Hermansky-Pudlak Syndrome

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2021-01-18

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Genes

HPS4, HPS3, BLOC1S3, DTNBP1, BLOC1S6, HPS6, HPS5, AP3D1, AP3B1, HPS1, RAB38, BLOC1S4, BLOC1S5, VPS33A, SLC7A11, KXD1, RABGGTA, CP, TFF1, MARK4, FGL1, TYRP1, RAB32, CD63, TYR, PI4K2A, RASGRF1, SOS1, OCA2, LGALS3, CHI3L1, SLC2A4RG, PDIA2, FUZ, FBXW7, MAP1LC3B, PADI1, BHLHE22, SLC35D3, PRDX5, PWAR4, VPS39, ACTB, HSPB3, NXF1, ABCC4, CD1B, CHM, LYST, ELANE, F2R, GDI1, HLA-C, P2RY1, P4HB, PAWR, PAX6, RMRP, SFTPC, PMEL, TNF, VWF, TCAP, VAMP8, SLC25A20, F2RL3, ARHGEF2, RAB9A, RIMS2, SFTPA1

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Summary

Clinical characteristics.

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

Diagnosis/testing.

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

Management.

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

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

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

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

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

Genetic counseling.

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

Diagnosis

Suggestive Findings

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

Clinical features

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

Laboratory features (coagulation studies)

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

Establishing the Diagnosis

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

Clinical Findings

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

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

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

Molecular Genetic Testing

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

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

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

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

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

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

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

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

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered particularly because of the large number of genes associated with HPS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1a.

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

Gene ^1, 2	Proportion of HPS Attributed to Pathogenic Variants in Gene		Proportion of Pathogenic Variants ³ Detectable by Method
Gene ^1, 2	Non-Puerto Rican ⁴	Puerto Rican ⁵	Sequence analysis ⁶	Gene-targeted deletion/duplication analysis ⁷
AP3B1	~10%		~90%	~10% ⁸
HPS1	~37%	~82% ⁹	~99%	2 individuals ¹⁰
HPS3	~12%	~20% ¹¹	100%	100% of Puerto Ricans ^11, 12
HPS4	~11.5%		100%	Unknown ¹³
HPS5	~9%		99%	1 individual ¹⁴
HPS6	~16.5% ¹⁵		98%	1 individual ¹⁶

1.: HGNC-approved gene symbols, listed alphabetically. Click here (pdf) for gene symbol aliases.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Based on approximately 278 individuals with HPS of non-Puerto Rican ancestry reported as of July 2017
5.: Based on approximately 311 individuals with HPS of Puerto Rican ancestry reported as of July 2017
6.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
7.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
8.: Jung et al [2006], Wenham et al [2010], Jessen et al [2013]; a homozygous chromosome 5 inversion with a breakpoint in AP3B1 has also been reported [Jones et al 2013].
9.: Homozygosity for the HPS1 c.1470_1486dup16 is found in approximately 80% of all affected individuals of (northwest) Puerto Rican ancestry [Santiago Borrero et al 2006].
10.: A ~14-kb insertion/deletion [Griffin et al 2005] and an exon 15-18 deletion [Wei et al 2016]
11.: Anikster et al [2001]
12.: Apart from the Puerto Rican 3.9-kb deletion, no other large insertions/deletions have been reported in HPS3.
13.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
14.: A 1.4-kb HPS5 deletion was reported in one individual [Michaud et al 2017].
15.: This includes 20 individuals of Israeli-Bedouin descent homozygous for the c.1066_1067insG frameshift variant [Schreyer-Shafir et al 2006].
16.: A heterozygous ~20-kb deletion in HPS6 has been identified in one individual [Huizing et al 2009].

Table 1b.

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

Gene ^1, 2, 3	Reference
AP3D1	Ammann et al [2016]
BLOC1S3	Morgan et al [2006], Cullinane et al [2012]
BLOC1S6	Badolato et al [2012], Yousaf et al [2016]
DTNBP1	Li et al [2003], Lowe et al [2013], Bryan et al [2017]

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

Clinical Characteristics

Clinical Description

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

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

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

Photophobia may accompany severe foveal hypoplasia.

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

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

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

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

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

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

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

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

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

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

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

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

Phenotype Correlations by Gene

All individuals with HPS exhibit oculocutaneous albinism (due to aberrant melanosome formation) and a bleeding diathesis (due to 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]. These complexes are described in Molecular Pathogenesis.

AP3B1, AP3D1 (AP-3 Deficiency)

As of July 2017, 30 individuals with pathogenic variants in AP3B1 or AP3D1 have been reported. These individuals differ from those with other forms of HPS in that they exhibit immunodeficiency. They have an increased susceptibility to infections due to congenital neutropenia and impaired NK-cell cytotoxicity. It has been suggested that the neutropenia is caused by mislocalization of granule proteins in neutrophils [de Boer et al 2017], including elastase [Di Pietro et al 2006, Jung et al 2006].

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

BLOC1S3, BLOC1S6, DTNBP1 (BLOC-1 Deficiency)

As of July 2017, 12 individuals with pathogenic variants in BLOC1S3, BLOC1S6, or DTNBP1 have been described [Li et al 2003, Morgan et al 2006, Badolato et al 2012, Cullinane et al 2012, Lowe et al 2013, Yousaf et al 2016, Bryan et al 2017]. Data are insufficient to determine whether individuals with BLOC-1 deficiency are prone to complications besides albinism and a bleeding diathesis. It appears that these individuals have a silvery/blond/gold hair color at birth that may turn darker with age [Cullinane et al 2012, Lowe et al 2013].

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

HPS3, HPS5, HPS6 (BLOC-2 Deficiency)

As of July 2017, about 190 individuals with pathogenic variants in HPS3, HPS5, or HPS6 have been reported (including ~55 Puerto Rican individuals homozygous for a 3.9-kb deletion in HPS3 and 20 Israeli-Bedouin individuals homozygous for a frameshift variant in HPS6). Individuals with pathogenic variants in HPS3, HPS5, or HPS6 are BLOC-2 deficient and generally have milder symptoms than those with BLOC-3 deficiency (pathogenic variants in HPS1 or HPS4) [Huizing et al 2008]. The albinism in individuals with BLOC-2-related HPS can present with such minimal hypopigmentation that some individuals may be diagnosed with ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better.

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

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

HPS1, HPS4 (BLOC-3 Deficiency)

As of July 2017, approximately 390 individuals with pathogenic variants in HPS1 or HPS4 have been reported (including ~255 Puerto Rican individuals homozygous for a 16-bp duplication in HPS1). These individuals with BLOC-3 deficiency exhibit a generally severe form of oculocutaneous albinism and bleeding diathesis [Huizing et al 2008].

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

Significant granulomatous colitis occurs primarily in individuals with HPS1 or HPS4 pathogenic variants [Hussain et al 2006].

Genotype-Phenotype Correlations

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

Nomenclature

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

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

Prevalence

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

The prevalence per subtype can differ due to founder variants. The prevalence of HPS1-related HPS in northwestern Puerto Rico is 1:1800 [Witkop et al 1989].

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

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

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

Differential Diagnosis

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

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

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

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

Management

Evaluations Following Initial Diagnosis

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

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

Treatment of Manifestations

Eyes

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

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

Bleeding

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

Pulmonary fibrosis

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

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

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

Prevention of Secondary Complications

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

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

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

Surveillance

The following are appropriate:

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

Agents/Circumstances to Avoid

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

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

Evaluation of Relatives at Risk

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

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

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

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

Pregnancy Management

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

Therapies Under Investigation

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

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

Other

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

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