Hermansky-Pudlak Syndrome

Clinical characteristics.

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency. Ocular findings include nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), and strabismus in many individuals. Hair color ranges from white to brown; skin color ranges from white to olive and is usually at least a shade lighter than that of other family members. The bleeding diathesis can result in variable degrees of bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and/or other surgeries. Pulmonary fibrosis, colitis, and/or neutropenia have been reported in individuals with pathogenic variants in some HPS-related genes. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early 30s 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 clinical diagnosis of HPS can be established in a proband with hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absence of platelet delta granules (dense bodies) on electron microscopy. 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; preferential seating in school; low-vision consultant as needed; UV-blocking sunglasses; surgery for strabismus as needed; protection from sun exposure with protective clothing and sunscreen; standard treatment for skin cancer; thrombin-soaked Gelfoam^® for skin wounds with prolonged bleeding; medical alert bracelet and bleeding management plan; humidifier to reduce frequency of epistaxis; oral contraceptives and IUD for menorrhagia; DDAVP^® (desmopressin acetate) for wisdom tooth extraction and invasive procedures; platelet or red blood cell transfusions for surgery or protracted bleeding; HLA-matched single-donor platelets as needed; maximize pulmonary function with prompt treatment of asthma and pulmonary infections; influenza, pneumococcal, and COVID-19 vaccines; regular moderate exercise; supplemental oxygen for advanced-stage pulmonary fibrosis; lung transplantation for end-stage pulmonary disease; steroids, other anti-inflammatory agents, and/or Remicade^® for granulomatous colitis. Immunodeficiency, when present, is lifelong and granulocyte colony-stimulating factor responsive, and affected individuals benefit from an infection prevention plan.

Surveillance: Annual ophthalmologic examination including assessment for refractive errors; annual skin examination for evidence of sun-induced skin damage (e.g., solar keratoses [premalignant lesions], basal cell carcinoma, and squamous cell carcinoma); annual pulmonary function testing in those older than age 20 years; colonoscopy in those with symptoms of colitis (e.g., cramping, mucoid stools, hematochezia, melena); assessment for clinical and laboratory manifestations of immunodeficiency.

Agents/circumstances to avoid: Over-the-counter nonsteroidal anti-inflammatory products, aspirin-containing products, and other anticoagulants unless medically indicated; activities that increase the risk of bleeding; all tobacco and vaping products and inhalation of chemical and physical substances injurious to the lungs; unprotected and direct sun exposure.

Evaluation of relatives at risk: In families with HPS3-, HPS5-, or HPS6-related HPS (milder types of HPS in which hypopigmentation and nystagmus may not be clinically evident), it is appropriate to clarify the status of apparently asymptomatic at-risk sibs in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling.

HPS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception 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. Once the HPS-causing pathogenic variants are identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

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

Clinical findings

• Nystagmus, low vision, photophobia, strabismus
• Skin and hair color lighter than other family members
• Increased bruising, epistaxis, gingival bleeding, and prolonged bleeding after minor procedures (e.g., circumcision, tooth extraction)

Laboratory findings

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

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of HPS can be established in a proband with oculocutaneous albinism and absence of platelet delta granules (dense bodies), or the molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1.

Molecular Diagnosis

The molecular diagnosis of HPS is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1.

Note: (1) Per ACMG/AMP 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 [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, targeted analysis) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with either oculocutaneous albinism or platelet dense bodies are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

A multigene panel that includes AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, HPS6, and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) 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.

Targeted analysis for pathogenic variants can be performed first in individuals of Puerto Rican, Ashkenazi Jewish, or Israeli Bedouin ancestry (see Table 6).

• HPS1 pathogenic variant c.1472_1487dup16 in individuals of northwestern Puerto Rican ancestry. Homozygosity for HPS1 c.1472_1487dup16 is found in approximately 80% of affected individuals of Puerto Rican ancestry [Santiago Borrero et al 2006].
• HPS3 deletion/duplication analysis for the common 3.9-kb deletion (g.339_4260del3904) in individuals of central Puerto Rican ancestry [Anikster et al 2001]. This deletion accounts for 20% of HPS-related pathogenic variants in Puerto Ricans [Santiago Borrero et al 2006].
• HPS3 splice site variant c.1163+1G>A in individuals of Ashkenazi Jewish ancestry [Huizing et al 2001]
• HPS6 frameshift variant c.1065dupG in individuals of Israeli Bedouin descent [Schreyer-Shafir et al 2006]

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

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

Table 1.

Molecular Genetic Testing Used in Hermansky-Pudlak Syndrome

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 HPS have nystagmus at birth, often noticed by the parents and the examining physician in infancy. Children with HPS may also have periodic alternating nystagmus, wandering eye movements, and lack of visual attention. The nystagmus can be very fast early in life and generally slows with time, but nearly all individuals have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable in lateral eye gaze, or when an individual is tired or anxious.

Iris color may remain blue or change to a green/hazel or brown/tan color. Iris 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.

Photophobia may accompany severe foveal hypoplasia.

Foveal hypoplasia is associated with significant visual acuity loss. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood.

Individuals with HPS have increased crossing of the optic nerve fibers.

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

Hair/skin. 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 of lightly pigmented skin to the sun 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.

Some affected individuals have solar damage manifesting as actinic keratoses and nevi. Freckles, solar lentigines, and basal cell carcinoma also occur with increased frequency among individuals with HPS.

Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, and/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. 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. Symptoms usually begin in the 30s and may be fatal within a decade. Pulmonary fibrosis has been described largely in affected individuals from northwestern Puerto Rico (HPS1-related HPS), but also occurs in other individuals with pathogenic variants in AP3B1, HPS1, and HPS4 [Gahl et al 2002, Gochuico et al 2012, Velázquez-Díaz et al 2021, Yokoyama & Gochuico 2021]. Some individuals with HPS1-related pulmonary fibrosis successfully underwent bilateral or single-lung transplantations [Yokoyama & Gochuico 2021, Benvenuto et al 2022]. Convincing evidence of pulmonary fibrosis has not been reported in affected individuals with pathogenic variants in other HPS-related genes.

Colitis. A bleeding granulomatous colitis resembling Crohn 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. 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. HPS-related colitis may be responsive to corticosteroids, anti-inflammatory drugs, immune modulators, or anti-tumor necrosis factor alpha drugs [Schinella et al 1980, O'Brien et al 2021]. Partial or total colectomy was performed in some individuals with severe disease unresponsive to therapy [Schinella et al 1980, Gahl et al 1998, Hussain et al 2006].

Neutropenia. Neutropenia and/or additional immune defects (e.g., impaired NK cell cytotoxicity) 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, Mohammed et al 2019].

Other. Other features have been reported rarely in individuals with HPS, including cardiomyopathy and renal failure [Gahl et al 1998], thrombocytopenia and leukemia [Badolato et al 2012, Okamura et al 2018], or neurologic involvement [Okamura et al 2018, Michaud et al 2021].

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.

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 (Batten disease). In HPS, the nervous system appears to be spared.

Individuals with HPS with mild hypopigmentation and 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 one to nine in 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 [Santiago Borrero et al 2006].

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 g.339_4260del3904 variant (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, the Middle East, South America, and Western and Eastern Europe.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HPS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Hermansky-Pudlak Syndrome

Treatment of Manifestations

There is no cure for HPS or its associated manifestations. Preventative and supportive care improves quality of life, maximizes function, and reduces complications. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

Treatment of Manifestations in Individuals with Hermansky-Pudlak Syndrome

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Table 5.

Recommended Surveillance for Individuals with Hermansky-Pudlak Syndrome

Agents/Circumstances to Avoid

The following should be avoided:

• All nonsteroidal anti-inflammatory medications and aspirin-containing products
• Therapeutic anticoagulants (should be used only if medically indicated)
• High-impact sports and activities that could increase the risk of bleeding
• Tobacco products (which decrease pulmonary function and may exacerbate pulmonary fibrosis)
• Other pulmonary toxicants (e.g., inorganic and organic fibers, volatile chemicals, polluted environments)
• Direct sun exposure without protection (e.g., protective clothing, sunscreen, and UV-blocking sunglasses)

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 families with other types of HPS (caused by pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS3, HPS5, or HPS6), some of which are milder types of HPS in which hypopigmentation and nystagmus may not be clinically evident, it is appropriate to clarify the status of apparently asymptomatic at-risk sibs in order to identify as early as possible 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 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

No medications are currently approved by the US Food and Drug Administration as treatment for HPS.

Some medications for HPS-related pulmonary fibrosis have been investigated. Corticosteroid drugs were not effective and are not recommended for therapy [Vicary et al 2016]. Clinical trials investigating pirfenidone, an oral antifibrotic drug approved as treatment for idiopathic pulmonary fibrosis (IPF), were inconclusive [Gahl et al 2002, O'Brien et al 2011, O'Brien et al 2018]. Other antifibrotic therapies being studied as treatment for IPF, including tyrosine kinase inhibitors, are potential therapeutic candidates for HPS-related pulmonary fibrosis [Yokoyama & Gochuico 2021].

Gene therapy and gene editing are potential future treatments for HPS [Nieto-Alamilla et al 2022]. Preclinical studies of gene editing for HPS1 variant c.1472_1487dup16 [Iyer et al 2019] and gene replacement of HPS1 [Ikawa et al 2015] or AP3B1 [Young et al 2012] are ongoing.

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 HPS-related pulmonary fibrosis exists. Steroids are often tried but have no apparent beneficial effect.

Mode of Inheritance

Hermansky-Pudlak syndrome (HPS) is inherited in an autosomal recessive manner.

Rarely, families with two-generation pseudodominant inheritance have been identified. Pseudodominance (i.e., an autosomal recessive condition present in individuals in two or more generations) may occur when an affected individual has children with a reproductive partner who is heterozygous (i.e., a carrier) for a pathogenic variant in the same HPS-associated gene.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an HPS-causing pathogenic variant.
• 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-causing pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has HPS or is a carrier (see Prevalence), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an HPS-related gene.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HPS-causing pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members requires prior identification of the AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 pathogenic variants in the family.

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 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.
• Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with HPS should be considered, particularly if both partners are of the same ethnic background. Founder variants have been identified in individuals of Puerto Rican, Ashkenazi Jewish, European, Japanese, Swiss, and Israeli Bedouin ancestry (see Table 6).

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). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the HPS-causing pathogenic variants have been identified in an affected family member, prenatal 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.

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 cargo transport, cargo recycling, and cargo removal to maintain lysosome-related organelle (LRO) homeostasis [Huizing et al 2008, Bowman et al 2019]. The four complexes are the following:

• 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], four 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]

Genetic defects in HPS-related genes result in deficiency of the associated HPS protein complex, which leads to aberrant function of all LROs or only an individual LRO, resulting in a variety of clinical features. LROs affected in HPS include melanosomes in melanocytes (underlying pigmentation defects), platelet delta granules (underlying bleeding diathesis), lamellar bodies in alveolar type II cells (contributing to pulmonary fibrosis), and cytolytic granules in T cells and NK cells (contributing to immunodeficiency) [Huizing et al 2008, Bowman et al 2019, Li et al 2022].

Mechanism of disease causation. Loss of function

Table 6.

Hermansky-Pudlak Syndrome: Notable Pathogenic Variants by Gene

Author Notes

Dr Wendy J Introne, MD, is a pediatrician and medical and biochemical geneticist who performs clinical research on rare diseases.

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

Kevin O'Brien, RN, MS-CRNP, is an internal medicine nurse practitioner working in the medical genetics field.

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

Acknowledgments

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

Author History

William A Gahl, MD, PhD (2000-present)
Bernadette R Gochuico, MD; National Human Genome Research Institute (2017-2023)
Marjan Huizing, PhD (2012-present)
Wendy J Introne, MD (2023-present)
May Christine V Malicdan, MD, PhD (2017-present)
Kevin J O'Brien, RN, MS-CRNP (2023-present)

Revision History

• 25 May 2023 (wi) Revision: clarification of preferred method of electron microscopy in Establishing the Diagnosis
• 16 March 2023 (sw) Comprehensive update posted live
• 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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