Dermatologic Manifestations of Hermansky-Pudlak Syndrome

Updated: Dec 13, 2019
  • Author: Jaclyn Scholtz, MD; Chief Editor: Dirk M Elston, MD  more...
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Hermansky-Pudlak syndrome (HPS) is a rare group of autosomal recessive diseases whose manifestations include oculocutaneous albinism, bleeding diathesis, and lysosomal ceroid accumulation. [1] Its etiology has been related to defects in 7 genes: HPS1, HPS2 (AP3B1) , HPS3, HPS4, HPS5, HPS6, and HPS7. Before 2016, only 9 types of Hermansky-Pudlak syndrome were defined; in 2016, a tenth type was defined based on mutations in the AP3D1 gene. [2] See the image below.

The face of a Puerto Rican girl with Hermansky-Pud The face of a Puerto Rican girl with Hermansky-Pudlak syndrome. Note the blond hair and the pale skin.

Hermansky-Pudlak syndrome is a tyrosinase-positive type of albinism. Varying amounts of pigmentation may be present since patients with this syndrome can produce some melanin. For example, some patients have blond hair and others have brown hair. Additionally, patients with Hermansky-Pudlak syndrome may develop visual defects, including photophobia (light sensitivity), strabismus (crossed eyes), and nystagmus (involuntary eye movements), occur.

The bleeding problems of Hermansky-Pudlak syndrome result from platelet dysfunction and manifest with easy bruisability, nose bleeds, and extended bleeding times.

Due to progressive ceroid accumulation in the reticuloendothelial system and visceral organs, these patients may develop pulmonary fibrosis, inflammatory bowel disease, and kidney disease.



Hermansky-Pudlak syndrome results from the abnormal formation of intracellular vesicles. The impaired function of specific organelles indicates that the causative genes encode protein complexes that regulate vesicle trafficking in the endolysosomal system including AP-3, BLOC-1, BLOC-2, and BLOC-3. Four such genes, HPS1, ADTB3A, HPS3, and HPS4, are associated with the 4 known subtypes of Hermansky-Pudlak syndrome: 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. HPS1 is the most common subtype and involves the BLOC-3 protein complex. 

HPS-2 is caused by a mutation in the gene encoding the beta-3A subunit of the heterotetrameric AP3 complex (AP3BA), which assists in the vesicle formation from the trans-Golgi network or late endosome. AP3B1 is located on chromosome 5. 

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). [3] 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. [3]

Less pronounced severity of immunodeficiency can be due to a novel 2 bp-deletion (c.3222_3223delTG) in the final exon of AP3B1, causing a frameshift and thus a prolonged altered HPS2 protein. The place of the deletion is at the very C-terminal's end, preventing a complete loss of the HPS2 protein. [4]

The HPS3 gene is located on band 3q24. HPS3 is a biogenesis of the lysosome-related organelles complex (BLOC)–2 component. [5]

HPS4 is located at band 22q11.2–q12.2. Similar to HPS1, HPS4 involves the BLOC-3 protein complex.

Hermansky-Pudlak syndrome type 5 (HPS-5) results from a deficiency of the HPS5 protein, a component of BLOC-2. [6] Cells deficient in the HPS5 protein maintain early-stage melanosome formation and Pmel-17 trafficking. [6] However, tyrosinase and TYRP1 are mistrafficked and thus fail to be efficiently delivered to melanosomes of HPS-5 melanocytes. [6] Falcon-Perez et al [7] 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. [8]

The HPS6 gene (ruby-eye protein) has recently been cloned and linked to Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of BLOC-1. Studies in mutant mice show it expresses no dysbindin protein, owing to a deletion in the gene DTNBP1 (encoding dysbindin); this mutation of the human ortholog DTNBP1 causes the novel form 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 Hermansky-Pudlak syndrome in mice. [9]

A germline mutation in BLOC1S3/ reduces pigmentation and results in a novel variation of Hermansky-Pudlak syndrome, type 8 (HPS-8). [10]

Studies have revealed that many Hermansky-Pudlak syndrome gene products are stable components of at least 3 distinct, ubiquitously expressed protein complexes, named BLOC-1, BLOC-2, BLOC-3, and BLOC-4. Hermansky-Pudlak syndrome–associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; BLOC-1, consisting of 4 Hermansky-Pudlak syndrome proteins (pallidin, muted, cappuccino, HPS-7/sandy); BLOC-2, consisting of HPS-6/ruby-eye, HPS-5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS-1/pale ear and HPS-4/light ear. In the cytosol, HPS-1 (but not HPS-4) is part of yet another complex, termed BLOC-5.

In some investigations, rab geranylgeranyl transferase plays a role in Hermansky-Pudlak syndrome.

Systemic manifestations of Hermansky-Pudlak syndrome 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 Hermansky-Pudlak syndrome, 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. [11] Fatal hemocytophagic lymphohistiocytosis has been reported. [12] The Swiss variant has fewer systemic manifestations.

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

Di Pietro et al [13] noted that BLOC-1 interacts with BLOC-2 and the AP-3 complex, facilitating protein trafficking on endosomes, and, when BLOC-1 is defective, Hermansky-Pudlak syndrome results.

A new homozygous nonsense mutation resulting in HPS1 was described in 2014. [14]

Jung et al [15] identified a homozygous deletion in the AP3B1 gene that causes HPS-2.

Hermansky-Pudlak syndrome protein complexes interface with phosphatidylinositol 4-kinase type II-alpha (PI4KII-alpha) in neuronal and non-neuronal cells. [16] Specifically, BLOC-1 deficiencies, but not BLOC-2 or BLOC-3 deficiencies, impact PI4KII-alpha inclusion into AP-3 complexes. BLOC-1, PI4KII-alpha, and AP-3 belong to a tripartite complex involved with down-regulation of PI4KII-alpha, BLOC-1, and AP-3 complexes.

In 2016, a type of Hermansky-Pudlak syndrome was defined based on mutations in the AP3D1 gene; this type causes seizures and immunodeficiency. [2]

Receptors of Chitinase 3-like-1 and Chitinase 3-like-1 are associated with lung disease in HPS. [17]


Etiology of Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome 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 Hermansky-Pudlak syndrome 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 Hermansky-Pudlak syndrome 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 Hermansky-Pudlak syndrome who marry persons who are carriers.




United States

Hermansky-Pudlak syndrome may be the most frequent single-gene disorder in Puerto Rico. There is an estimated a frequency of about 1 case in 1800 Puerto Ricans with an estimated carrier frequency of 1 in 21. Screening programs for Hermansky-Pudlak syndrome have been carried out in Puerto Rico because of the higher prevalence of the disorder in this population. [18]


Hermansky-Pudlak syndrome 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. Hermansky-Pudlak syndrome has now been reported in African Americans, specifically in 2 brothers who carried compound heterozygous mutations in HPS-1: 1 mutation previously noted, p.M325WfsX6 (c.972delC), and a novel silent mutation that resulted in a splice defect at p.E169E (c.507G > A). [19] Hermansky-Pudlak syndrome has also been reported in a patient of Indian descent. [20]


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.


Hermansky-Pudlak syndrome affects the sexes equally.


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.



Most patients with Hermansky-Pudlak syndrome (about 70%) die from associated complications. Pulmonary fibrosis causes death in almost 50% of patients with Hermansky-Pudlak syndrome, usually in the fourth decade of life. Pulmonary complications are more common in Puerto Rican patients. Mortality due to bleeding complications occurs in about 10% of patients with Hermansky-Pudlak syndrome. These patients also have an increased risk of blood-borne illness due to  blood and platelet transfusions. Some patients have colitis, and about 13% of patients die from complications relating to this. Other causes of death include intestinal, liver, and kidney failure. While some cases are treatable, some are intractable, such as a case reported in 2014 of a 52-year-old man whose HPS-1 was untreatable and resulted in death. [21]

Most patients with Hermansky-Pudlak syndrome are legally blind. Cataracts can also develop at an earlier age than in healthy control subjects. 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 Hermansky-Pudlak syndrome ranges from 20/60 to 20/400.

Patients with Hermansky-Pudlak syndrome manifest with skin pathology related to albinism. Clinical studies report that 80% of patients with Hermansky-Pudlak syndrome have freckles or lentigines. Melanoma, solar keratoses, squamous cell carcinoma, and basal cell carcinoma have been reported.


Patient Education

Patients need extensive education regarding visual impairment and visual enhancement. They need to understand the implications of photophobia, low-vision aids, nystagmus, and strabismus. The benefits of protective sunglasses must be explained to patients. Sunglasses with ultraviolet protection minimize the harmful visual effects of ultraviolet rays. Further, blue blockers, yellow tint, or polarized glasses may decrease photophobia in these patients. Low-vision aids enhance the lives of patients with Hermansky-Pudlak syndrome, as they can facilitate educational activities. Additional resources may include telescopic lenses, high-contrast school materials, and font magnifiers. Grønskov et al [22] have suggested that people with diseases such as Hermansky-Pudlak syndrome (1) use glasses (possibly bifocals) and dark glasses or photochromic lenses to abate effects of reduced visual activity and photophobia and (2) consider having strabismus and nystagmus corrected if necessary.

It must be stressed to patients that their skin is sensitive to the sun. They must wear broad-spectrum sunblock with a high SPF daily and avoid sun exposure. Wearing wide-brimmed hats is also encouraged. Patients should perform monthly self-skin examinations and have frequent dermatologic evaluations to evaluate for skin cancer. Patients and families need to understand the implications of the increased bleeding tendency. Patients must avoid contact sports and physical trauma. Surgery should be undertaken with caution.

Patients should be encouraged to follow up closely with their healthcare provider, given that they may develop complications related to their lung and heart function.

Since patients with Hermansky-Pudlak syndrome have many health issues, they might require psychological, educational, and social assistance from appropriate specialists.