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Hermansky-Pudlak Syndrome

, MD, PhD and , PhD.

Author Information
, MD, PhD
Clinical Director, National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland
, PhD
Clinical Project Manager, National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: December 11, 2014.

Summary

Disease characteristics.

Hermansky-Pudlak syndrome (HPS) is a multisystem disorder characterized by: tyrosinase-positive oculocutaneous albinism; a bleeding diathesis resulting from a platelet storage pool deficiency; and, in some cases, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The albinism is characterized by: hypopigmentation of the skin and hair; and ocular findings of 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 easy bruising, frequent 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 are associated primarily with HPS-2.

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 dense bodies on whole mount electron microscopy of platelets. Pathogenic variants in HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN) are known to cause HPS.

Management.

Treatment of manifestations: Correction of refractive errors and use of low vision aids; 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 over 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, cigarette smoke.

Evaluation of relatives at risk: In rare families with the milder types (HPS-3, HPS-5, or HPS-6), 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 diagnosis for pregnancies at increased risk are possible for those families in which the pathogenic variants have been identified.

Diagnosis

Clinical Diagnosis

The diagnosis of Hermansky-Pudlak syndrome (HPS) is established by clinical findings of oculocutaneous albinism in combination with a bleeding diathesis of variable severity [Gahl et al 1998, Huizing et al 2008].

The diagnosis of 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 [King et al 2001]

Testing

Absence of platelet dense bodies. The sine qua non for diagnosis of HPS is absence of dense bodies on whole mount electron microscopy of platelets [Witkop et al 1987]. 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 none in the platelets of individuals with HPS.

Coagulation studies

  • The secondary aggregation response of platelets is impaired.
  • Bleeding time is generally prolonged.
  • Coagulation factor activity and platelet counts are normal.

Ceroid lipofuscin. The demonstration of a yellow, autofluorescent, amorphous lipid-protein complex (called ceroid lipofuscin) in urinary sediment and parenchymal cells is characteristic of HPS; however, this laboratory finding is virtually never used in diagnosis.

Molecular Genetic Testing

Genes. The genes in which pathogenic variants are known to cause HPS are HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and BLOC1S6.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in HPS

Gene 1
(HPS Subtype)
Proportion of HPS Attributed to Mutation of This GeneTest Method
Puerto RicanNon-Puerto Rican
HPS1
(HPS-1)
~74% 2, 30%Targeted mutation analysis 4
~ 1% 343% 5Sequence analysis 6
0%~1% 7Deletion/duplication analysis 8
AP3B1
(HPS-2)
0%~10% 9Sequence analysis 6
~1% 10Deletion/duplication analysis 8
HPS3
(HPS-3)
0%~13% 11Sequence analysis 6
25% 120%Deletion/duplication analysis 8
HPS4
(HPS-4)
0%~12% 13Sequence analysis 6
HPS5
(HPS-5)
0%~9% 14Sequence analysis 6
HPS6
(HPS-6)
0%~7% 15Sequence analysis 6
<1% 16Deletion/duplication analysis 8
DTNBP1
(HPS-7)
0%~1% 17Sequence analysis 6
BLOC1S3
(HPS-8)
0%1% 18Sequence analysis 6
BLOC1S6
(HPS-9)
0%1% 19Sequence analysis 6
Deletion/duplication analysis 8
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Homozygosity for the c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication) is found in approximately 74% of all affected individuals of Puerto Rican ancestry [Santiago Borrero et al 2006] and in most affected individuals from northwestern Puerto Rico [Oh et al 1996, Huizing et al 2008]. To date, the c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication) has been found exclusively in affected individuals of Puerto Rican ancestry.

3.

Three Puerto Rican individuals with HPS-1 were compound heterozygotes for the 16-bp duplication and a second HPS1 pathogenic variant [Carmona-Rivera et al 2011b].

4.

Targeted mutation analysis is typically for c.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication). Note: Pathogenic variants included in a panel may vary by laboratory.

5.

HPS1 is mutated in approximately 45% of affected non-Puerto Ricans, including Japanese, Indian, Swiss, and African Americans [Oh et al 1996, Oh et al 1998, Shotelersuk & Gahl 1998, Shotelersuk et al 1998, Oetting & King 1999, Hermos et al 2002, Huizing & Gahl 2002, Ito et al 2005, Merideth et al 2009, Vincent et al 2009]. Homozygotes as well as compound heterozygotes for HPS1 pathogenic variants have been identified. Several non-Puerto Rican Hispanic individuals with HPS1 pathogenic variants have been reported [Carmona-Rivera et al 2011a].

6.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

A ~14k insertion/deletion has been reported [Griffin et al 2005].

8.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9.

Pathogenic variants in AP3B1 have been identified in at least 13 individuals: two adult brothers [Dell'Angelica et al 1999], a boy age six years [Huizing et al 2002], another child [Clark et al 2003], two cousins with consanguineous Turkish parents [Jung et al 2006], two Italian sibs [Fontana et al 2006], a child originally diagnosed with Griscelli syndrome [Enders et al 2006], three unrelated individuals with typical findings of HPS-2 [Chiang et al 2010, Wenham et al 2010], and a Lebanese girl with consanguineous parents harboring a homozygous chromosomal inversion within the AP3B1 gene [Jones et al 2013] .

10.

Deletions of 8 kb [Jung et al 2006] and ~0.6 kb [Wenham et al 2010] have been reported, as well as a chromosome 5 inversion with a breakpoint in AP3B1 [Jones et al 2013].

11.

Sequence analysis of individuals known to have HPS is expected to identify pathogenic variants in HPS3 ~15% of the time. In addition to novel variants, sequence analysis will identify individuals with HPS who are of Ashkenazi Jewish background with the c.1303+1G>A splice site variant [Huizing et al 2001a]. Of six individuals with this pathogenic variant, four were homozygotes and two were compound heterozygotes.

12.

Homozygosity for g.339_4260del3904, (also referred to as the 3.9-kb deletion) has been identified in affected individuals of Puerto Rican ancestry only [Anikster et al 2001]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes [Torres-Serrant et al 2010].

13.

Pathogenic variants in HPS4 have been reported in at least 17 affected individuals [Suzuki et al 2002, Anderson et al 2003, Jones et al 2012], including a Sri Lankan [Bachli et al 2004] and a Uruguayan [Carmona-Rivera et al 2011a].

14.

Pathogenic variants in HPS5 have been found in at least nine individuals, including a Turkish boy age three years [Zhang et al 2003], sisters of Swiss extraction age 43 and 51 years [Huizing et al 2004], a woman of English and Irish background age 21 years [Huizing et al 2004], a boy of English, Irish, Dutch, and Swedish background age ten years [Huizing et al 2004], a Turkish woman age 38 years [Korswagen et al 2008], a Mexican boy age eight months [Carmona-Rivera et al 2011a], a Cuban-Venezuelan boy age three years [Carmona-Rivera et al 2011a], and a male age 92 years, the oldest individual with HPS documented in the literature [Ringeisen et al 2013].

15.

Six individuals with ten different pathogenic variants in HPS6 have been reported [Zhang et al 2003, Huizing et al 2009, Summers & Schimmenti 2014], in addition to an Israeli Bedouin family with a homozygous founder frameshift variant [Schreyer-Shafir et al 2006].

16.

One large ~20-kb deletion has been identified in one subject with HPS-6 [Huizing et al 2009].

17.

About 1% of individuals with HPS have HPS-7, caused by pathogenic variants in DTNBP1. Homozygous nonsense variants in DTNBP1 have been reported in two subjects, a Portuguese woman age 48 years [Li et al 2003] and a 77 year-old woman of northern European background [Lowe et al 2013].

18.

A family in Britain was identified with a homozygous frameshift variant in BLOC1S3 [Morgan et al 2006], and an Iranian boy age six years with a homozygous nonsense variant has been described [Cullinane et al 2012].

19.

A homozygous nonsense variant in BLOC1S6 was identified in a male of Indian descent age nine months [Cullinane et al 2011] and in an Italian female age 17 years [Badolato et al 2012].

Testing Strategy

To confirm/establish the diagnosis in a proband presumably manifesting signs of oculocutaneous albinism and bleeding, the following are appropriate.

Electron microscopy (preferably “whole mount” as opposed to transmission) of platelets to show absent dense bodies should be performed to confirm the diagnosis of HPS.

Molecular genetic testing. Following electron microscopy, molecular genetic testing may be considered:

  • One genetic testing strategy is serial single gene molecular genetic testing based on the individual’s ethnicity or the severity of clinical findings.

    In a person of northwest Puerto Rican ancestry, the HPS1 founder variant should be pursued first.

    In a person of central Puerto Rican or Ashkenazi Jewish ancestry, the HPS3 founder variants should be investigated.

    For other individuals, the order of testing may depend on the severity of clinical findings; visual acuity provides a rough measure of severity:
    • Severely affected individuals can be tested for HPS1 and HPS4 pathogenic variants initially.
    • Mildly affected individuals can be tested for HPS3, HPS5, or HPS6 pathogenic variants first.
    • If an affected individual had neutropenia or infections as a child, testing of AP3B1 (HPS-2) should be considered.
    • If the above HPS-associated gene testing does not identify biallelic pathogenic variants in the same gene, testing for pathogenic variants in DTNBP1 (HPS-7), BLOC1S3 (HPS-8), and BLOC1S6 (PLDN) (HPS-9) should be considered.
  • An alternative genetic testing strategy is use of a multi-gene panel that includes HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and BLOC1S6 and other genes of interest (see Differential Diagnosis link). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
  • Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of HPS, genomic testing may be considered. Such testing may include whole exome sequencing (WES) or whole genome sequencing (WGS.
    Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014].

Protein analysis. If fibroblasts are available, immunoblotting of cell extracts with antibodies against one of the subunits of each of the four HPS protein complexes can identify which complex is deficient [Nazarian et al 2008, Carmona-Rivera et al 2011a, Cullinane et al 2011, Cullinane et al 2012] (see Molecular Genetic Pathogenesis).

Clinical Description

Natural History

The clinical characteristics of Hermansky-Pudlak syndrome (HPS) consist of oculocutaneous albinism, a bleeding diathesis, a platelet storage pool deficiency, and other organ involvement [Huizing et al 2001b, Huizing & Gahl 2002, 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, and less marked when s/he is well rested and relaxed.

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 pulmonary fibrosis of HPS typically causes symptoms in the thirties and is usually fatal within a decade. The pulmonary fibrosis has been described largely in individuals with HPS-1 from northwestern Puerto Rico [Brantly et al 2000, Avila et al 2002], but also occurs in other individuals with HPS-1 [Brantly et al 2000, Hermos et al 2002] or HPS-4 [Anderson et al 2003, Bachli et al 2004] or HPS-2 [Gochuico et al 2012]. To date, convincing evidence of pulmonary fibrosis has not been reported for HPS-3, HPS-5, HPS-6, HPS-7, HPS-8, or HPS-9. The fibrosis consists of progressive, restrictive lung disease with an extremely variable time course [Gahl et al 1998, Brantly et al 2000, Gahl et al 2002].

Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents, on average, at age 15 years, with wide variability [Gahl et al 1998]. The colitis is severe in 15% of cases 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 primarily in persons with HPS-1 or HPS-4 [Hussain et al 2006]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected.

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

Neutropenia and/or immune defects have been associated with HPS-2 [Shotelersuk et al 2000, Huizing & Gahl 2002, Clark et al 2003, Fontana et al 2006].

Pathogenesis. The mechanism of pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure remains unknown.

Genotype-Phenotype Correlations

Correlations between specific HPS-causing variants in any one gene and particular clinical presentations are not convincing. However, individuals with pathogenic variants in the same HPS protein complex exhibit similar clinical characteristics [Huizing et al 2008]. Those complexes are described in Molecular Genetic Pathogenesis.

Molecular subtyping in HPS is important for prognosis with respect to the occurrence of pulmonary fibrosis [Huizing et al 2008, Thielen et al 2010]. The lethal pulmonary fibrosis of HPS is associated with defects in BLOC-3 (HPS-1 and HPS-4), as demonstrated in Puerto Ricans homozygous for the c.1470_1486dup CCAGCAGGGGAGGCCC pathogenic variant in HPS1 [Gahl et al 1998], in an Irish individual with HPS1 pathogenic variants [Brantly et al 2000] and in Sri Lankan [Bachli et al 2004] and eastern European [Anderson et al 2003] individuals with HPS4 pathogenic variants. Pulmonary fibrosis has also been associated with AP-3 defects. At least three of the thirteen known individuals with HPS-2 have documented interstitial lung disease [Gochuico et al 2012]. Pulmonary fibrosis has not been reported in studies of individuals with HPS-3 [Huizing et al 2001a], HPS-5 [Huizing et al 2007], HPS-6 [Huizing et al 2009], HPS-7 [Li et al 2003, Lowe et al 2013], HPS-8 [Morgan et al 2006, Cullinane et al 2012], or HPS-9 [Cullinane et al 2011, Badolato et al 2012].

There appears to be no genotype-phenotype relationship between pathogenic variants in AP3B1 and clinical severity. Two brothers with compound heterozygous pathogenic variants (a missense mutation and a small AP3B1 deletion) and a six-year-old boy with biallelic nonsense mutations in AP3B1 had typical HPS but also persistent neutropenia and an increased frequency of infections in childhood [Shotelersuk et al 2000, Huizing & Gahl 2002]. A boy age two years with homozygous AP3B1 nonsense mutations diagnosed with HPS-2 had fatal hemophagocytic lymphohistiocytosis [Enders et al 2006], and two Italian sibs with compound heterozygous AP3B1 mutations (frame shift and nonsense) had an immune defect involving abnormal natural killer cell function [Fontana et al 2006]. Two Turkish sibs with HPS-2 manifested developmental delay and dysmorphic features, but consanguinity was also involved [Jung et al 2006]. A three-year-old Hispanic boy with HPS-2 homozygous for an AP3B1 splice site mutation had partial albinism, bleeding diathesis, congenital neutropenia and frequent, severe pulmonary symptoms. He also displayed hypothyroidism, congenital adrenal hyperplasia, and cardiac arrhythmia, previously unreported features in HPS-2 [Chiang et al 2010]. A consanguineous female infant with recurrent severe febrile illnesses displayed a balanced chromosomal inversion in chromosome 5 involving AP3B1. She had typical features of HPS-2 including reduced pigmentation, neutropenia, and recurrent infections. She was not dysmorphic nor did she show any other non-HPS related features that could be ascribed to another gene involved in the chromosomal inversion [Jones et al 2013].

Individuals with HPS3 pathogenic variants have milder symptoms than those with HPS1 pathogenic variants [Huizing et al 2001a]. The albinism in HPS-3 is characterized by such minimal hypopigmentation that some individuals have been given the diagnosis of 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. Significant granulomatous colitis occurs primarily in HPS-1 and HPS-4 [Hussain et al 2006]. The severity of clinical symptoms does not appear to correlate with the severity of the molecular defect.

The variability and severity of oculocutaneous albinism and bleeding diathesis found in HPS-4 are similar to those of HPS-1 [Suzuki et al 2002, Anderson et al 2003]. No correlation has been found between the severity of symptoms and specific pathogenic variants.

HPS-5 and HPS-6 resemble HPS-3 in their mildness of hypopigmentation and lack of pulmonary disease. These subjects can go undiagnosed for decades: a recent report described a new diagnosis of HPS-5 in a 92-year-old man who had 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].

It is difficult to discern the severity of HPS-7, HPS-8, or HPS-9 based on the few cases reported for each. There is limited information to establish whether the HPS-7, HPS-8, and HPS-9 subtypes are prone to complications besides albinism and a bleeding diathesis. It also appears that these subjects have a silvery/blond/gold hair color at birth that may turn darker with age [Li et al 2003, Morgan et al 2006, Cullinane et al 2011, Cullinane et al 2012, Lowe et al 2013].

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 occurs worldwide and has an estimated prevalence of 1:500,000 to 1:1,000,000 in non-Puerto Rican populations.

Prevalence of HPS-1 in northwestern Puerto Rico is 1:1800. HPS-1 has been reported in a small isolate in a Swiss village and as a genetic isolate in Japan [Ito et al 2005].

HPS-3 occurs as a genetic isolate in central Puerto Rico [Anikster et al 2001, Santiago Borrero et al 2006].

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. Disorders with albinism included in the differential diagnosis:

  • Oculocutaneous albinism type 1 (OCA1), caused by pathogenic variants in TYR. Ocular findings include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity usually in the range of 20/100 to 20/400, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irises that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irises that change to green/hazel or brown/tan with age. Visual acuity may be 20/60 or better in some individuals.
  • Oculocutaneous albinism type 2 (OCA2), caused by pathogenic variants in OCA2. Affected individuals usually have pigmented hair at birth and usually do not tan later in life, but some have been identified who have white hair at birth. Individuals with OCA2 are usually recognized within the first three to six months of life because of the ocular features of visual inattention, nystagmus, and strabismus. Vision is stable to slowly improving after early childhood until mid- to late teens, and no major change or loss of established visual acuity occurs related to the albinism. The amount of cutaneous pigmentation in OCA2 ranges from minimal to near-normal compared to others of the same ethnic and family backgrounds. The irises usually develop some pigment that can be seen by the hazel/green to tan/brown color or by globe transillumination.
  • Oculocutaneous albinism type 4 (OCA4), caused by pathogenic variants in SLC45A2 (also known as MATP, membrane-associated transporter protein). Studies suggest that OCA4 is the second most common type of OCA in Japanese individuals. The phenotype is similar to that of OCA2 in individuals of northern European origin.
  • X-linked ocular albinism (XLOA), 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 pathogenic variants in LYST (previously known as CHS1). Affected individuals have a significantly increased frequency of infection in childhood, mild oculocutaneous albinism, and a bleeding diathesis [Introne et al 1999, Huizing et al 2008]. This entity is characterized by huge, fused, dysfunctional lysosomes and macromelanosomes. Individuals with CHS always have giant intracellular granules in their neutrophils on a 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 has been reported in a single person with HPS (HPS-2) [Enders et al 2006]. Without bone marrow transplantation, individuals with classic Chediak-Higashi syndrome die in childhood.
  • Griscelli syndrome (GS1 [OMIM 214450], GS2 [607624], GS3 [609227]). Affected individuals have mild hypopigmentation and immunodeficiency and can have the accelerated phase of lymphohistiocytosis. A distinguishing finding is silvery-gray hair.
    Note: Elejalde syndrome (OMIM 256710) is considered a type of Griscelli syndrome in which neurologic involvement (rather than immunodeficiency and lymphohistiocytosis) occurs.
  • Cross syndrome (OMIM 257800). Affected individuals have hypopigmentation, ocular anomalies, and severe central nervous system involvement with developmental delay; the latter findings are not part of Hermansky-Pudlak syndrome [Huizing et al 2000b].
  • Pulmonary fibrosis. Individuals with familial pulmonary fibrosis or with idiopathic pulmonary fibrosis do not have hypopigmentation, visual defects, or a bleeding diathesis; the only feature shared with HPS is a diathesis toward interstitial lung disease.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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:

  • 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 (PFTs) should be performed in individuals older than age 20 years.
  • Medical genetics consultation

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.
  • One individual with HPS-1 remains well after undergoing lung transplantation [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, sun screens with a high SPF value (total blocks with SPF 45-50+) are appropriate; for less sun-sensitive individuals, sun screens 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 (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

Eyes. Annual ophthalmologic examination, including assessment of refractive error, is indicated.

Skin. 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. Examination for these findings should be performed at least annually.

Pulmonary fibrosis. Pulmonary function testing should be performed annually in adults.

Colitis. Colitis is suspected in those with a history of cramping, increased mucus in the stool, and rectal bleeding; colonoscopy is used to confirm the diagnosis.

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 HPS-1 and HPS-4, the diagnosis of HPS will be apparent because the hypopigmentation and nystagmus are clinically evident.

In rare families with the milder types (HPS-3, HPS-5, or HPS-6), the evaluation of apparently unaffected sibs may yield a positive diagnosis:

  • 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 aggregation or 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 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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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., carriers of one HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 pathogenic variant).
  • 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 his/her being a carrier is 2/3.
  • 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 HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene of interest or custom prenatal testing.

Requests for prenatal testing for conditions which (like HPS) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 pathogenic variants have been identified.

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: 800-789-9477; 516-922-3440
    Fax: 516-922-4022
    Email: hpsnet@worldnet.att.net
  • National Organization for Albinism and Hypopigmentation (NOAH)
    PO Box 959
    East Hampstead NH 03826-0959
    Phone: 800-473-2310 (toll-free); 603-887-2310
    Fax: 800-648-2310 (toll-free)
    Email: info@albinism.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

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

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HPS1HPS110q24​.2Hermansky-Pudlak syndrome 1 proteinAlbinism Database Mutations of the Hermansky-Pudlak Syndrome-1 gene (HPS1)
Hermansky-Pudlak Syndrome Database (HPS1)
Retina International Mutations of the ep-Gene (HPS1)
HPS1
HPS2AP3B15q14​.1AP-3 complex subunit beta-1Albinism Database Mutations of the b3A subunit of the AP-3 complex gene (AP3B1)
AP3B1base: Mutation registry for Hermansky-Pudlak syndrome 2
Hermansky-Pudlak Syndrome Database (AP3B1)
Retina International Mutations of the Adaptin b3a Gene (ADTB3A) (AP3B1)
AP3B1 database
Resource of Asian Primary Immunodeficiency Diseases (AP3B1)
AP3B1
HPS3HPS33q24Hermansky-Pudlak syndrome 3 proteinAlbinism Database Mutations of the Hermansky-Pudlak Syndrome-3 gene (HPS3)
Hermansky-Pudlak Syndrome Database (HPS3)
Retina International Mutations of the HPS3 Gene
HPS3 database
HPS3
HPS4HPS422q12​.1Hermansky-Pudlak syndrome 4 proteinHermansky-Pudlak Syndrome Database (HPS4)
Retina International Mutations of the Human light ear Gene (le, HPS4)
HPS4 database
HPS4
HPS5HPS511p15​.1Hermansky-Pudlak syndrome 5 proteinHermansky-Pudlak Syndrome Database (HPS5)
HPS5 database
HPS5
HPS6HPS610q24​.32Hermansky-Pudlak syndrome 6 proteinHermansky-Pudlak Syndrome Database (HPS6)
HPS6 database
HPS6
HPS7DTNBP16p22​.3DysbindinHermansky-Pudlak Syndrome Database (DTNBP1)
DTNBP1 database
DTNBP1
HPS8BLOC1S319q13​.32Biogenesis of lysosome-related organelles complex 1 subunit 3Hermansky-Pudlak Syndrome Database (BLOC1S3)
BLOC1S3 database
BLOC1S3
HPS9BLOC1S615q21​.1PallidinHermansky-Pudlak Syndrome Database (BLOC1S6)
BLOC1S6 database
BLOC1S6

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

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

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

Molecular Genetic Pathogenesis

The proteins encoded by the nine 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. The four complexes include:

HPS locus heterogeneity and new subtypes may be identified in the future. Candidate genes for new HPS subtypes may come from HPS mouse models, including mocha, cappuccino, muted, subtle gray, chocolate (defective in the mouse homologues of the human genes AP3D1, CNO, MUTED, SLC7A11, RAB38, respectively [Li et al 2004, Huizing et al 2008] or HPS fly models, including garnet, carmine, ruby, light, lightoid, snapin (defective in the fly homologues of the human genes AP3D1, APsM1, AP3S1/2, VPS41, RAB38, SNAPIN, respectively) [Huizing et al 2008, Cheli et al 2010]. HPS candidate genes also come from HPS complex members or interactors [Huizing et al 2008], including BLOC-1 protein-encoding genes CNO, MUTED, SNAPAP, BLOC1S1, BLOC1S2 [Lee et al 2012], genes encoding the BLOC-3-interacting protein RAB32/38 [Gerondopoulos et al 2012], or genes encoding the BLOC-1-interacting proteins KXD1 [Yang et al 2012], Msb3 [John Peter et al 2013], and PI4KIIα and WASH complex [Ryder et al 2013].

HPS1

Gene structure. Normal HPS1 (formerly known as HPS) is 30.5 kb in length and its longest transcript variant (NM_000195.3) has 20 exons with a 2103-bp open reading frame [Oh et al 1996, Bailin et al 1997]. Four alternative splicing events have been described, including a common splice removing 99 bp of exon 9 [Wildenberg et al 1998]; this protein product lacks amino acids 257-289. A rare splicing event adds 43 nucleotides of the donor site of intron 6 and results in a frameshift. Two other splicing events can occur in untranslated regions of the HPS1 transcript. On northern blot analysis, the main transcript is 3.0 kb, but minor 3.9-kb and 4.4-kb species appear as well. A 1.5-kb transcript with the same 5' sequence as the published cDNA but with a different 3' sequence has been reported in bone marrow and melanoma cells. A partial pseudogene of HPS1 exists [Huizing et al 2000a]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Eighteen benign variants have been reported, including four that change amino acids (p.Gly283Trp, p.Pro491Arg, p.Arg603Gln, p.Val630Ile) [Shotelersuk & Gahl 1998]. See Table 2.

Pathogenic allelic variants. At least 24 distinct pathogenic variants in HPS1 have been reported [Oh et al 1996, Oh et al 1998, Shotelersuk & Gahl 1998, Shotelersuk et al 1998, Oetting & King 1999, Hermos et al 2002, González-Conejero et al 2003, Griffin et al 2005, Ito et al 2005, Iwakawa et al 2005]. All except four – p.Ile56del, p.Leu239Pro, p.Leu668Pro, and c.398+5G>A – result in a truncated protein. Among the pathogenic variants, founder effects have been reported for the c.1470_1486dup CCAGCAGGGGAGGCCC in exon 15 (in northwestern Puerto Rico), for the p.Met325HisfsTer128 pathogenic variant (in a Swiss Alpine village), and for c.398+5G>A, a splicing mutation in affected Japanese and Indian [Vincent et al 2009] individuals. 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. Following the convention that the most 3' change in a nucleotide repeat is arbitrarily assigned to be the one that is changed, these pathogenic variants are p.Met325HisfsTer128 and p.Met325TrpfsTer6. Both mutations are frameshifts that predict a new translational stop codon at amino acids 453 and 331, respectively. The tract of eight C nucleotides in this region is an apparent hot spot for mutation. Multiple other intragenic specific deletions and insertions have been reported. Other pathogenic variants are listed in Table 2.

Table 2.

Selected HPS1 Allelic Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.847G>Tp.Gly283TrpNM_000195​.2
NP_000186​.2
c.1472C>Gp.Pro491Arg
c.1808G>Ap.Arg603Gln
c.1888G>Ap.Val630Ile
Pathogenicc.166_168delATC
(369-371delATC)
p.Ile56del
(Ile55del)
c.288delT
(494delT)
p.Asp97ThrfsTer27
c.355delC
(561delC)
p.His119ThrfsTer5
c.391C>Tp.Arg131Ter
c.397G>Tp.Glu133Ter
c.398+5G>A
(c.644+5G>A)
(IVS5+5G>A)
--
c.418delG
(624delG)
p.Ala140ArgfsTer35
c.532dupC
(178insC)
p.Gln178ProfsTer4
c.716T>Cp.Leu239Pro
c.962delG
(1168delG)
p.Gly321AlafsTer10
c.972delC
(T322delC)
p.Met325TrpfsTer6
(324ProfsTer330)
c.972dupC
(T322insC)
p.Met325HisfsTer128
(His325ProfsTer452)
c.1189delC
(1395delC)
p.Gln397SerfsTer2
c.1323dupA
(1528-1529insA)
p.Gln442ThrfsTer11
c.1375delA
(1581delA)
p.Ser459ValfsTer16
c.1470_1486dup16 or
c.1470_1486dupCCAGCAGGGGAGGCCC
(16-bp duplication)
p.His497ProfsTer24
c.1691delAp.Lys564ArgfsTer22
c.1744-2A>C
(c.1990-2A>C)
(IVS17-2A>C)
--
c.1749G>Ap.Trp583Ter
c.1996G>Tp.Glu666Ter
c.2003T>Cp.Leu668Pro
c.932delG
(1178delG)
p.Ser311ThrfsTer20
c.532dupC
(532insC)
p.Gln178ProfsTer4
c.974_975insC
(insC974)
p.Met325IlefsTer128

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 peptide with a predicted molecular weight of 79.3 kd and without homology to other proteins. 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, Oh et al 2000]. Cellular and biochemical evidence indicates that HPS1 gene product interacts with the HPS4 protein in biogenesis of lysosome-related organelles complex-3 (BLOC-3) [Suzuki et al 2002, Chiang et al 2003, Martina et al 2003, Nazarian et al 2003]. The function of the protein was long predicted to be involved in vesicle formation or trafficking [Huizing et al 2001c, Sarangarajan et al 2001]. Recently, BLOC-3 (HPS1/HPS4 complex) was found to function as a Rab32/38 guanine nucleotide exchange factor [Gerondopoulos et al 2012].

Abnormal gene product. The mutant alleles of HPS1 are generally predicted to produce truncated, dysfunctional proteins. Further understanding of the abnormal gene products awaits determination of the function of the normal HPS1 gene product.

AP3B1

Gene structure. The organization of AP3B1 has been described for the mouse [Gorin et al 1999], and the human cDNA is expressed as a 4.2-kb transcript in a variety of tissues [Dell'Angelica et al 1997, Simpson et al 1997]. The longest human transcript variant (NM_003664.4) 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 Symbol.

Pathogenic allelic variants. AP3B1 pathogenic variants have been identified in at least a dozen individuals with HPS-2; including two adult brothers [Dell’Angelica et al 1999], a six-year-old boy [Huizing et al 2002], another child [Clark et al 2003], two siblings with consanguineous Turkish parents [Jung et al 2006], two Italian siblings [Fontana et al 2006], a child originally diagnosed with Griscelli syndrome [Enders et al 2006], and three more unrelated individuals with typical findings of HPS-2 [Chiang et al 2010, Wenham et al 2010]. A Lebanese girl with HPS-2 had a homozygous pericentric inv(5)(p15.1q14.1) in chromosome 5, with an apparent breakpoint in AP3B1 [Jones et al 2013]. See Table 3.

Table 3.

Selected AP3B1 Pathogenic Variants

DNA Nucleotide Change 1
(Alias) 2
Protein Amino Acid Change 1
(Alias) 2
Reference Sequences
c.155_158delAGAGp.Glu52AlafsTer11 3NM_003664​.3
NP_003655​.3
c.904A>Tp.Arg302Ter 4
c.1063_1064delinsTATCAATATCp.Gln355TyrfsTer6 5
(IVS10+5G>A)Unconfirmed splicing defect 6
c.1166_1228del
(exon 12 skip)
(IVS11-1G>C)
p.Leu390_Gln410del 7
(147279..155450del)(Thr491_Gln550del)
(deletion of exon 15) 8
c.1473+6T>C
(exon 15 skip)
(IVS14+6T>C)
p.Thr491_Gln550del 9
c.1525C>Tp.Arg509Ter 10
c.1619dupGp.Ala541SerfsTer25 9
c.1739T>Gp.Leu580Arg 7
(1789dupA) (Ile597AsnfsTer12) 5
c.1975G>Tp.Glu659Ter 10
c.2078_2165delp.Glu693ValfsTer13 3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designations are updated to current naming conventions; therefore, not all directly correlate to the nomenclature in their original publications.

2. Variant designation that does not conform to current naming conventions

3. Wenham et al [2010]

4. Enders et al [2006]

5. Fontana et al [2006]. Nomenclature updated to current naming conventions.

6. Chiang et al [2010]

7. Dell’Angelica et al [1999]. Compound heterozygous for a missense variant, and a deletion, which was later found to result from a splice site mutation. Nomenclature updated to current naming conventions.

8. Jung et al [2006]

9. Clark et al [2003]

10. Huizing et al [2002]

Normal gene product. The product of AP3B1 is a 1094-amino acid peptide with a predicted mass of 121.35 kd. The protein has an amino-terminal region (residues 1-642), a hydrophilic span (residues 643-809), and a carboxy-terminal region (810-1094). The gene product is the beta-3A subunit of adaptor complex-3 (AP-3, also known as beta-3A adaptin), 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. Beta-3A adaptin interacts with the other AP-3 subunits to perform this function.

Abnormal gene product. Compound heterozygosity for the two in-frame pathogenic variants of AP3B1 results in a very small amount of beta-3A adaptin on western blot, reduced amounts of another AP-3 subunit (mu), and decreased internalization of certain integral lysosomal membrane proteins into fibroblasts [Dell'Angelica et al 1999]. Compound heterozygosity for the two nonsense variants of AP3B1 produces no beta-3A adaptin on western blot and a more severe cellular phenotype, i.e., significant default trafficking of selected lysosomal membrane proteins through the plasma membrane [Huizing et al 2002]. Compound heterozygosity for the missense and splice site mutations result in cytotoxic T-lymphocytes with enlarged lytic granules that cannot move along microtubules and dock in secretory domains of the immunologic synapse [Clark et al 2003]. The Italian patients with an insertion-deletion and an insertion have natural killer cell dysfunction [Fontana et al 2006], and the person homozygous for a nonsense pathogenic variant in exon 8 had lymphohistiocytosis [Enders et al 2006].

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. The transcript is 4.4 kb in size. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. A founder variant in central Puerto Rico, consisting of a g.339_4260del3904 deletion that removes all of exon 1 and 673 bp of intron 1, accounts for the bulk of the molecular pathogenesis in HPS-3. This mutant allele produces no HPS3 mRNA. A second founder variant, c.1303+1G>A, occurs among Ashkenazi Jews, causes skipping of exon 5, and produces negligible amounts of mRNA [Huizing et al 2001a]. Other reported pathogenic variants include: three splice site variants, c.1831+2T>G, c.2433-2A>G, and c.2729+1G>C; and a missense variant, g.44101G>A, which creates a new splice site resulting in the insertion of an 89-bp alternative exon 16A and a missense variant (p.Arg397Trp) [Huizing & Gahl 2002]. See Table 4.

Table 4.

Selected HPS3 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.1189C>Tp.Arg397TrpNM_032383​.3
NP_115759​.2
c.1303+1G>A
(1163+1G>A)
(IVS5+1G>A)
--
c.1831+2T>G
(c.1691+2T>G or
IVS9+2T>G)
--
c.2433-2A>G
(c.2481-2A>G or
IVS13-2A>G)
--
c.2729+1G>C
(c.2589+1G>C)
--
g.339_4260del3904
(3.9-kb del)
--AF375663
g.44101G>A--

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 HPS3 has 1004 amino acids 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 protein to clathrin has been demonstrated [Helip-Wooley et al 2005]. The function of the gene product is not known, but it has been shown to interact within a complex called BLOC-2 including the products of HPS5 and HPS6 [Di Pietro et al 2004, Gautam et al 2004].

Abnormal gene product. The central Puerto Rican 3904-bp deletion produces no transcript and no protein. The c.1303+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. Similarly, truncated protein may be produced from the c.1831+2T>G splice mutant. The p.Arg397Trp allele is expected to produce a normal-sized HPS3 product.

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 and the minor transcript (NM_152841.2) producing a 703-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Eight non-pathogenic DNA polymorphisms have been reported, including four that change an amino acid [Anderson et al 2003].

Pathogenic allelic variants. Reported pathogenic variants are listed in Table 5.

Table 5.

Selected HPS4 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.57dupT
(F19delT)
p.Leu20SerfsTer3NM_022081​.4
NP_071364​.4
c.412G>Tp.Glu138Ter
c.461A>Gp.His154Arg
c.541C>Tp.Gln181Ter
c.649C>Tp.Arg217Ter
c.664G>Tp.Glu222Ter
c.949_972dup
(c.947_961dup24)
p.Ala317_Glu324dup
(Glu316_Asn325dupACPDGRKE)
c.1866delC
(c.1865delC)
p.Thr623ProfsTer13
(Pro685LeufsTer30)
c.1891C>Tp.Gln631Ter
c.2089_2093dup
(c.2093_2094ins or Q698insAAGCA)
p.Lys699SerfsTer5

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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]. HPS4 has been shown to interact with the HPS1 gene product in BLOC-3 and is long considered to be involved in intracellular vesicle biogenesis [Suzuki et al 2002]. Recently, BLOC-3 (HPS1/HPS4 complex) was found to function as a Rab32/38 guanine nucleotide exchange factor [Gerondopoulos et al 2012].

Abnormal gene product. No information is available on the abnormal gene products of HPS4.

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 Symbol.

Pathogenic allelic variants. Reported pathogenic variants are listed in Table 6.

Table 6.

Selected HPS5 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.879dupC
(c.879insC)
p.Lys294GlnfsTer6
(293GlnfsTer or p293insC)
NM_181507​.1
NP_852608​.1
c.1871T>Gp.Leu624Arg
c.2025_2028delAGTTp.Val676ValfsTer8
c.2593C>Tp.Arg865Ter
c.2624delT
(1875delT)
p.Leu875CysfsTer20
(Leu875CysfsTer)
c.2929_2930dupGA
(T977insGA)
p.Asp978GlnfsTer14
c.3293C>Tp.Thr1098Ile

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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 HPS5 protein 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 [DiPietro et al 2004, Gautam et al 2004]. HPS5 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].

Abnormal gene product. No information is available on the abnormal gene products of HPS5.

HPS6

Gene structure. HPS6 is a one-exon gene. 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 Symbol.

Pathogenic allelic variants. Reported pathogenic variants are listed in Table 7. Five HPS6 pathogenic variants have been reported, occurring in patients of European descent [Zhang et al 2003, Huizing et al 2009]. One pathogenic variant, p.Leu356ArgfsTer11, was found in a highly consanguineous Israeli Bedouin family [Schreyer-Shafir et al 2006].

Table 7.

Selected HPS6 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.223C>Tp.Gln75TerNM_024747​.4
NP_079023​.2
c.238dupGp.Asp80GlyfsTer96
c.815C>Tp.Thr272Ile
c.913C>Tp.Gln305Ter
c.1066_1067insGp.Leu356ArgfsTer11
c.1234C>Tp.Gln412Ter
c.1713_1716delTCTG p.Leu572AlafsTer40
c.1865_1866delTGp.Leu622ArgfsTer12
del 19,972-bp-

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.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]. HPS6 interacts with the HPS3 and HPS5 proteins to form BLOC-2 [Di Pietro et al 2004].

Abnormal gene product. Cellular studies performed on melanocytes of affected individuals with aberrant HPS6 protein 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 as those described for other BLOC-2 deficient (HPS3 and HPS5) melanocytes [Boissy et al 2005, Helip-Wooley et al 2007]. These findings confirmed that the BLOC-2 subunits HPS3, HPS5, and HPS6 act in the same pathway of lysosome-related organelles biogenesis.

DTNBP1

Gene structure. The genomic organization of human DTNBP1 has not been described, although the gene is known to contain ten exons. Its longest transcript variant (NM_032122.4) contains a 1056-bp open reading frame. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Six neutral polymorphisms have been reported [Li et al 2003].

Pathogenic allelic variants. See Table 8. Two nonsense variants have been described [Li et al 2003, Lowe et al 2013].

Table 8.

Selected DTNBP1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.177G>Ap.Trp59TerNM_032122​.3
NP_115498​.2
c.307C>Tp.Gln103Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by DTNBP1 is dysbindin (also known as dystrobrevin binding protein 1), whose longest protein isoform consists of 351 amino acids. Dysbindin binds to dystrobrevins in muscle and non-muscle cells and is also a component of biogenesis of lysosome-related organelles complex 1 (BLOC-1) [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002, Ciciotte et al 2003].

Abnormal gene product. No information is available on the abnormal gene products of DTNBP1.

BLOC1S3

Gene structure. BLOC1S3 contains two exons, but its mRNA (NM_212550.3) open reading frame of 609 bp is contained within a single coding exon [Morgan et al 2006]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 9. Two pathogenic variants in BLOC1S3 have been identified in the homozygous state. One pathogenic variant, p.Gly150ArgfsTer75, was identified in affected individuals of a single consanguineous Pakistani family [Morgan et al 2006], and the other pathogenic variant, p.Ser44Ter, was identified in an Iranian boy [Cullinane et al 2012].

Table 9.

Selected BLOC1S3 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.131C>A p.Ser44TerNM_212550​.3
NP_997715​.1
c.448delCp.Gly150ArgfsTer75

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by BLOC1S3 has 202 amino acids and combines with seven other proteins to form BLOC-1. BLOC1S3 contains an unstructured amino terminal domain followed by an alpha-helical domain. The function of the BLOC1S3 subunit is unknown; BLOC-1 is hypothesized to regulate SNARE complex formation in the endocytic pathway [Falcon-Perez et al 2002].

Abnormal gene product. The homozygous p.Ser44Ter pathogenic variant resulted in aberrantly expressed BLOC1S3 protein in the patient’s melanocytes, which destabilized the BLOC1 complex and caused mis-trafficking of the melanogenic protein TYRP1, which abnormally accumulated in the Golgi region and cell membrane, resulting in severely reduced pigment production [Cullinane et al 2012].

BLOC1S6

Gene structure. The genomic organization of BLOC1S6 has been described; the gene contains six exons. BLOC1S6 has two known human mRNA transcripts. The longest transcript 1 (NM_012388.2) contains five coding exons with a 519-bp open reading frame, and transcript 2 (AK128626) has three coding exons; only exon 2 is shared by the two transcripts [Cullinane et al 2011]. Transcript 1 is ubiquitously expressed (with notable exception of brain) and transcript 2 is tissue-specific expressed only in adult brain, testis, and leukocytes as well as in fetal brain, lung, and thymus [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002, Cullinane et al 2011]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 10. A homozygous nonsense variant in BLOC1S6, c.232C>T; p.Gln78Ter, has been identified in a male of Indian ancestry [Cullinane et al 2011] and in a northern Italian female [Badolato et al 2012].

Table 10.

Selected BLOC1S6 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.232C>Tp.Gln78TerNM_012388​.2
NP_036520​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by BLOC1S6 (ubiquitously expressed variant 1, AF080470; encoded by NM_012388.2) comprises 172 amino acids and shares no homology to any known protein. The first 60 amino acids give rise to an unstructured protein, followed by two highly α-helical coiled-coil regions (amino acids 60-100 and 109-172). The two coiled-coil regions have been shown to be essential for pallidin to bind to itself and to syntaxin-13, an early endosomal t-SNARE [Moriyama & Bonifacino 2002, Cullinane et al 2011]. BLOC1S6 also combines with seven other proteins to form BLOC-1 [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002].

Abnormal gene product. The homozygous p.Gln78Ter pathogenic variant affects only transcript 1 of BLOC1S6 resulting in a truncated protein product. The absence of functional BLOC1S6 in melanocytes of affected people destabilized other BLOC-1 subunits; decreased syntaxin-13-BLOC-1 binding; caused mistrafficking of the melanogenic protein TYRP1, which accumulated in the Golgi region, the early endosome compartment, and cell membrane; and severely reduced pigment production [Cullinane et al 2011].

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Suggested Reading

  1. Bonifacino JS. Insights into the biogenesis of lysosome-related organelles from the study of the Hermansky-Pudlak syndrome. Ann N Y Acad Sci. 2004;1038:103–14. [PubMed: 15838104]
  2. Di Pietro SM, Dell'Angelica EC. The cell biology of Hermansky-Pudlak syndrome: recent advances. Traffic. 2005;6:525–33. [PubMed: 15941404]
  3. Gautam R, Novak EK, Tan J, Wakamatsu K, Ito S, Swank RT. Interaction of Hermansky-Pudlak Syndrome genes in the regulation of lysosome-related organelles. Traffic. 2006;7:779–92. [PubMed: 16787394]
  4. Huizing M, Helip-Wooley A, Westbroek W, Gunay-Aygun M, Gahl WA. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu Rev Genomics Hum Genet. 2008;9:359–86. [PMC free article: PMC2755194] [PubMed: 18544035]
  5. King RA, Hearing VJ, Creel DJ, Oetting WS. Albinism. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). 2015. New York, NY: McGraw-Hill. Chap 220.
  6. Summers CG, Knobloch WH, Witkop CJ, King RA. Hermansky-Pudlak syndrome. Ophthalmic findings. Ophthalmology. 1988;95:545–54. [PubMed: 3174014]
  7. Swank RT, Novak EK, McGarry MP, Rusiniak ME, Feng L. Mouse models of Hermansky Pudlak syndrome: a review. Pigment Cell Res. 1998;11:60–80. [PubMed: 9585243]
  8. Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. 2006;19:19–42. [PubMed: 16420244]

Chapter Notes

Author Notes

Dr. Gahl 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.

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

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

  • 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 to live Web site
  • 20 December 2004 (me) Comprehensive update posted to live Web site
  • 2 January 2003 (tk) Comprehensive update posted to live Web site
  • 24 July 2000 (me) Review posted to live Web site
  • 27 January 2000 (wg) Original submission

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