Dermatologic Manifestations of Hermansky-Pudlak Syndrome

Updated: Feb 05, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Hermansky-Pudlak syndrome (HPS) is a rare group of autosomal recessive diseases whose manifestations include oculocutaneous albinism, bleeding, and lysosomal ceroid storage. 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. [1] 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.

See 13 Common-to-Rare Infant Skin Conditions, a Critical Images slideshow, to help identify rashes, birthmarks, and other skin conditions encountered in infants.

The type of albinism associated with Hermansky-Pudlak syndrome is a tyrosinase-positive form. Because patients with Hermansky-Pudlak syndrome can produce some melanin, varying amounts of pigmentation may be present; some patients have blond hair and others have brown hair. Secondary to the albinism that results from Hermansky-Pudlak syndrome, 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.

Pulmonary fibrosis, inflammatory bowel disease, and kidney disease are all symptoms linked to ceroid accumulation in the cells of these organs.

Hermansky-Pudlak syndrome was first noted in 1959 by Hermansky and Pudlak, who described 2 unrelated persons with albinism with lifelong bleeding tendencies and peculiar pigmented reticular cells in the bone marrow as well as in biopsy samples of the lymph node and the liver.

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Pathophysiology

Hermansky-Pudlak syndrome results from the abnormal formation of intracellular vesicles. The impaired function of specific organelles indicates that the causative genes encode proteins operative in the formation of lysosomes and vesicles. 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.

HPS-2 is caused by a mutation in the gene encoding the beta-3A subunit of the heterotetrameric AP3 complex (ADTB3A), which resides on chromosome 5. ADTB3A is known to assist in vesicle formation from the trans-Golgi network or late endosome.

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). [2] 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. [2]

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. [3]

The HPS3 gene is located on band 3q24. HPS-3 is a biogenesis of the lysosome-related organelles complex (BLOC)–2 component. [4]

HPS4 involves the human homolog of the mouse light-ear gene. It is located at band 22q11.2–q12.2. Its function remains to be defined.

HPS5 (ruby-eye 2) function has been recently defined. Hermansky-Pudlak syndrome type 5 (HPS-5) results from a deficiency of the HPS-5 protein, a component of BLOC-2. [5] Cells deficient in the HPS-5 protein maintain early-stage melanosome formation and Pmel-17 trafficking. [5] However, tyrosinase and TYRP1 are mistrafficked and thus fail to be efficiently delivered to melanosomes of HPS-5 melanocytes. [5] Syrzycka et al [6] demonstrated that the pink gene encodes the Drosophila ortholog of the human HPS5 gene.

HPS6 (ruby-eye) have recently been cloned and linked to Hermansky-Pudlak syndrome.

A seventh type of Hermansky-Pudlak syndrome (HPS-7) has been described. HPS-7 results from mutant dysbindin, a member of BLOC-1. The sdy mutant mouse expresses no dysbindin protein, owing to a deletion in the gene DTNBP1 (encoding dysbindin); this mutation of the human ortholog DTNBP1 causes a novel form of Hermansky-Pudlak syndrome called 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. [7]

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. 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 bodies (DBs) or have smaller or fewer DBs. DBs are required for the second phase of platelet aggregation. DBs are storage sites for serotonin, calcium, and pyrophosphate.

Falcon Perez et al [8] found that the Drosophila ortholog of the HPS-5 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. [9]

A germline mutation in BLOC1S3/reduced pigmentation results in a novel variation of Hermansky-Pudlak syndrome (HPS8). [10]

Di Pietro et al [11] 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. [12]

Jung et al [13] 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. [14] 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 tenth type of Hermansky-Pudlak syndrome was defined based on mutations in the AP3D1gene; this type causes seizures and immunodeficiency. [1]

Receptors of Chitinase 3-like-1 and Chitinase 3-like-1 are associated with lung disease in HPS. [15]

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Epidemiology

Frequency

United States

Hermansky-Pudlak syndrome may be the most frequent single-gene disorder in Puerto Rico. Some have estimated a frequency of about 1 case in 2000 population among Puerto Ricans. Others state that, in Puerto Rico, Hermansky-Pudlak syndrome has a frequency of about 1 case in 1800 population, 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. [16]

International

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). [17] Hermansky-Pudlak syndrome has also been reported in a patient of Indian descent. [18]

Race

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.

Sex

Hermansky-Pudlak syndrome affects the sexes equally.

Age

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.

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