutaneous albinism", section on 'Defective melanin biosynthesis'.)

The platelet dense bodies, which play a role in secondary platelet aggregation, are absent in platelets from individuals with HPS, resulting in a platelet storage pool disorder and bleeding diathesis [12,13]. The absence of platelet dense bodies can only be identified by whole mount electron microscopy. Routine blood count or smear are likely to be normal.

The number of platelet dense bodies is also severely reduced in Chediak-Higashi syndrome, in which giant intracytoplasmic granules are also seen (picture 1). (See "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

Weibel-Palade bodies are secretory organelles within vascular endothelium that contain von Willebrand factor and other proteins. von Willebrand factor aids clotting, coagulation, and wound healing. BLOC-2 dysfunction is thought to impair von Willebrand factor secretion and contribute to bleeding [9].

The pathogenesis of the organ damage associated with some types of HPS is unclear. Ceroid lipofuscin, an amorphous, autofluorescent, lipid-protein material, has been identified in abnormal lysosomes of multiple organs (including alveolar macrophages, and cells of the gastrointestinal tract, bone marrow, liver, spleen, lymph nodes, and heart) in patients with HPS. Accumulation in the cardiac muscle and kidney is less common. Ceroid lipofuscin is thought to cause granulomatous colitis (HPS type 1) and lung interstitial fibrosis in HPS types 1, 2, and 4 [14], but the pathogenic mechanism remains largely unknown. (See "Genetic factors in inflammatory bowel disease", section on 'Hermansky-Pudlak syndrome' and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)

Loss of AP-3 complex and disruption of azurophilic granules in neutrophils is thought to cause neutropenia and immunodeficiency in HPS type 2 [15]. Immunodeficiency is also a feature of HPS types 9 and 10, although the mechanism is unclear, and immunodeficiency is not always reported [16].

CLINICAL MANIFESTATIONS — All individuals with Hermansky-Pudlak syndrome (HPS) exhibit oculocutaneous albinism and a bleeding diathesis. Other clinical manifestations, such as granulomatous colitis and pulmonary fibrosis, occur in specific types depending on the specific genetic defect.

Of note, individuals with mutations affecting the same HPS protein complex (adapter protein 3 [AP-3] and biogenesis of lysosome-related organelles complex [BLOC-1, BLOC-2, or BLOC-3]) present similar clinical characteristics (table 1). Mutations in BLOC-1 (HPS types 7, 8, 9, and 11) and BLOC-2 (HPS types 3, 5, and 6) produce milder symptoms, whereas variants in BLOC-3 (HPS types 1 and 4) or AP-3 (HPS types 2 and 10) are associated with more severe disease. (See 'Pathogenesis' above.)

HPS types 1 and 4 are recognized as severe forms of the disorder and are associated with pulmonary fibrosis. Types 3, 5, 6, and 11 are generally associated with a milder phenotype [17-19]. The phenotypes of the more recently described types of HPS are not complete due to the paucity of identified cases.

Skin and eye findings

Patients with HPS present with decreased pigmentation of the skin and hair. The skin color is variable, ranging from white to tan, but usually lighter than that of other family members [20]. The hair color varies from silvery-white to light brown/reddish (picture 2). Older individuals may have prominent signs of solar skin damage, including skin thickening, lentigines, and actinic keratosis (picture 3). Individuals with HPS have an increased risk of skin cancer, in particular, squamous cell and basal cell carcinoma.

The eyes show reduced iris pigmentation and vary in color from light blue, light green, or hazel. In patients with HPS, the ocular abnormalities are similar to those seen in patients with oculocutaneous albinism and include early-onset nystagmus, ocular sensitivity to bright light, iris transillumination, reduced retinal pigmentation, foveal hypoplasia, and reduced visual acuity for age, although visual impairment is widely variable among and within specific types [21-25]. (See "Oculocutaneous albinism", section on 'Ocular findings'.)

Systemic manifestations

Bleeding diathesis — Patients with HPS often present with a bleeding diathesis due to absent dense granules in platelets. (See "Inherited platelet function disorders (IPFDs)", section on 'Hermansky-Pudlak syndrome'.)

Affected patients may present with easy bruising; gingival bleeding; epistaxis; or prolonged bleeding with venipuncture, menstruation, after delivery, or following dental or surgical procedures, such as circumcision. The severity of bleeding varies considerably across HPS types and may be unnoticed in some [8]. Routine coagulation studies show a prolonged bleeding time, normal prothrombin time and partial thromboplastin time, and normal platelet count and morphology. (See 'Diagnosis' below.)

Pulmonary fibrosis — Pulmonary fibrosis similar to idiopathic pulmonary fibrosis occurs only in patients with HPS types 1, 2, 4, and, to a milder degree, in other types (table 1) [2,26]. The disease is characterized by irreversible and progressive fibrosis of the lung parenchyma and interalveolar septa.

The manifestations usually begin by the early 30s in HPS type 1, with earlier onset in HPS type 2. Patients have slow onset of dyspnea on exertion or at rest and a nonproductive cough, ultimately leading to the need for chronic supplementary oxygen and respiratory failure.

Typical radiographic findings include subpleural and central infiltrates; ground-glass, diffuse opacities; reticulation; and subpleural honeycombing [27]. Histopathology shows vacuolated hyperplastic type II cells with lamellar bodies in addition to macrophages with lipofuscin deposits [28]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)

Granulomatous colitis — A granulomatous colitis resembling Crohn disease clinically and histologically occurs in patients with HPS types 1 and 4. Symptoms usually begin during adolescence and include abdominal pain, fever, weight loss, malabsorption, and frequent watery and bloody diarrhea [14]. Cases of granulomatous colitis have been reported in other subtypes. The colon is involved in most cases, but typical lesions may develop through the entire gastrointestinal tract. Metastatic granulomatous skin lesions have also been reported in patients with HPS [29,30]. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

Other — Recurrent infections due to severe neutropenia and immunodeficiency have been described in some individuals as a distinctive feature in HPS types 2 and 10 [15,27,31-33]. Cardiomyopathy and renal failure have been rarely reported in HPS patients [34].

DIAGNOSIS — The diagnosis of Hermansky-Pudlak syndrome (HPS) is suspected in a patient with skin and hair color lighter than that of other family members, early-onset nystagmus, and one or more of the following:

●Bleeding history, such as easy bruising, gingival bleeding, epistaxis, or prolonged bleeding after venipuncture, dental procedures, parturition, menstruation, circumcision, or other surgical procedures

●History of respiratory problems or early-onset pulmonary fibrosis, usually starting in the early 30s (particularly for types 1 and 4, earlier for type 2)

●Granulomatous colitis similar to Crohn disease (particularly for types 1 and 4)

Laboratory studies, a comprehensive eye examination, and molecular genetic testing, if available, are necessary to establish the diagnosis.

●Laboratory studies

•Electron microscopy of platelets using the "whole mount" technique (available in specialized referral laboratories) will show the absence of dense bodies. This test can establish the diagnosis of HPS.

•Routine coagulation studies, including bleeding time (or the platelet function analyzer [PFA-100]), prothrombin time, partial thromboplastin time, and platelet count and morphology, typically demonstrate (see "Approach to the adult with a suspected bleeding disorder" and "Inherited platelet function disorders (IPFDs)" and "Platelet function testing"):

-Prolonged bleeding time

-Normal prothrombin time and partial thromboplastin time

-Normal platelet count and morphology on peripheral smear

•Platelet aggregation testing (available in specialized laboratories) can demonstrate impaired secondary platelet aggregation, suggesting a storage pool disease.

●Eye examination – In patients with suspected HPS, a comprehensive eye examination is warranted. The ocular abnormalities that support the diagnosis of HPS are similar to those found in oculocutaneous albinism and include nystagmus, high refractive errors, reduction in best-corrected visual acuity, iris transillumination, strabismus, retinal hypopigmentation, and foveal hypoplasia. (See "Oculocutaneous albinism", section on 'Ophthalmologic examination'.)

●Genetic testing – Genetic testing, if available, helps to confirm the diagnosis of HPS and determines the HPS type [35]. This is especially relevant, as different genetic types (table 1) manifest phenotypic differences that impact prognosis, surveillance, and genetic counseling [36].

One approach involves the use of a multigene panel containing the 11 recognized genes associated with HPS [1]. An alternative approach is step-wise, single-gene testing guided by consideration of clinical features and ethnic background [2]. As an example, single-gene testing for HPS1 pathogenic variants should be performed first in persons from Northwest Puerto Rico, while the HPS3 founder variant should be investigated in those of central Puerto Rican or Ashkenazi Jewish descent. HPS1 and HPS4 should be examined first in those who are severely affected or present with symptoms of pulmonary fibrosis.

DIFFERENTIAL DIAGNOSIS — Patients with Hermansky-Pudlak syndrome (HPS) types associated with a mild phenotype presenting with a minimal or unrecognized bleeding tendency may be misdiagnosed with congenital nystagmus syndrome or oculocutaneous albinism (see "Oculocutaneous albinism"). Conversely, children with oculocutaneous albinism type 1 may display easy bruising, more easily recognized due to their lighter skin type, but do not have HPS [37]. Other diseases that share clinical features with HPS include:

●Chediak-Higashi syndrome – Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent pyogenic infections, progressive neurologic abnormalities, mild coagulation defects, and a lymphoma-like accelerated phase. The demonstration on peripheral blood smear of giant cytoplasmic granules in neutrophils and platelets, which are always absent in HPS, establishes the diagnosis (picture 1). (See "Chediak-Higashi syndrome".)

●Griscelli syndrome – Griscelli syndrome is a rare autosomal recessive disorder characterized by pigmentary dilution of skin and hair, presence of large clumps of pigment in hair shafts, and variable association with immunodeficiency, neurologic abnormalities, and manifestations of hemophagocytic lymphohistiocytosis. Microscopic examination of the hair shaft can be used to confirm the diagnosis. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)

MANAGEMENT — The management of patients with Hermansky-Pudlak syndrome (HPS) involves lifelong sun protection measures, treatment of visual impairment with glasses or contact lenses, and treatment of associated systemic manifestations [14]. A support group can provide advice and information for patients and families living with HPS.

●Sun protection – As for patients with oculocutaneous albinism, strict sun protection should begin in infancy. Measures include sun avoidance in the peak hours of the day; use of wide-brimmed hats, sunglasses, and other protective clothing; and year-round use of a broad-spectrum sunscreen with a minimum sun protection factor of 30 on all exposed skin. Because of their increased risk of skin cancer, patients with HPS should have a skin examination at 6- to 12-month intervals starting in adolescence. Patients should also be educated about the importance of skin self-examination and the recognition of concerning skin lesions, such as new lesions in sun-exposed areas, nonhealing lesions or lesions undergoing changes, and lesions associated with symptoms like pain, itching, or bleeding. (See "Oculocutaneous albinism", section on 'Sun protection'.)

●Refractive errors – Eye examinations should be frequently performed in the preschool years but can be reduced to yearly thereafter. Refractive errors are managed with glasses or contact lenses (see "Oculocutaneous albinism", section on 'Management of eye abnormalities'). However, despite refractive correction, vision often remains abnormal. Extraocular muscle surgery may be needed to align the eye in cases with strabismus and improve nystagmus with or without associated compensatory abnormal head postures. Appropriate support in school is recommended.

●Bleeding diathesis – Because of the associated bleeding diathesis, patients with HPS should wear a medical alert bracelet or necklace, indicating their diagnosis and bleeding tendency. Childhood vaccinations should be given according to the American Academy of Pediatrics' schedule, although caregivers should be advised about the potential for intramuscular bleeding at the vaccine site [14]. Patients with HPS should avoid aspirin-containing products, bismuth subsalicylate, and nonsteroidal anti-inflammatory drugs (NSAIDs). Humidifiers may decrease epistaxis [1]. Oral or other hormonal contraceptives may decrease blood loss from menstruation [1].

For minor bleeding, pressure and a clean dressing with petrolatum jelly with or without thrombin-soaked, absorbable gelatin are often sufficient. For patients undergoing invasive surgery with the potential for bleeding, DDAVP (1-desamino-8-D-arginine vasopressin) may be needed [14]. Platelet transfusions are used judiciously to avoid alloimmunization, particularly in those who may later require lung transplantation. (See "Inherited platelet function disorders (IPFDs)", section on 'Treatment'.)

Precautions to minimize bleeding during dental procedures may be needed, including use of DDAVP. Use of a soft toothbrush and gentle brushing technique can reduce trauma to gums [27].

●Granulomatous colitis – If granulomatous colitis is suspected due to cramping, bowel habit changes, and/or bleeding, colonoscopy is recommended to confirm the diagnosis. Granulomatous colitis may be treated with systemic corticosteroids or other anti-inflammatory agents used for the management of Crohn disease. There are reports of severe cases successfully treated with anti-tumor necrosis factor (TNF) agents [38-41]. (See "Medical management of moderate to severe Crohn disease in adults".)

●Pulmonary fibrosis – Patients with HPS types 1, 2, and 4 and others who are symptomatic should undergo pulmonary function tests annually starting by age 20. Early high-resolution computed tomography scans should be obtained in all patients with HPS and abnormal lung function tests [2]. To minimize radiation exposure, chest imaging could be spaced by three- to five-year intervals, unless worsening symptoms or pulmonary function test decline prompt more frequent screening [27]. Pulmonary infections should be treated promptly. Patients should be counseled to avoid the use of all tobacco and other inhaled products and to obtain yearly influenza, coronavirus disease 2019 (COVID-19), and respiratory syncytial virus (RSV) vaccinations. Patients who develop pulmonary fibrosis may eventually require lung transplantation [26,27,42,43].

For patients with HPS types 1, 2, and 4, initial discussion about lung transplant evaluation is recommended as soon as there is evidence of pulmonary fibrosis progression. Bleeding complications in HPS are not considered a contraindication, since successful lung transplants are reported with successful bleeding management [27]. (See "Treatment of idiopathic pulmonary fibrosis" and "Lung transplantation: Disease-based choice of procedure".)

●Infection prevention – For patients with HPS type 2, infection prevention with guidance from an infectious disease specialist is recommended [1,15].

GENETIC CONSULTATION — Patients should be offered genetics consultation prior to childbearing years. Parents of affected children should be offered genetics referral to assess reproductive risk in future pregnancies.

PROGNOSIS — The prognosis is guarded in patients with Hermansky-Pudlak syndrome (HPS) who develop hemorrhagic, gastrointestinal, and pulmonary complications. Pulmonary fibrosis is the leading cause of death in these patients. The life expectancy in patients with pulmonary fibrosis is approximately 10 years after diagnosis of restrictive lung disease in the absence of lung transplantation [2].

SUMMARY AND RECOMMENDATIONS

●Definition – Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement, including pulmonary fibrosis and granulomatous colitis, specific to certain types. HPS prevalence is high in Northwest Puerto Rico (1 in 1800). (See 'Introduction' above and 'Epidemiology' above.)

●Pathogenesis – HPS is caused by mutations in genes involved in intracellular protein trafficking and biogenesis of lysosome-related organelles in a variety of tissues (table 1). The hypopigmentation in HPS is secondary to impaired melanosome formation, trafficking, or transfer to keratinocytes, while the melanin biosynthesis is unaffected. The bleeding diathesis is caused by the absence of platelet dense bodies, which are involved in secondary platelet aggregation. (See 'Pathogenesis' above.)

●Clinical manifestations – All individuals with HPS exhibit oculocutaneous albinism (picture 2) and a bleeding diathesis. Pulmonary fibrosis similar to idiopathic pulmonary fibrosis occurs in patients with HPS types 1, 2, and 4. A granulomatous colitis resembling Crohn disease clinically and histologically occurs in patients with HPS types 1 and 4. Severe neutropenia and immunodeficiency have been reported in individuals with HPS types 2 and 10. Individuals with HPS also have an increased risk of skin cancer, in particular, squamous cell and basal cell carcinoma. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of HPS is suspected in a patient with skin and hair color lighter than that of other family members, early-onset nystagmus, and a history of easy bruising starting in infancy, epistaxis or gingival bleeding, or excessive bleeding after medical or surgical procedures. The demonstration of absent dense bodies on electron microscopy of platelets using the "whole mount" technique (available in specialized referral laboratories) establishes the diagnosis of HPS. Genetic testing, if available, can confirm the diagnosis and determine the HPS type. (See 'Diagnosis' above.)

●Management – The management of patients with HPS involves lifelong sun protection measures and regular skin examination at 6- to 12-month intervals, starting in adolescence, for early detection and treatment of skin cancer. (See 'Management' above.)

•Eye examinations should be performed frequently in the preschool years but can be reduced to yearly thereafter. Refractive errors are corrected with glasses or contact lenses. Extraocular muscle surgery may be needed to correct strabismus or nystagmus. Appropriate support in school is recommended.

•Granulomatous colitis is treated with systemic corticosteroids and other anti-inflammatory agents used for the treatment of Crohn disease. (See "Medical management of moderate to severe Crohn disease in adults".)

•Patients with HPS who develop pulmonary fibrosis may eventually require lung transplantation. (See "Treatment of idiopathic pulmonary fibrosis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges C Gail Summers, MD, who contributed to earlier versions of this topic review.