Hermansky-Pudlak Syndrome

Marjan Huizing; May Christine V Malicdan; Bernadette R Gochuico; William A Gahl

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Hermansky-Pudlak Syndrome

Marjan Huizing, PhD, May Christine V Malicdan, MD, PhD, Bernadette R Gochuico, MD, and William A Gahl, MD, PhD.

Author Information

Initial Posting: July 24, 2000; Last Revision: March 18, 2021.

Estimated reading time: 41 minutes

Summary

Clinical characteristics.

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.

Diagnosis/testing.

The diagnosis of HPS is established by clinical findings of hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absent delta granules (dense bodies) on whole-mount electron microscopy of platelets. Identification of biallelic pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Correction of refractive errors and use of low vision aids; humidifier to reduce frequency of epistaxis; oral contraceptives can limit the duration of menstrual periods; thrombin-soaked Gelfoam^® for skin wounds with prolonged bleeding; DDAVP (1-desamino-8-D-arginine vasopressin) for wisdom tooth extraction and invasive procedures; platelet or red blood cell transfusions for surgery or protracted bleeding; supplemental oxygen and, ultimately, lung transplantation for severe pulmonary disease; steroids, other anti-inflammatory agents, and/or Remicade^® for granulomatous colitis. Immunodeficiency, when present, is granulocyte colony-stimulating factor (G-CSF) responsive.

Prevention of secondary complications: Protection of the skin from the sun; wearing a medical alert bracelet that explicitly describes the functional platelet defect; maximizing pulmonary function before development of pulmonary fibrosis by prompt treatment of pulmonary infections, immunizing with influenza and pneumococcal vaccines, and regular moderate exercise.

Surveillance: Annual ophthalmologic examination; at least annual examination of the skin for solar keratoses (premalignant lesions), basal cell carcinoma, squamous cell carcinoma; annual pulmonary function testing in those older than age 20 years; routine history for symptoms of colitis (e.g., cramping, increased mucus in the stool, rectal bleeding).

Agents/circumstances to avoid: Aspirin-containing products; activities that increase the risk of bleeding; cigarette smoke; direct sun exposure.

Evaluation of relatives at risk: In rare families with the milder types (HPS3, HPS5, and HPS6-related HPS), the evaluation of apparently unaffected sibs may yield a positive diagnosis.

Genetic counseling.

HPS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for those families in which the pathogenic variants have been identified.

Diagnosis

Suggestive Findings

Hermansky-Pudlak syndrome (HPS) should be suspected in a proband with the following clinical and laboratory features.

Clinical features

Nystagmus, wandering eye movements, lack of visual attention
Skin and hair color lighter than that of other family members
Prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction), bruising, epistaxis, gingival bleeding

Laboratory features (coagulation studies)

Platelet aggregation testing showing impaired secondary aggregation response
Prothrombin time, partial thromboplastin time, and platelet counts typically normal
Bleeding time generally prolonged
Absence of platelet delta granules (dense bodies) on whole mount electron microscopy

Establishing the Diagnosis

The diagnosis of Hermansky-Pudlak syndrome (HPS) is established in a proband with the clinical findings of oculocutaneous albinism in combination with the absence of platelet delta granules (dense bodies) on whole-mount electron microscopy (the sine qua non for HPS). Identification of biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1a or Table 1b confirms the diagnosis if clinical features are inconclusive, and allows for family studies.

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Clinical Findings

Oculocutaneous albinism is established by finding hypopigmentation of the skin and hair on physical examination associated with the following characteristic ocular findings:

Nystagmus
Reduced iris pigment with iris transillumination
Reduced retinal pigment on fundoscopic examination
Foveal hypoplasia associated with significant reduction in visual acuity
Increased crossing of the optic nerve fibers

Absence of platelet delta granules (dense bodies) is identified by electron microscopy (preferably "whole mount" as opposed to transmission) [Witkop et al 1989]. On stimulation of platelets, the dense bodies, which contain ADP, ATP, serotonin, calcium, and phosphate, release their contents to attract other platelets. This process constitutes the secondary aggregation response, which cannot occur in the absence of the dense bodies. There are normally four to eight dense bodies per platelet; there are no dense bodies in the platelets of individuals with HPS.

Molecular Genetic Testing

Approaches can include serial single-gene testing, use of a multigene panel, or more comprehensive genomic testing.

Serial single-gene testing. Targeted analysis for the HPS1 pathogenic variant c.1470_1486dup16 can be performed first in individuals of northwestern Puerto Rican ancestry.

Targeted analysis for the HPS3 splice site variant c.1163+1G>A can be performed first in individuals of Ashkenazi Jewish ancestry.

Targeted analysis for the HPS3 g.339_4260del3904 variant (also referred to as the 3.9-kb deletion) can be performed first in individuals of central Puerto Rican ancestry.

For other individuals, the order of testing may be guided by the severity of clinical findings; visual acuity provides a rough measure of severity:

Sequence analysis of HPS1 and HPS4 can be considered first in severely affected individuals (severe oculocutaneous albinism or signs of pulmonary fibrosis).
Sequence analysis of HPS3, HPS5, and HPS6 can be considered first in mildly affected individuals.
If an affected individual had neutropenia or infections as a child, sequence analysis of AP3B1 and AP3D1 should be considered first, followed by gene-targeted deletion/duplication testing if biallelic pathogenic variants are not identified.

A multigene panel that includes AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, HPS6, and other genes of interest (see Differential Diagnosis) can be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. In some laboratories, panel options may include custom laboratory-designed panels and/or custom phenotype-focused exome analysis. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered particularly because of the large number of genes associated with HPS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1a.

Molecular Genetics of Hermansky-Pudlak Syndrome: Most Common Genetic Causes

Gene ^1, 2	Proportion of HPS Attributed to Pathogenic Variants in Gene		Proportion of Pathogenic Variants ³ Detectable by Method
Gene ^1, 2	Non-Puerto Rican ⁴	Puerto Rican ⁵	Sequence analysis ⁶	Gene-targeted deletion/duplication analysis ⁷
AP3B1	~1%		~90%	~10% ⁸
HPS1	~37.5%	~78% ⁹	~99%	2 individuals ¹⁰
HPS3	~11%	~22% ¹¹	100%	100% of Puerto Ricans ^11, 12
HPS4	~10.5%		100%	Unknown ¹³
HPS5	~7.5%		99%	1 individual ¹⁴
HPS6	~16.5% ¹⁵		98%	1 individual ¹⁶

1.: HGNC-approved gene symbols, listed alphabetically. Click here (pdf) for gene symbol aliases.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: See Molecular Genetics for information on variants detected in this gene.
4.: Based on approximately 398 individuals with HPS of non-Puerto Rican ancestry reported as of March 2021
5.: Based on approximately 333 individuals with HPS of Puerto Rican ancestry reported as of March 2021
6.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
7.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
8.: Jung et al [2006], Wenham et al [2010], Jessen et al [2013]; a homozygous chromosome 5 inversion with a breakpoint in AP3B1 has also been reported [Jones et al 2013].
9.: Homozygosity for the HPS1 c.1470_1486dup16 is found in approximately 80% of all affected individuals of (northwest) Puerto Rican ancestry [Santiago Borrero et al 2006].
10.: A ~14-kb insertion/deletion [Griffin et al 2005] and an exon 15-18 deletion [Wei et al 2016]
11.: Anikster et al [2001]
12.: Apart from the Puerto Rican 3.9-kb deletion, no other large insertions/deletions have been reported in HPS3.
13.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
14.: A 1.4-kb HPS5 deletion was reported in one individual [Michaud et al 2017].
15.: This includes 20 individuals of Israeli Bedouin descent homozygous for the c.1066_1067insG frameshift variant [Schreyer-Shafir et al 2006].
16.: A heterozygous ~20-kb deletion in HPS6 has been identified in one individual [Huizing et al 2009].

Table 1b.

Molecular Genetics of Hermansky-Pudlak Syndrome: Less Common Genetic Causes

Gene ^1, 2, 3	Reference
AP3D1	Ammann et al [2016], Mohammed et al [2019]
BLOC1S3	Morgan et al [2006], Cullinane et al [2012], Pennamen et al [2021]
BLOC1S5	Pennamen et al [2020]
BLOC1S6	Badolato et al [2012], Yousaf et al [2016], Okamura et al [2018], Liu et al [2021], Michaud et al [2021]
DTNBP1	Li et al [2003], Lowe et al [2013], Bryan et al [2017], Bastida et al [2019]

: Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., they account for <1% of Hermansky-Pudlak syndrome).
1.: HGNC-approved gene symbols, listed alphabetically. Click here (pdf) for gene symbol aliases.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: Click here (pdf) for further information on the genes included in this table.

Clinical Characteristics

Clinical Description

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and other organ involvement in specific subtypes [Huizing et al 2008]. Signs and symptoms of oculocutaneous albinism in HPS are variable but visual acuity generally remains stable.

Eyes. Nearly all children with the albinism of HPS have nystagmus at birth, often noticed by the parents in the delivery room and by the examining physician. Children with HPS may also have periodic alternating nystagmus [Gradstein et al 2005], wandering eye movements, and lack of visual attention. The initial diagnosis of albinism is sometimes made by the ophthalmologist.

The nystagmus can be very fast early in life, and generally slows with time, but nearly all individuals with albinism have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable when an individual is tired or anxious. Individuals with HPS have increased crossing of the optic nerve fibers [King et al 2001].

Photophobia may accompany severe foveal hypoplasia.

Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina.

Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood [Iwata et al 2000].

Alternating strabismus is found in many individuals with albinism and is generally not associated with the development of amblyopia.

Skin/hair. The hair color ranges from white to brown, and can occasionally darken with age. Skin color can be white to olive, but is generally at least a shade lighter than that of other family members.

Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare.

Affected Puerto Ricans typically have solar damage manifesting as actinic keratoses and nevi. Ephelids, lentigines, and basal cell carcinoma also occur with increased frequency among Puerto Ricans with HPS [Toro et al 1999].

Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal [Huizing et al 2007]. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, or other surgeries. Typically, cuts bleed longer than usual but heal normally. Bruising generally first appears at the time of ambulation. Epistaxis occurs in childhood and diminishes after adolescence. Menstrual cycles may be heavy and irregular. Prolonged bleeding after tooth extraction can lead to the diagnosis of HPS. Affected individuals with colitis may bleed excessively per rectum. Exsanguination as a complication of childbirth, trauma, or surgery is extremely rare.

Pulmonary fibrosis. The fibrosis consists of progressive restrictive lung disease with an extremely variable time course [Gahl et al 2002]. Symptoms usually begin in the thirties and are fatal within a decade. Pulmonary fibrosis has been described largely in affected individuals from northwestern Puerto Rico [Brantly et al 2000, Avila et al 2002], but also occurs in other individuals with pathogenic variants in HPS1, HPS4, and AP3B1 [Gochuico et al 2012]. To date, convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes (see Table 1a, Table 1b).

Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents on average at age 17 years, with wide variability [Gahl et al 1998, O'Brien et al 2021]. The colitis is severe in 15% of affected individuals and occasionally requires colectomy; affected individuals may have the inflammatory bowel disease of HPS without the explicit diagnosis of colitis. Objective signs of colitis have been found in persons with pathogenic variants in HPS1, HPS3, HPS4, or HPS6 [Hussain et al 2006, O'Brien et al 2021]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected.

Neutropenia. Neutropenia and/or immune defects have been associated with AP-3-deficient HPS, including individuals with pathogenic variants in AP3B1 [Fontana et al 2006, de Boer et al 2017] or AP3D1 [Ammann et al 2016].

Other. Cardiomyopathy and renal failure have also been reported in individuals with HPS [Witkop et al 1989].

Pathogenesis. The mechanism of pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure remains unknown. It is likely associated with aberrant biogenesis of lysosome-related organelles in specialized cells [Huizing et al 2008]. Ceroid lipofuscin, a poorly defined, amorphous, granular, electron-dense, autofluorescent lipid-protein material, has been found to accumulate in the lysosomes of HPS cells, including renal tubular cells, alveolar macrophages, and cells of the gastrointestinal tract, bone marrow, liver, spleen, lymph nodes, and heart. The clinical consequences of lipofuscin accumulation in HPS remain greatly unexplored, as does the underlying cellular cause [Gahl et al 1998].

Phenotype Correlations by Gene

All individuals with HPS exhibit oculocutaneous albinism (as a result of aberrant melanosome formation) and a bleeding diathesis (as a result of absent platelet delta granules). Other clinical features occur per subtype and are listed below; individuals with pathogenic variants in the same HPS protein complex of AP-3, BLOC-1, BLOC-2, or BLOC-3 exhibit similar clinical characteristics [Huizing et al 2008, Huizing et al 2020]. These complexes are described in Molecular Pathogenesis.

AP3B1, AP3D1 (AP-3 Deficiency)

As of March 2021, 40 individuals with pathogenic variants in AP3B1 or AP3D1 have been reported. These individuals differ from those with other forms of HPS in that they exhibit immunodeficiency. They have an increased susceptibility to infections as a result of congenital neutropenia and impaired NK-cell cytotoxicity. It has been suggested that the neutropenia is caused by mislocalization of granule proteins in neutrophils [de Boer et al 2017], including elastase [Di Pietro et al 2006, Jung et al 2006].

The one individual reported with AP3D1-related HPS, a boy of consanguineous Turkish parents, also exhibited neurodevelopmental delay, generalized seizures, and impaired hearing, features not commonly seen in individuals with AP3B1-related HPS. The boy died at age 3.5 years of septic pneumonia [Ammann et al 2016]. See Less Common Genetic Causes, AP3D1 (pdf) for variant details.

BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1 (BLOC-1 Deficiency)

As of March 2021, 29 individuals with pathogenic variants in genes encoding subunits of BLOC-1 have been described, including BLOC1S3 (13 individuals), BLOC1S5 (2 individuals), BLOC1S6 (6 individuals), or DTNBP1 (8 individuals) have been described [Huizing et al 2020, Pennamen et al 2020, Liu et al 2021, Michaud et al 2021, Pennamen et al 2021]. Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism and a bleeding diathesis. These individuals appear to have a silvery/blond/gold hair color at birth that may turn darker with age [Cullinane et al 2012, Lowe et al 2013, Pennamen et al 2020].

No pulmonary defects have been reported in these individuals. One Italian individual with BLOC1S6-related HPS presented with immunodeficiency [Badolato et al 2012]; therefore, close follow up of other individuals is required to determine if immunodeficiency is a feature of BLOC-1 deficiency.

HPS3, HPS5, HPS6 (BLOC-2 Deficiency)

As of March 2021, about 212 individuals with pathogenic variants in HPS3, HPS5, or HPS6 have been reported (including ~72 Puerto Rican individuals homozygous for a 3.9-kb deletion in HPS3 and 20 Israeli Bedouin individuals homozygous for a frameshift variant in HPS6) [Huizing et al 2020]. Individuals with pathogenic variants in HPS3, HPS5, or HPS6 are BLOC-2 deficient and generally have milder symptoms than those with BLOC-3 deficiency (pathogenic variants in HPS1 or HPS4) [Huizing et al 2008]. The albinism in individuals with BLOC-2-related HPS can present with such minimal hypopigmentation that some individuals may be diagnosed with ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better.

Bleeding is also mild and pulmonary involvement has not been observed in individuals with BLOC-2 deficiency.

Individuals with BLOC-2 deficiency can go undiagnosed for decades: a new diagnosis of HPS5-related HPS was described in a man age 92 years with light skin and hair, nystagmus, decreasing visual acuity with age, and a bleeding history. He is the oldest reported individual with HPS [Ringeisen et al 2013].

HPS1, HPS4 (BLOC-3 Deficiency)

As of March 2021, approximately 452 individuals with pathogenic variants in HPS1 or HPS4 have been reported (including ~261 Puerto Rican individuals homozygous for a 16-bp duplication in HPS1) [Huizing et al 2020]. These individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [Huizing et al 2008].

BLOC-3 deficiency is associated with lethal pulmonary fibrosis. The lung fibrosis is a restrictive lung disease and individuals with BLOC-3-deficiency typically begin to display symptoms in their early thirties and progress to death within a decade, unless lung transplantation is achieved [Gahl et al 2002, Huizing et al 2008].

Significant granulomatous colitis occurs primarily in individuals with HPS1, HPS3, HPS4, or HPS6 pathogenic variants [Hussain et al 2006, O'Brien et al 2021].

Genotype-Phenotype Correlations

Correlations between specific HPS-causing variants in any one gene and particular clinical presentations are not convincing.

Nomenclature

HPS may have been referred to as non-neuronal ceroid-lipofuscinosis to differentiate it from neuronal ceroid-lipofuscinosis, or Batten disease. In HPS, the nervous system appears to be spared.

Individuals with HPS with mild hypopigmentation but a bleeding disorder could be referred to as having "delta storage pool deficiency"; however, individuals with isolated delta storage pool deficiency do not have vision defects.

Prevalence

HPS is a rare disorder with an estimated worldwide prevalence of 1-9 per 1,000,000 individuals (www.orpha.net).

The prevalence per subtype can differ because of founder variants. The prevalence of HPS1-related HPS in northwestern Puerto Rico is 1:1,800 [Witkop et al 1989].

HPS1-related HPS has also been reported in a small isolate in a Swiss village [Schallreuter et al 1993] and as a genetic isolate in Japan [Ito et al 2005].

HPS3-related HPS occurs as a genetic isolate in central Puerto Rico, where about 1:16,000 individuals are affected [Anikster et al 2001, Santiago Borrero et al 2006]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes with the common variant g.339_4260del3904 (also referred to as the 3.9-kb deletion) [Torres-Serrant et al 2010].

Individuals with HPS have been identified in many other regions, including China, India, South America, and Western Europe.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be caused by pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6.

Differential Diagnosis

Albinism. The diagnosis of Hermansky-Pudlak syndrome (HPS) should be considered in anyone with oculocutaneous albinism or ocular albinism, as the bleeding diathesis can be mild, unrecognized, or previously disregarded. Some would advocate screening all individuals with albinism for HPS by examining their platelets for absent dense bodies. The following disorders with albinism are included in the differential diagnosis:

Oculocutaneous albinism (OCA) including OCA1 (OMIM 203100, 606952) OCA2 (OMIM 203200), OCA3 (OMIM 203290), OCA4, OCA5 (OMIM 615312), OCA6 (OMIM 113750), and OCA7 (OMIM 615179), consists of a group of autosomal recessive disorders characterized by reduction or complete lack of melanin pigment in the skin, hair, and eyes. Individuals with OCA-related albinism often present with white/blonde/light hair, white or light skin that does not tan and is very susceptible to damage from the sun including skin cancer, and fully translucent irises that do not darken with age. Ocular findings can include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. All individuals with OCA have severe visual changes, but the amount of skin, hair, and iris pigment can vary depending on the gene (or type of OCA) and pathogenic variant involved. The seven types of OCA are caused by pathogenic variants in different genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10orf11).
X-linked ocular albinism (XLOA) (OMIM 300500) is caused by pathogenic variants in GPR143. Affected males have minor skin manifestations and congenital and persistent visual impairment. XLOA is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common.

Disorders of platelet-dense bodies. Reviewed in Gunay-Aygun et al [2004], these disorders include the following:

Chediak-Higashi syndrome (CHS), caused by biallelic pathogenic variants in LYST. Affected individuals have a significantly increased frequency of infection in childhood, mild oculocutaneous albinism, and a bleeding diathesis. This entity is characterized by huge, fused, dysfunctional lysosomes and macromelanosomes. Individuals with CHS always have giant intracellular granules in their neutrophils on peripheral blood smear; individuals with HPS never exhibit this finding. Persons with CHS also frequently develop fatal lymphohistiocytosis or the accelerated phase of CHS, a finding that also sporadically occurs in AP3B1-related HPS [Enders et al 2006, de Boer et al 2017]. Without bone marrow transplantation, individuals with classic Chediak-Higashi syndrome die in childhood.
Griscelli syndrome including GS1 (OMIM 214450), GS2 (OMIM 607624), and GS3 (OMIM 609227). Affected individuals have mild hypopigmentation and immunodeficiency and can have the accelerated phase of lymphohistiocytosis. A distinguishing finding is silvery-gray hair. GS1, GS2, and GS3 are inherited in an autosomal recessive manner.
Note: Elejalde syndrome (OMIM 256710) is considered a type of Griscelli syndrome in which neurologic involvement (rather than immunodeficiency and lymphohistiocytosis) occurs.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Hermansky-Pudlak syndrome (HPS), the following are recommended if they have not already been completed:

Complete ophthalmologic evaluation
Skin examination for severity of hypopigmentation and, after infancy, for evidence of skin damage and skin cancer
History of bleeding problems and symptoms suggesting pulmonary fibrosis and/or colitis. For evaluation for lung fibrosis, pulmonary function tests should be performed in individuals older than age 20 years.
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Eyes

The majority of individuals with albinism have significant hyperopia (far-sightedness) or myopia (near-sightedness), and astigmatism. Correction of these refractive errors can improve visual acuity.
Strabismus surgery is usually not required but can be performed for cosmetic purposes, particularly if the strabismus is marked or fixed. The surgery is not always successful.
Aids such as hand-held magnifying devices or bioptic lenses are helpful adjuncts in the care of visually impaired individuals with HPS.
Preferential seating in school is beneficial, and a vision consultant may be useful.

Skin. Treatment of skin cancer does not differ from that in the general population.

Bleeding

Humidifiers may reduce the frequency of nosebleeds.
Oral contraceptives can limit the duration of menstrual periods. Menorrhagia has been treated with a levonorgestrel-releasing intrauterine system [Kingman et al 2004] and with recombinant factor VIIa [Lohse et al 2011].
Treatment of minor cuts includes placing thrombin-soaked Gelfoam^® over an open wound that fails to clot spontaneously.
For more invasive trauma, such as wisdom tooth extraction, DDAVP (1-desamino-8-D-arginine vasopressin, 0.2 µg/kg in 50 mL of normal saline) can be given as a 30-minute intravenous infusion just prior to the procedure. The use of DDAVP may or may not improve the bleeding time [Cordova et al 2005].
For extensive surgeries or protracted bleeding, platelet or red blood cell transfusions may be required.

Pulmonary fibrosis

When the pulmonary disease becomes severe, oxygen therapy can be palliative.
Several individuals with HPS1-related pulmonary fibrosis successfully underwent bilateral or single-lung transplantations [Lederer et al 2005]. The authors know of several additional successful lung transplantations.

Colitis. The granulomatous colitis of HPS resembles Crohn's colitis and, as such, may respond to steroids and other anti-inflammatory agents [Mora & Wolfsohn 2011]. Remicade^® has also been used with benefit [Erzin et al 2006, Felipez et al 2010].

Immunodeficiency. When present, immunodeficiency is typically responsive to granulocyte colony-stimulating factor (G-CSF).

Prevention of Secondary Complications

Skin. Skin care in HPS is dictated by the amount of pigment in the skin and the cutaneous response to sunlight. Protection from the sun should be provided to prevent burning, other skin damage, and skin cancer. In very sensitive individuals, sun exposure as short as five to ten minutes can be significant, while exposure of 30 minutes or more is usually significant in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, and socks). For extremely sun-sensitive individuals, sunscreen with a high SPF value (total blocks with SPF 45-50+) are appropriate; for less sun-sensitive individuals, sunscreen with SPF values of 15 or above can be used.

Bleeding. Individuals with HPS should consider obtaining a medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (e.g., platelet count, prothrombin time, partial thromboplastin time) are normal in HPS.

Pulmonary fibrosis. Prior to the development of pulmonary fibrosis, attention should be paid to maximizing pulmonary function. This entails avoidance of cigarette smoke, prompt treatment of pulmonary infections, immunization with influenza and pneumococcal vaccines, and regular moderate exercise.

Surveillance

The following are appropriate:

Eyes. Annual ophthalmologic examination, including assessment of refractive error
Skin. Annual skin examination for basal cell carcinoma and squamous cell carcinoma, and more frequent examinations for individuals with concerning lesions or a history of skin cancer
Pulmonary fibrosis. Annual pulmonary function testing in those older than age 20 years. A CT examination of the chest with high-resolution images to screen for pulmonary fibrosis is recommended for young adults with pathogenic variants in HPS1, HPS4, and AP3B1.
Colitis. Colonoscopy to confirm the diagnosis when colitis is suspected (i.e., by presence of a history of cramping, increased mucus in the stool, and rectal bleeding)

Agents/Circumstances to Avoid

Bleeding. All aspirin-containing products as well as activities that could involve the risk of a bleeding episode should be avoided.

Pulmonary fibrosis. Cigarette smoking decreases pulmonary function and may worsen progression of pulmonary fibrosis.

Evaluation of Relatives at Risk

In individuals with HPS1- and HPS4-related HPS, the diagnosis will be apparent because the hypopigmentation and nystagmus are clinically evident.

In rare families with the milder types (HPS3, HPS5, and HPS6-related HPS), the evaluation of apparently unaffected sibs may identify an affected individual and allow identification as early as possible of those who would benefit from prompt initiation of treatment and preventive measures:

If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
If the pathogenic variants in the family are not known, platelet whole-mount electron microscopy studies can be used to clarify the genetic status of at-risk sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancies should proceed normally for an affected mother or an affected fetus. Delivery, however, carries risk for bleeding in a woman with HPS; surveillance and a hematology consultation for anticipation of bleeding complications during delivery should be initiated once pregnancy is confirmed.

Therapies Under Investigation

Initial studies suggest a salutary effect on pulmonary function of the investigational drug pirfenidone in affected individuals with pulmonary function greater than 50% of normal [Gahl et al 2002]. A follow-up clinical trial was unable to confirm this finding, but also did not refute it [O'Brien et al 2011].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision.

No successful therapy for or prophylaxis against the pulmonary fibrosis of HPS exists. Steroids are often tried but have no apparent beneficial effect.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

All types of Hermansky-Pudlak syndrome (HPS) are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 pathogenic variant based on family history).
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HPS-related pathogenic variant and to allow reliable recurrence risk assessment.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.
Once an at-risk sib is known to be unaffected, the chance of the sib being a carrier is two thirds.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

The offspring of an individual with HPS are obligate heterozygotes (carriers) for a pathogenic variant.
Rarely, families with two-generation pseudodominance have been identified; these result from an affected individual having children with a reproductive partner who is heterozygous (i.e., a carrier) for a pathogenic variant in the same HPS-associated gene.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Hermansky-Pudlak Syndrome Network, Inc.
One South Road
Oyster Bay NY 11771-1905
Phone: 800-789-9HPS
Fax: 516-624-0640
Email: info@hpsnetwork.org
www.hpsnetwork.org
European Society for Immunodeficiencies (ESID) Registry
Dr. Gerhard Kindle
University Medical Center Freiburg Centre of Chronic Immunodeficiency
Engesserstrasse 4
79106 Freiburg
Germany
Phone: 49-761-270-34450
Email: esid-registry@uniklinik-freiburg.de
ESID Registry
eyeGENE - National Ophthalmic Disease Genotyping Network Registry
Phone: 301-435-3032
Email: eyeGENEinfo@nei.nih.gov
www.nei.nih.gov/eyegene

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hermansky-Pudlak Syndrome: Genes and Databases

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
AP3B1	5q14.1	AP-3 complex subunit beta-1	AP3B1 database AP3B1base: Mutation registry for Hermansky-Pudlak syndrome 2 Albinism Database Mutations of the b3A subunit of the AP-3 complex gene (AP3B1)	AP3B1	AP3B1
AP3D1	19p13.3	AP-3 complex subunit delta-1		AP3D1	AP3D1
BLOC1S3	19q13.32	Biogenesis of lysosome-related organelles complex 1 subunit 3	BLOC1S3 database	BLOC1S3	BLOC1S3
BLOC1S5	6p24.3	Biogenesis of lysosome-related organelles complex 1 subunit 5		BLOC1S5	BLOC1S5
BLOC1S6	15q21.1	Biogenesis of lysosome-related organelles complex 1 subunit 6	BLOC1S6 database	BLOC1S6	BLOC1S6
DTNBP1	6p22.3	Dysbindin	DTNBP1 database	DTNBP1	DTNBP1
HPS1	10q24.2	Hermansky-Pudlak syndrome 1 protein	Albinism Database Mutations of the Hermansky-Pudlak Syndrome-1 gene (HPS1)	HPS1	HPS1
HPS3	3q24	Hermansky-Pudlak syndrome 3 protein	HPS3 database Albinism Database Mutations of the Hermansky-Pudlak Syndrome-3 gene (HPS3)	HPS3	HPS3
HPS4	22q12.1	Hermansky-Pudlak syndrome 4 protein	HPS4 database	HPS4	HPS4
HPS5	11p15.1	Hermansky-Pudlak syndrome 5 protein	HPS5 database	HPS5	HPS5
HPS6	10q24.32	Hermansky-Pudlak syndrome 6 protein	HPS6 database	HPS6	HPS6

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Hermansky-Pudlak Syndrome (View All in OMIM)

203300	HERMANSKY-PUDLAK SYNDROME 1; HPS1
603401	ADAPTOR-RELATED PROTEIN COMPLEX 3, BETA-1 SUBUNIT; AP3B1
604310	BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 6; BLOC1S6
604982	HPS1 BIOGENESIS OF LYSOSOMAL ORGANELLES COMPLEX 3, SUBUNIT 1; HPS1
606118	HPS3 BIOGENESIS OF LYSOSOMAL ORGANELLES COMPLEX 2, SUBUNIT 1; HPS3
606682	HPS4 BIOGENESIS OF LYSOSOMAL ORGANELLES COMPLEX 3, SUBUNIT 2; HPS4
607145	DYSTROBREVIN-BINDING PROTEIN 1; DTNBP1
607246	ADAPTOR-RELATED PROTEIN COMPLEX 3, DELTA-1 SUBUNIT; AP3D1
607289	BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 5; BLOC1S5
607521	HPS5 BIOGENESIS OF LYSOSOMAL ORGANELLES COMPLEX 2, SUBUNIT 2; HPS5
607522	HPS6 BIOGENESIS OF LYSOSOMAL ORGANELLES COMPLEX 2, SUBUNIT 3; HPS6
608233	HERMANSKY-PUDLAK SYNDROME 2; HPS2
609762	BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 3; BLOC1S3
614072	HERMANSKY-PUDLAK SYNDROME 3; HPS3
614073	HERMANSKY-PUDLAK SYNDROME 4; HPS4
614074	HERMANSKY-PUDLAK SYNDROME 5; HPS5
614075	HERMANSKY-PUDLAK SYNDROME 6; HPS6
614076	HERMANSKY-PUDLAK SYNDROME 7; HPS7
614077	HERMANSKY-PUDLAK SYNDROME 8; HPS8
614171	HERMANSKY-PUDLAK SYNDROME 9; HPS9
617050	HERMANSKY-PUDLAK SYNDROME 10; HPS10
619172	HERMANSKY-PUDLAK SYNDROME 11; HPS11

Molecular Pathogenesis

The proteins encoded by the eleven genes in which pathogenic variants are known to cause HPS associate into four HPS protein complexes, which are involved in intracellular vesicle formation and trafficking [Huizing et al 2008]. The four complexes:

AP-3, a heterotetrameric complex of which two subunits, encoded by AP3B1 and AP3D1, have pathogenic variants causing HPS [Dell'Angelica et al 1999, Ammann et al 2016]
BLOC-1 (biogenesis of lysosome-related organelles complex-1), consisting of eight subunits [Falcón-Pérez et al 2002], three of which have pathogenic variants causing HPS: the protein products of BLOC1S3, BLOC1S5, BLOC1S6, and DTNBP1
BLOC-2, including subunits encoded by HPS3, HPS5, and HPS6 [Di Pietro et al 2004]
BLOC-3, including subunits encoded by HPS1 and HPS4 [Martina et al 2003]

AP3B1

Gene structure. The longest human AP3B1 mRNA transcript (NM_003664) consists of 27 exons and has an open reading frame of 3285 bp. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 31 AP3B1 pathogenic variants have been identified in about 40 individuals with HPS [de Boer et al 2017, Huizing et al 2020], including a child originally diagnosed with Griscelli syndrome [Enders et al 2006], several individuals originally diagnosed with Chediak-Higashi syndrome [de Boer et al 2017], and an individual with a homozygous pericentric inv(5)(p15.1q14.1) in chromosome 5, with a breakpoint in AP3B1 [Jones et al 2013]. Pathogenic variants in AP3B1 are reported in individuals of various backgrounds, including northern European, Chinese, Lebanese, and Mexican. There are no frequently occurring pathogenic variants in AP3B1, nor any apparent founder variants.

Normal gene product. The product of AP3B1 is the 1094-amino acid (~121.3-kd) protein AP3B1 (AP-3 β3A), which is a subunit of adaptor complex-3 (AP-3) [Dell'Angelica et al 1999]. The protein has an amino-terminal region (residues 1-642), a hydrophilic span (residues 643-809), and a carboxy-terminal region (810-1094). AP-3 is a heterotetrameric coat protein complex that forms intracellular vesicles (presumably lysosomes and lysosome-related organelles, including melanosomes, dense bodies, and lytic granules) from the trans-Golgi network and endosomes in a clathrin-mediated fashion. AP3B1 interacts with three other AP-3 subunits (δ, μ, and σ) to perform its function [Dell'Angelica et al 1999].

Abnormal gene product. Cellular analysis of some individuals with AP3B1-related HPS demonstrated that pathogenic variants in AP3B1 not only reduce expression of the AP3B1 protein, but also of other AP-3 subunits, likely by destabilizing AP-3 complex assembly [Dell'Angelica et al 1999, Huizing et al 2002, de Boer et al 2017]. AP-3 deficiency was shown to decrease internalization of certain integral lysosomal membrane proteins into fibroblasts and default trafficking of selected lysosomal membrane proteins through the plasma membrane [Dell'Angelica et al 1999, Huizing et al 2002], such as the neutrophil granule protein elastase [Di Pietro et al 2006, Jung et al 2006]. AP-3 deficient cytotoxic T-lymphocytes exhibit enlarged lytic granules that cannot move along microtubules and dock in secretory domains of the immunologic synapse [Clark et al 2003].

HPS1

Gene structure. The longest HPS1 transcript variant (NM_000195.3) has 20 exons with a 2103-bp open reading frame [Bailin et al 1997]. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 149 non-Puerto Rican individuals and 77 distinct pathogenic HPS1 variants have been reported [Huizing et al 2020]. There are also at least 261 (northwest) Puerto Rican individuals reported homozygous for the HPS1 pathogenic founder variant c.1470_1486dup16 in exon 15. Other HPS1 pathogenic founder variants are reported in a Swiss Alpine village (c.972dupC) [Schallreuter et al 1993] and in Japanese and Indian individuals (c.398+5G>A) [Ito et al 2005, Vincent et al 2009]. Otherwise, the most common reported pathogenic variants among non-Puerto Ricans involve the insertion or deletion of a C nucleotide in a repeat tract of eight Cs that occur in exon 11 (c.972delC and c.972dupC) and exon 13 (c.1189delC).

Table 2.

HPS1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change (Alias ¹⁾	Predicted Protein Change (Alias ¹)	Reference Sequences
c.398+5G>A (c.644+5G>A) (IVS5+5G>A)		NM_000195.2 NP_000186.2
c.972delC (T322delC)	p.Met325TrpfsTer6 (324ProfsTer330)
c.1189delC (1395delC)	p.Gln397SerfsTer2
c.972dupC (T322insC)	p.Met325HisfsTer128 (His325ProfsTer452)
c.1472_1487dupCCAGCAGGGGAGGCCC	p.His497GlnfsTer90	NM_000195.5 NP_000186.2

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: Variant designation that does not conform to current naming conventions.

Normal gene product. The protein product of HPS1 is a 700-amino acid protein (~79.3 kd). It has two potential N-linked glycosylation sites (residues 528 and 560) and a possible melanosomal localization signal, PLL, at the carboxy terminus. Although two transmembrane domains (at residues 79-95 and 369-396) have been proposed to exist, the protein is largely cytosolic in location, with a slight portion associating with membranes [Dell'Angelica et al 2000]. Cellular and biochemical evidence indicates that HPS1 gene product interacts with the HPS4 gene product in biogenesis of lysosome-related organelles complex-3 (BLOC-3) [Martina et al 2003]. BLOC-3 was found to interact with Rab9 [Kloer et al 2010] and to function as a Rab32/38 guanine nucleotide exchange factor [Gerondopoulos et al 2012]. Recently, it was suggested that BLOC-3 also acts in SNARE protein recycling in the late endosomal system, based on the demonstration that retrieval of the v-SNARE VAMP7 (required for melanogenesis) from melanosomes after cargo delivery requires BLOC-3 [Dennis et al 2015].

Abnormal gene product. The mutated alleles of HPS1 are generally predicted to produce truncated, dysfunctional proteins. Pathogenic variants in one member of BLOC-3 (gene products of HPS1 or HPS4) destabilizes the entire complex, causing degradation of the other protein in the complex. By using a specific antibody to the gene product of HPS4, deficiency of HPS1 and HPS4 gene products can be demonstrated [Nazarian et al 2008, Carmona-Rivera et al 2011].

HPS3

Gene structure. The genomic organization of HPS3 has been described [Anikster et al 2001]. Its longest transcript variant (NM_032383.3) comprises 17 exons with an open reading frame of 3015 bp. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 38 HPS3 pathogenic variants have been identified in about 43 individuals with HPS [Huizing et al 2020]. In addition, at least 72 (central) Puerto Rican individuals homozygous for a 3.9-kb HPS3 deletion that removes all of exon 1 and 673 bp of intron 1 have been reported [Anikster et al 2001]. A second founder variant, c.1163+1G>A, occurs among Ashkenazi Jews [Huizing et al 2001].

Table 3.

HPS3 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change (Alias ¹)	Predicted Protein Change	Reference Sequences
c.1163+1G>A (1303+1G>A or IVS5+1G>A)		NM_032383.4 NP_115759.2
g.339_4260del3904 (3.9-kb del)		AF375663.1

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: Variant designation that does not conform to current naming conventions

Normal gene product. HPS3 encodes Hermansky-Pudlak syndrome 3 protein, a 1004-amino acid protein with a predicted molecular weight of 113.7 kd [Anikster et al 2001]. It is predicted to have no glycosylation sites or transmembrane regions, but to be 43% alpha-helix, 19% extended strand, 30% random coil, and 7% beta-turn. A clathrin binding motif exists at residues 172-176, and binding of the HPS3 gene product to clathrin has been demonstrated [Helip-Wooley et al 2005]. The HPS3 gene product interacts with the HPS5 and HPS6 gene products in BLOC-2 [Di Pietro et al 2004]. It was suggested that BLOC-2 facilitates trafficking of lysosome-related organelle components (e.g., TYRP1) from an early/sorting endosomal compartment to the developing lysosome-related organelle [Helip-Wooley et al 2007, Dennis et al 2015].

Abnormal gene product. The central Puerto Rican g.339_4260del3904 deletion produces no transcript and no protein [Anikster et al 2001]. The 1303+1G>A (c.1163+1G>A) pathogenic variant eliminates exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a truncated protein if mRNA escapes the nonsense-mediated decay pathway [Huizing et al 2001]. The mutated alleles of HPS3 are generally predicted to produce truncated, dysfunctional proteins. Cellular studies performed on melanocytes of affected individuals with pathogenic HPS3 variants indicated abnormal distribution patterns of the melanogenic proteins TYRP1 and TYR, as well as increased trafficking of TYRP1 through the plasma membrane [Boissy et al 2005, Helip-Wooley et al 2007].

Pathogenic variants in one member of BLOC-2 (gene products of HPS3, HPS5, or HPS6) destabilizes the entire complex, causing degradation of the other proteins in the complex. By using a specific antibody to the gene products of HPS5 or HPS6, deficiency of HPS3, HPS5, and HPS6 gene products can be demonstrated in patients' cells [Nazarian et al 2008, Carmona-Rivera et al 2011].

HPS4

Gene structure. The genomic organization of HPS4 has been described [Anderson et al 2003]. HPS4 has 14 exons covering 32 kb of genomic DNA. Two transcripts of HPS4 differ at their 5' ends, with the major, longest transcript (NM_022081.5) harboring a 2127-bp open reading frame, encoding a 708-amino acid peptide (~76.9 kd) and the minor transcript (NM_152841.2) producing a 703-amino acid protein [Anderson et al 2003]. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 35 HPS4 pathogenic variants have been identified in about 42 individuals with HPS [Huizing et al 2020], The variant c.2089_2093dupAAGCA is frequently occurring in individuals of European descent [Suzuki et al 2002, Anderson et al 2003].

Table 4.

HPS4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change (Alias ¹)	Predicted Protein Change	Reference Sequences
c.2089_2093dupAAGCA (c.2093_2094ins or Q698insAAGCA)	p.Lys699SerfsTer5	NM_022081.5 NP_071364.4

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
1.: Variant designation that does not conform to current naming conventions

Normal gene product. The protein encoded by HPS4 has 708 amino acids with a predicted molecular weight of 76.9 kd [Suzuki et al 2002]. The HPS4 gene product has been shown to interact with the HPS1 gene product in BLOC-3, which is considered to be involved in intracellular vesicle biogenesis [Suzuki et al 2002, Martina et al 2003]. BLOC-3 was found to interact with Rab9 [Kloer et al 2010] and to function as a Rab32/38 guanine nucleotide exchange factor [Gerondopoulos et al 2012]. Recently, it was suggested that BLOC-3 also acts in SNARE protein recycling in the late endosomal system, based upon the demonstration that retrieval of the v-SNARE VAMP7 (required for melanogenesis) from melanosomes after cargo delivery requires BLOC-3 [Dennis et al 2015].

Abnormal gene product. No information is available on the abnormal gene products of HPS4. Pathogenic variants in HPS4 result in decreased expression of the protein product and cause destabilization of BLOC-3 assembly [Nazarian et al 2008, Carmona-Rivera et al 2011].

HPS5

Gene structure. The genomic organization of HPS5 has been described [Huizing et al 2004]. HPS5 has 23 exons, spans 43.5 kb of genomic DNA, and has three splice variants, the longest of which (NM_181507.1) is 4.8 kb and contains 23 exons encoding an 1129-amino acid protein. A second splice variant differs in the 5' UTR and lacks the first 114 amino acids coded for by exon 2. The third variant resembles variant 2 in lacking the first 114 amino acids, but also lacks a portion of exon 1 [Huizing et al 2004]. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 31 individuals and 33 HPS5 pathogenic variants have been reported [Michaud et al 2017, Huizing et al 2020]. There are no apparent frequently occurring pathogenic variants reported in HPS5.

Normal gene product. The HPS5 protein product has 1129 amino acids (127.4 kd) and contains two WD40 domains at low statistical likelihood [Zhang et al 2003]. It interacts with the products of HPS3 and HPS6 in BLOC-2 [Di Pietro et al 2004]. HPS5 protein product function is not known, but in its absence, LAMP-3-containing fibroblast vesicles cluster around the nucleus and fail to normally populate the cell periphery [Huizing et al 2004]. It was suggested that BLOC-2 facilitates trafficking of lysosome-related organelle components (e.g., TYRP1) from an early/sorting endosomal compartment to the developing lysosome-related organelle [Helip-Wooley et al 2007, Dennis et al 2015].

Abnormal gene product. The mutated alleles of HPS5 are generally predicted to produce truncated, dysfunctional proteins. Pathogenic variants in one member of BLOC-2 (gene products of HPS3, HPS5, or HPS6) destabilizes the entire complex, causing degradation of the other protein in the complex. By using a specific antibody to the gene products of HPS5 or HPS6, deficiency of HPS3, HPS5, and HPS6 gene products can be demonstrated in patients' cells [Nazarian et al 2008, Carmona-Rivera et al 2011].

HPS6

Gene structure. HPS6 has one exon. Its mRNA (NM_024747.5) contains a 2328-bp open reading frame [Zhang et al 2003]. A multiple-tissue northern blot demonstrated that HPS6 was expressed in all tissues tested, displaying a transcript size of approximately 2.6 kb, and no alternatively spliced transcripts were present [Huizing et al 2009]. For a detailed summary of gene and protein information, see Table A, Gene. Click here (pdf) for gene symbol aliases.

Pathogenic variants. As of March 2021, an estimated 46 individuals and 45 pathogenic HPS6 variants have been reported. In addition, another 20 Israeli Bedouin individuals homozygous for the pathogenic variant c.1066_1067insG have been described [Schreyer-Shafir et al 2006].

Table 5.

HPS6 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change	Predicted Protein Change	Reference Sequences
c.1066_1067insG	p.Leu356ArgfsTer11	NM_024747.4 NP_079023.2

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The human HPS6 open reading frame is predicted to code for a 775-amino acid, 83-kd protein of unknown function. The protein is highly homologous to its mammalian orthologs, but lacks homology to any other protein. No functional domains, leader sequence, or N-glycosylation sites are predicted [Zhang et al 2003, Huizing et al 2009]. The HPS6 gene product interacts with the HPS3 and HPS5 products in BLOC-2 [Di Pietro et al 2004]. It was suggested that BLOC-2 facilitates trafficking of lysosome-related organelle components (e.g., TYRP1) from an early/sorting endosomal compartment to the developing lysosome-related organelle [Helip-Wooley et al 2007, Dennis et al 2015].

Abnormal gene product. Cellular studies performed on melanocytes of affected individuals with aberrant HPS6 gene product expression indicated abnormal distribution patterns of the melanogenic proteins TYRP1 and TYR, as well as increased trafficking of TYRP1 through the plasma membrane [Huizing et al 2009], similar to those described for other BLOC-2 melanocytes [Boissy et al 2005, Helip-Wooley et al 2007]. These findings confirmed that the BLOC-2 subunits act in the same pathway of lysosome-related organelles biogenesis. Pathogenic variants in one member of BLOC-2 (gene products of HPS3, HPS5, or HPS6) destabilizes the entire complex, causing degradation of the other protein in the complex. By using a specific antibody to the gene products of HPS5 or HPS6, deficiency of HPS3, HPS5, and HPS6 gene products can be demonstrated in the cells of affected individuals [Nazarian et al 2008, Carmona-Rivera et al 2011].

For information about genes in Table 1b click here (pdf).

Chapter Notes

Author Notes

Dr Huizing, PhD, is a cell biologist and geneticist who performs basic research on HPS and related disorders. She genetically subtyped more than 250 patients with HPS, studied their cells for the underlying cellular defects, and published extensively on the disease.

Dr Malicdan, MD, PhD, is a cell biologist and geneticist who performs basic and translational research on HPS and related disorders.

Dr Gochuico, MD, is a pulmonologist who initiated and developed a translational program to study subpopulations of pulmonary fibrosis. She is performing clinical research on the pulmonary fibrosis of HPS. Her publications on the subject contributed to the understanding of pathogenic mechanisms of subclinical and symptomatic pulmonary fibrosis.

Dr Gahl, MD, PhD, is a pediatrician, medical geneticist, and biochemical geneticist who performs clinical and basic research into rare diseases. He has seen more than 350 patients with HPS and published more than 75 original articles and reviews on the subject in the past nine years.

Acknowledgments

This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Revision History

18 March 2021 (aa,mh) Revision: added BLOC1S5; updated proportion of HPS attributed to pathogenic variants in HPS-related genes based on newly reported data; added associated references
26 October 2017 (sw) Comprehensive update posted live
11 December 2014 (me) Comprehensive update posted live
28 February 2013 (cd) Revision: deletion/duplication analysis available for AP3B1, HPS3, HPS6, and BLOC1S6; sequence analysis available for BLOC1S6
11 October 2012 (me) Comprehensive update posted live
8 July 2010 (cd) Revision: sequence analysis available clinically for mutations in AP3B1 (HPS2), HPS5, HPS6, and BLOC1S3 (HPS8)
4 May 2010 (me) Comprehensive update posted live
27 November 2007 (cd) Revision: sequence analysis available clinically for HPS1 and HPS4; prenatal diagnosis available for HPS4.
21 March 2007 (me) Comprehensive update posted live
20 December 2004 (me) Comprehensive update posted live
2 January 2003 (tk) Comprehensive update posted live
24 July 2000 (me) Review posted live
27 January 2000 (wg) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Hermansky-Pudlak Syndrome" is in the public domain in the United States of America.

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Huizing M, Malicdan MCV, Gochuico BR, et al. Hermansky-Pudlak Syndrome. 2000 Jul 24 [Updated 2021 Mar 18]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.
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GeneReviews® [Internet].

Hermansky-Pudlak Syndrome

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Establishing the Diagnosis

Clinical Findings

Molecular Genetic Testing

Table 1a.

Table 1b.

Clinical Characteristics

Clinical Description

Phenotype Correlations by Gene

AP3B1, AP3D1 (AP-3 Deficiency)

BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1 (BLOC-1 Deficiency)

HPS3, HPS5, HPS6 (BLOC-2 Deficiency)

HPS1, HPS4 (BLOC-3 Deficiency)

Genotype-Phenotype Correlations

Nomenclature

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Management

Evaluations Following Initial Diagnosis

Treatment of Manifestations

Prevention of Secondary Complications

Surveillance

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Pregnancy Management

Therapies Under Investigation

Other

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

AP3B1

HPS1

Table 2.

HPS3

Table 3.

HPS4

Table 4.

HPS5

HPS6

Table 5.

Chapter Notes

Author Notes

Acknowledgments

Revision History

References

Literature Cited

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