Hermansky–Pudlak Syndrome

Class of eleven autosomal recessive disorders of the biogenesis of lysosome-related organelles, defined by the combination of oculocutaneous albinism and a bleeding diathesis due to absent platelet dense granules, with pulmonary fibrosis, granulomatous colitis, immunodeficiency or neurological disease depending on the protein complex affected.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

Table sources: GeneReviews (Tables 1, A and B), Orphanet and Huizing 2020, with OMIM numbers, cytobands and inheritance checked against the 22 phenotypic and gene OMIM entries. All indicate autosomal recessive inheritance, each of the 11 genes has the respective HPS type as its only OMIM phenotype, and HPS-10 is the only gene–phenotype relationship flagged as provisional (symbol «?»), with the gene entry recording a single patient [1–3, 27–48].

1. Introduction

1.1. Original description and historical course

In 1959, Frantisek Hermansky and Paulus Pudlak, in Czechoslovakia, described in the journal Blood two unrelated individuals with albinism, a bleeding diathesis and unusual pigmented reticular cells in the bone marrow, documented by histochemical studies [2, 49]. This marrow pigment corresponds to the ceroid-lipofuscin material that accumulates in the lysosomes of macrophages in various organs and that led, for some time, to the disease being called «non-neuronal ceroid lipofuscinosis», to distinguish it from the neuronal ceroid lipofuscinoses (Batten disease), since in Hermansky-Pudlak syndrome (HPS) the central nervous system appears to be spared in most types [1]. According to OMIM, the two patients, a man and a woman, were both 33 years old; the man, a farmer, went on to develop chronic interstitial pulmonary fibrosis, and the woman's autopsy showed the pigment disseminated in cells of the reticuloendothelial system and in the walls of small vessels [27]. The distinction from Chédiak-Higashi syndrome was made early on by two criteria: in HPS the leucocytes have no qualitative abnormalities and in Chédiak-Higashi there are no pigmented macrophages [27]. In the 1970s, the platelet disorder was characterised as a defect of ADP release and then as a δ granule storage disease (delta storage pool disease), first in patients of Puerto Rican ancestry [27].

In the following decades, HPS was recognised mainly in Puerto Rico, where Witkop and colleagues estimated a prevalence of about 1 in 1800 inhabitants in the north-west of the island, which made it the most frequent monogenic disease in that territory [2, 50]. In parallel, genetic isolates were described in a Swiss Alpine village and in Japan, as well as sporadic cases on every continent [1]. Witkop's estimate for Puerto Rico was about 1 in 2000, and Wildenberg's (1995) 1 in 1800, with a carrier frequency of 1 in 21; the origin of the Puerto Rican allele was attributed to southern Spain, on the basis of a personal communication without a published haplotype study [27]. In the isolate of the Swiss village in Valais, the course was usually mild, with normal life expectancy and no manifestations of ceroid storage [27]. The observation that these patients' platelets lacked dense granules (δ granules) on whole mount electron microscopy established the laboratory criterion that still defines the clinical diagnosis today [1]. By 2020, more than 715 cases had been reported worldwide, and GeneReviews counts about 770 individuals with biallelic variants published up to January 2023 [1, 2].

1.2. Molecular discovery

Positional cloning of HPS1, in 1996, identified homozygous frameshift variants in Puerto Rican, Swiss, Irish and Japanese patients and a transmembrane protein of then unknown function [50]. In 1999, Dell'Angelica and colleagues demonstrated, in two patients, variants in the β3A subunit of the adaptor complex AP-3 (AP3B1), with degradation of the mutant protein and increased surface expression of CD63, LAMP-1 and LAMP-2 in fibroblasts; this was the first human example of a disease caused by a defect in the machinery that sorts proteins to lysosomes [51]. In 2001, homozygosity mapping in pooled DNA from six families from central Puerto Rico localised HPS3 to 3q24 and revealed a large founder deletion, the second HPS founder on the island [52]; in the same year, Huizing and colleagues described HPS-3 in Ashkenazi Jews and in other non-Puerto Rican patients [53].

HPS4 was identified in 2002 as the human homologue of the murine light ear gene; at that time, only half of non-Puerto Rican patients had variants in HPS1, and the absence of the HPS1 protein in the tissues of le mice indicated that the two proteins act in the same pathway [54]. In 2003, the genes of the ruby-eye 2 and ruby-eye mice proved to be orthologues of HPS5 and HPS6, whose proteins interact directly [55], and the sandy mouse, lacking dysbindin, led to the description of HPS-7 (DTNBP1) in a Portuguese woman, with the demonstration that dysbindin is a component of BLOC-1 [2, 56]. These were followed by HPS-8 (BLOC1S3) in a consanguineous Pakistani family in 2006 [57], HPS-9 (BLOC1S6, pallidin) by exome sequencing in an HPS-like primary immunodeficiency in 2012 [58], HPS-10 (AP3D1) in a patient with albinism, neutropenia, seizures and hearing loss in 2016 [59] and HPS-11 (BLOC1S5) in 2020, from a French cohort of 230 patients with albinism without a molecular diagnosis [60].

1.3. Current nomenclature and classifications

The genetic classification numbers the types from HPS-1 to HPS-11 in order of gene identification, and OMIM assigns each type its own phenotypic entry in the series beginning at 203300 [1]. The functional classification, adopted by Orphanet and by the NIH (National Institutes of Health) reviews, groups the types by the protein complex affected: BLOC-3 deficiency (biogenesis of lysosome-related organelles complex 3; HPS-1 and HPS-4), BLOC-2 deficiency (HPS-3, HPS-5 and HPS-6), BLOC-1 deficiency (HPS-7, HPS-8, HPS-9 and HPS-11) and AP-3 deficiency (adaptor protein complex 3; HPS-2 and HPS-10) [2, 3]. This second classification has clinical value, because patients with variants in genes of the same complex have similar presentations, and the clinical spectrum is better understood as a disease of a complex than of an isolated gene [1, 2]. Orphanet maintains codes for the four complex groups and individual codes only for HPS-8 (ORPHA:231537), HPS-9 (ORPHA:280663), HPS-2 (ORPHA:664500) and HPS-10 (ORPHA:664511, «severe early-onset HPS with hearing loss, due to AP3D1 deficiency»), without individual codes for the remaining types [9, 10, 12, 13]. GenCC (Gene Curation Coalition) curation indexes the HPS3 and HPS6 forms under the designation «HPS without pulmonary fibrosis» [4].

There are three nomenclature discrepancies in the sources. The Saudubray textbook (2022) still refers to «ten types» of HPS, a count that predates the description of HPS-11 [61]. Gene-based numbering dates back to 1999, when Spritz proposed calling the AP3B1 form HPS2 and the original syndrome HPS1; OMIM retains the alternative symbol PLDN (pallidin) for BLOC1S6 [27, 28, 46]. The Oxford textbook places HPS1 at 10q23, an old cytoband (the original linkage disequilibrium mapping placed the gene at 10q23.1–q23.2), whereas GeneReviews and OMIM give 10q24.2; the heterogeneity section of the OMIM HPS-1 entry itself keeps HPS5 at 11p14, whereas the gene and phenotype entries give 11p15.1, and the table of Yokoyama and Gochuico (2021) uses other old cytobands (HPS4 22q11.2–q12.2; HPS5 11p15–p13; pallidin 15q15) [1, 14, 27, 31, 38, 42, 62]. The 2021 French albinism guidelines give OMIM numbers for HPS-9 (614071) and HPS-10 (614050) that differ from those of GeneReviews and Huizing 2020 (614171 and 617050); this article follows the latter [1, 2, 21]. The two numbers in the French guidelines belong to OMIM entries unrelated to HPS: 614071 is the entry for the MYZAP gene (15q21.3), whose biallelic loss-of-function variants cause dilated cardiomyopathy 2K, with autosomal recessive inheritance (OMIM 620894), and 614050 is familial atrial fibrillation type 12, associated with a heterozygous ABCC9 variant (12p12.1) described in a single patient [63–65]. This is therefore a transcription error in the guidelines and not an alternative numbering of types HPS-9 and HPS-10.

1.4. Definition of the entities in scope

HPS is defined clinically by the coexistence of oculocutaneous albinism and absence of platelet δ granules, and molecularly by the presence of biallelic pathogenic or likely pathogenic variants in one of the 11 genes [1]. All patients have some degree of albinism and bleeding diathesis; the other manifestations depend on the complex: pulmonary fibrosis in BLOC-3 and AP-3 deficiencies, immunodeficiency in AP-3 deficiencies, more prevalent and severe gastrointestinal symptoms in BLOC-3 deficiency, a milder phenotype without potentially fatal features described in BLOC-2 deficiency, and scarce data in BLOC-1 deficiency [2]. Identification of the subtype therefore has consequences for prognosis, surveillance and treatment options [2, 17].

Outside the definition of HPS, but covered in the differential diagnosis, are Chédiak-Higashi syndrome (LYST), the Griscelli syndromes, isolated δ granule deficiency, non-syndromic albinisms and the disease due to biallelic variants of BLOC1S1, a subunit shared between BLOC-1 and the BORC complex (BLOC-one-related complex), which causes a hypomyelinating leukodystrophy with epileptic encephalopathy and hypopigmentation milder than in BLOC-1 deficiency, and which the authors classify as a «BORCopathy» rather than classic HPS [66]. Haemophagocytic lymphohistiocytosis (HLH) associated with HPS-2 and the thrombocytopathies with glycoprotein defects (Glanzmann thrombasthenia and Bernard-Soulier syndrome) enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Lysosome-related organelles and the four complexes

Lysosome-related organelles (LRO) are specialised compartments that share with lysosomes their endosomal origin and some membrane proteins, but have secretory functions specific to each cell type: melanosomes of melanocytes, platelet δ granules, lamellar bodies of type II pneumocytes, cytolytic granules of T lymphocytes and NK (natural killer) cells, neutrophil granules and Weibel-Palade bodies of endothelial cells [1, 2, 67]. The proteins encoded by the 11 HPS genes form four ubiquitous complexes that ensure the cargo transport, recycling and removal needed for the biogenesis and homeostasis of these organelles; deficiency of one complex may compromise all LRO or only some, which explains the variation in organs affected between subtypes [1]. The mechanism is loss of function, and the lack of one subunit usually destabilises the whole complex, a property used in diagnosis by immunoblotting [1, 2].

AP-3 is a heterotetramer that sorts transmembrane proteins from the trans-Golgi network and endosomes to lysosomes and LRO; melanosomes, δ granules, cytotoxic granules and neutrophil granules depend on this pathway [4]. There is a ubiquitous and a neuronal form of AP-3: the δ subunit (AP3D1) is essential to both, whereas the β3A subunit (AP3B1) is replaced by β3B in the neuronal form, which explains why HPS-10 has severe neurological disease and HPS-2 does not [59]. BLOC-1 has eight subunits, of which four have human pathogenic variants (dysbindin, BLOC1S3, pallidin and muted/BLOC1S5); three subunits (BLOC1S1, BLOC1S2 and SNAPIN) are shared with the BORC complex, and in 2020 defects in these were considered unlikely to cause HPS, as they are lethal or highly deleterious in mice [1, 2]. The description, in 2026, of 11 individuals from seven families with biallelic BLOC1S1 variants and a phenotype dominated by BORC deficiency confirmed that these shared subunits produce a distinct neurological disease [66]. BLOC-2 is formed by HPS3, HPS5 and HPS6, and BLOC-3 by HPS1 and HPS4 [1]. BLOC-3 acts as a guanine nucleotide exchange factor (GEF) for RAB32 and RAB38, promoting their membrane localisation and the biogenesis of melanosomes and δ granules; reduction of HPS4 destabilises BLOC-3 and lowers the HPS1 protein [4, 14]. Dysbindin associates with BLOC-2 in AP-3-independent TYRP1 trafficking, and truncation of BLOC1S3 destabilises the whole of BLOC-1, with mistargeting of TYRP1 to the plasma membrane [4].

2.2. Tissue consequences

In melanocytes, abnormal melanosome formation reduces the synthesis and distribution of melanin in the skin, hair, iris and retinal pigment epithelium; hypopigmentation of the developing retina is associated with foveal hypoplasia and excessive crossing of optic nerve fibres at the chiasm [1]. In platelets, δ granules store ADP, ATP, serotonin, calcium, phosphate and polyphosphate, and their release after stimulation recruits other platelets and generates the secondary wave of aggregation; a normal platelet has 3 to 8 δ granules (4 to 8 according to GeneReviews), and in HPS it has none or very few, with normal α granules [1, 4, 14]. In BLOC-2 defects, a contribution from altered maturation of Weibel-Palade bodies, with reduced release of von Willebrand factor, has been proposed [2].

In the lung, the lamellar bodies of type II pneumocytes, LRO that store surfactant, become giant, and type II cells become hyperplastic and vacuolated, with endoplasmic reticulum stress, altered autophagy and defective surfactant secretion [14]. Bronchoalveolar lavage from HPS-1 patients, with and without fibrosis, shows increased CCL2, CCL3 and GM-CSF, indicating a pro-inflammatory microenvironment preceding fibrosis; alveolar macrophages are foamy, laden with ceroid-lipofuscin, and spontaneously secrete CCL2, CCL3 and CCL5 [14]. In murine models, targeted deletion of CCL2 in type II cells normalised macrophages, TGF-β and bleomycin-induced fibrosis, and re-expression of Ap3b1 in type II cells prevented fibrosis; the cell responsible for susceptibility is therefore epithelial and not haematopoietic [2, 14]. Galectin-3 and chitinase-3-like-1 have a pro-fibrotic action, circulating fibrocytes are elevated in HPS pulmonary fibrosis and their episodic increases were associated with death in a longitudinal study [14]. A 2026 NIH serum multi-omic study identified changes in the transsulfuration pathway, arginine metabolism and redox balance with progression, higher CCL22 and choline levels in HPS-1 patients with fibrosis than without fibrosis in two independent cohorts, and inducible nitric oxide synthase (iNOS) as an upstream regulator of pro-fibrotic mediators; the authors state that all individuals with HPS-1 eventually develop fibrosis [68, 69].

In cytotoxic T lymphocytes and NK cells, AP-3 deficiency impairs degranulation and cytotoxicity; in neutrophils, deficient AP-3 mislocalises myeloperoxidase, elastase and CD63, and dendritic cells have defective toll-like receptor recruitment and interferon production [1, 2]. The studies summarised by OMIM add three mechanisms in HPS-2: the lytic granules of CD8 T lymphocytes, enlarged and loaded with perforin and granzymes, no longer move along microtubules to the immunological synapse, with marked loss of cytotoxicity; NK cells have less perforin and neutrophils less intracellular elastase, with more surface CD63; and the CD1b molecule, which depends on AP-3 to reach lysosomes, is retained in the membrane and early endosomes, which impairs the presentation of microbial lipid antigens with normal trafficking of HLA class II molecules [28, 39]. In the fibroblasts of the first patients, the lack of AP-3 diverted the lysosomal membrane proteins CD63, LAMP-1 and LAMP-2 to the cell surface, without affecting non-lysosomal proteins [28]. Ceroid-lipofuscin accumulates in alveolar macrophages, gastrointestinal tract, renal tubules, bone marrow, lymph nodes, liver, spleen and heart; the end-stage renal failure of some patients has been attributed to this deposition [2].

2.3. Class table

Sources: GeneReviews, Huizing 2020, Yokoyama and Gochuico 2021, Kodali 2026, Pennamen 2020 and Boeckelmann 2021 [1, 2, 14, 60, 70, 71]. AR, autosomal recessive; ILD, interstitial lung disease; IBD, inflammatory bowel disease; CNV, copy number variation.

2.4. Genes and variant spectrum by type

HPS-1 (HPS1). The gene is located at 10q24.2, has 20 exons in the longest transcript and encodes a protein of 700 amino acids (about 79.3 kDa); the MANE Select transcript is NM_000195.5 [2, 72]. The founder variant of north-western Puerto Rico is the 16 bp duplication NM_000195.5:c.1472_1487dup, p.(His497GlnfsTer90), in exon 15, classified as pathogenic in ClinVar (VCV000005277) by several submitters; about 261 Puerto Ricans with this variant had been reported, with an estimated 400 or so existing cases on the island [2, 72, 73]. Outside Puerto Rico, about 137 HPS-1 patients had been reported, none homozygous for dup16 [2, 14]. Seventy-six variants have been described: 26% frameshift, 20% missense, 14.5% nonsense, 24% insertions/deletions, 14.5% splice and 1% start-loss (c.2T>A, p.Met1Lys); of the 15 missense variants, 7 are pathogenic or likely pathogenic by the ACMG/AMP criteria (American College of Medical Genetics and Genomics / Association for Molecular Pathology) and 8 are variants of uncertain significance (VUS), and 10 missense variants with an allele frequency above 0.001 should be regarded as probable polymorphisms [2]. The synonymous variant c.507G>A, p.Glu169=, causes a splicing defect in two African American siblings, which shows that a synonymous variant cannot be excluded without RNA analysis [2]. Three frameshift variants recur in several ethnic groups: c.972dup, p.(Met325HisfsTer128), founder of the Swiss isolate and frequent in Europeans; c.972del, p.(Met325TrpfsTer6), in Europeans and South Asians; and c.1189del, p.(Gln397SerfsTer2), in Europeans. In the NIH cohort, 19 of 49 non-Puerto Rican HPS-1 patients (39%) had at least one of these three [2, 72]. The splice variant c.398+5G>A (IVS5+5G>A in historical nomenclature) is a founder in Japanese and has been described in Indians [1, 72]. The OMIM entries, which use the nomenclature of the 1996–2000 papers, describe a frameshift hotspot in a tract of eight cytosines at codons 321–324: insertion of a cytosine (T322insC) in the Swiss isolate and in an Irish-German patient, with different flanking polymorphisms indicating independent origins, and deletion of a cytosine in the same tract in a Japanese patient; the correspondence of these designations with c.972dup and c.972del has not been checked in VariantValidator and is not assumed [38]. dup16 was found in homozygosity in 22 Puerto Rican patients and in heterozygosity in the 11 obligate heterozygotes tested, and in 1998 HPS1 variants were found in only about half of non-Puerto Rican patients, which led to the search for other loci [27, 38]. In a Japanese patient compound heterozygous for an insertion of G at codon 321 and for IVS5+5G>A, skin biopsy showed giant melanosomes and reduced hair eumelanin [38].

HPS-2 (AP3B1). The gene is located at 5q14.1, has 27 exons and encodes the β3A subunit of AP-3, with 1094 amino acids (about 121 kDa); the MANE Select transcript is NM_003664.5, and not NM_001271769 as indicated by GeneGuidance [2, 4, 72]. By 2020, about 35 patients (Caucasian, Chinese, Lebanese, Mexican) and 29 variants had been reported, with no founders or recurrent variants; these include a homozygous inversion of chromosome 5 with a breakpoint in the gene and several large deletions, which means that about 10% of variants require deletion/duplication detection methods [1, 2]. The missense variants p.Leu580Arg and p.Ser901Cys are likely pathogenic and p.Leu102Pro is a VUS [2]. The first patients illustrate the spectrum: the two brothers of 1999 were compound heterozygous for a 63 bp cDNA deletion and for the missense variant designated L540R in the original paper; two Turkish cousins from a highly consanguineous family, homozygous for a genomic deletion with in-frame skipping of exon 15, had microcephaly, prominent midface, coarse hair, mild intellectual disability, granulocytopenia, intermittent thrombocytopenia, splenomegaly, severe dental caries with periodontitis and abscesses or pneumonias, without prolonged bleeding and with reduced NK cells; and a boy of Native American ancestry, compound heterozygous for two nonsense variants (R509X and E659X) with mRNA decay, had severe respiratory infections from the first year, non-specific interstitial pneumonitis, hepatosplenomegaly, neutropenia, thrombocytopenia, facial dysmorphism, mild developmental delay and mild bilateral conductive hearing loss [28, 39]. The protein designations of these early papers have not been converted to NM_003664.5. In 2026, an HPS-2 was described caused, on one allele, by a 9.7 kb deletion (NM_003664.5:c.787-3320_1167+370del) and, on the other, by an insertion of about 2.63 kb of an SVA retrotransposon in intron 7 (NM_003664.5:c.786+11042_786+11043insSVA), detected by long-read sequencing after repeated exomes had shown only the heterozygous deletion [74].

HPS-3 (HPS3). The gene is located at 3q24, has 17 exons and encodes a protein of 1004 amino acids (about 113.7 kDa), with a clathrin-binding motif and dileucine and tyrosine sorting signals, which acts in the early stages of melanosome biogenesis [2, 4]. The founder variant of central Puerto Rico is a 3.9 kb deletion that removes exon 1 and flanking regions, described by Huizing 2020 as NM_032383.5:c.-2993_217+692del (published designation, whose start lies outside the transcript boundaries and cannot be validated in that form) and recorded in ClinVar as NC_000003.12:g.149126714_149130632del (VCV000004608, pathogenic); it is detected by multiplex PCR and there is an allele-specific assay for heterozygotes and homozygotes [2, 52, 73]. This deletion explains why about 60% of HPS3 variants are deletions and why sequencing alone misses most patients from central Puerto Rico [1]. In Ashkenazi Jews, the variant NM_032383.5:c.1163+1G>A (ClinVar VCV000004609, pathogenic), corresponding to the historical IVS5+1G>A/«1303+1G>A» with exon 5 skipping, was found in homozygosity in three patients and in heterozygosity in one of 235 anonymous Ashkenazi samples; the equivalence results from the exon description and ClinVar, not from manual conversion [53, 72, 73]. Huizing 2020 designates as the Ashkenazi founder (7 cases) the variant c.1691+2T>G (VCV000004610), which in 2001 appeared as an allele in compound heterozygosity; this article records both formulations and treats c.1163+1G>A as the homozygous founder variant [2, 53, 73]. Thirty-seven variants have been described, including the deep intronic c.2888-1612G>A (formerly c.2887+2500G>A), which creates an 89 bp pseudoexon [2]. The OMIM gene entry confirms the reading adopted for Ashkenazi Jews: in the 2001 series, three patients were homozygous for the allele then designated 1303+1G>A, one was compound heterozygous for that allele and for the one designated 1831+2T>G, and another for 1303+1G>A and 2621-2A>G [40]. The Puerto Rican deletion, of 3904 bp, encompasses exon 1, part of intron 1 and about 2.9 kb upstream, with the breakpoint in a sequence shared by two Alu repeats; the authors dated its origin to between 1880 and 1890 and linked it to the migration of families from the town of Ciales to Aibonito, Barranquitas and Naranjito, three of which descended from a common ancestor [29, 40]. The 89 bp insertion between exons 16 and 17, in an Irish-English boy, was the first description of the intronic pseudoexon [40].

HPS-4 (HPS4). The gene is located at 22q12.1, has 14 exons and encodes a protein of 708 amino acids; 37 patients had been reported plus 4 unpublished NIH patients, of Ashkenazi, Chinese, European, Indian, Japanese, Pakistani, Sinhalese and Uruguayan origin, with 34 variants [2]. The variant NM_022081.6:c.2089_2093dup, p.(Lys699SerfsTer5) (VCV000004126, pathogenic), is frequent in Europeans [2, 72, 73]. The missense p.His154Arg (c.461A>G) was found in homozygosity in two Japanese siblings with HPS and mental illness (schizophrenia and major depression) [2]. The same protein change appears in OMIM in another family, two siblings of English and Polish origin, in compound heterozygosity with R217X; the entry gives the nucleotide position in two different ways (694A>G and 649A>G), both in old numbering, and should not be used for conversions [41]. The 2002 series included patients from South Tyrol, southern Italy (Q181X in homozygosity in three families) and the Netherlands, and in three patients only one allele was found by the methods of the time [41]. In the Anderson series (2003), seven patients aged 3 to 61 years had visual acuity of 20/60 to 20/200, all had easy bruising, the three women had menorrhagia, three had restrictive lung disease (one with severe fibrosis) and one had granulomatous colitis with vaginal and rectal fistulae [30]. A 46-year-old Sinhalese man, the son of first cousins, with no history of bleeding and normal platelet numbers, had severe pulmonary fibrosis with digital clubbing, absence of the second wave of aggregation and of δ granules, and ceroid-laden macrophages in the skin and lung [30, 41].

HPS-5 (HPS5). The gene is located at 11p15.1, has 23 exons and encodes a protein of 1129 amino acids; about 29 patients had been reported, with 31 non-recurrent variants [2]. These include splice variants (c.1634+1G>A, c.285-10A>G, c.3058+3A>G) and the synonymous c.219G>A, p.Arg73=, predicted to cause a splicing defect at the exon 3 junction; p.Thr1098Ile (allele frequency 0.024) is a benign polymorphism, and p.Leu624Arg is the probable cause in two Swiss siblings [2]. The intronic variant c.285-10A>G (NM_181507.1), in a 27-year-old Turkish man, the son of first cousins, activates a cryptic acceptor and inserts nine nucleotides in frame, that is, three amino acids in a conserved domain [31, 42]. In the 92-year-old patient, the single-nucleotide deletion was published as c.1081delC (transcript variant 2) and renumbered c.1423delC in transcript 1, an example of how the transcript alters the designation of the same variant [42]. In the 2004 series, serum cholesterol was elevated in all four patients and triglycerides in three, a finding interpreted by the authors as a possible consequence of altered vesicular trafficking and not confirmed in later series in the sources consulted; the first patient, a 3-year-old Turkish boy, had moderate thrombocytopenia [31].

HPS-6 (HPS6). It is a single-exon gene at 10q24.32, encoding a protein of 775 amino acids; in an Israeli Muslim Bedouin family, about 20 affected individuals are homozygous for the insertion of a G described as c.1065insG, and about 45 other patients are Arab, Afghan, Caucasian, Chinese, Japanese and Pakistani [1, 2]. The variant NM_024747.6:c.2038C>T, p.(Gln680Ter) (VCV000431051), recurs in five Japanese patients [2, 73]. No splice variants have been described, which is consistent with the absence of introns [2]. The variants summarised by OMIM include a deletion of about 20 kb encompassing the whole gene, in compound heterozygosity with Q305X in a northern European man, which reinforces the need to look for CNV in this gene as well, and the pair c.1898del, p.(Pro633LeufsTer76), and c.2038C>T, p.(Gln680Ter), in two Japanese sisters; OMIM records the Bedouin variant as 1066insG, not 1065insG, and neither form has been normalised [32, 43, 72]. In the Bedouin family there was no mRNA decay, so synthesis of a truncated protein is presumed [43].

HPS-7 (DTNBP1). The gene is located at 6p22.3, has 10 exons and encodes dysbindin (351 amino acids) [2]. The type was discovered in a 48-year-old Portuguese woman homozygous for NM_032122.5:c.307C>T, p.(Gln103Ter) (VCV000003432, pathogenic); by 2020 there were seven cases, all homozygous or compound heterozygous for nonsense or frameshift variants, including four Portuguese (two siblings) homozygous for the same variant, a Caucasian woman diagnosed at 77 years and an Argentinian boy compound heterozygous for c.307C>T and c.1017_1020del [2, 56, 73]. In 2024 another Portuguese case was published, a 69-year-old woman, the daughter of first cousins, homozygous for p.(Gln103Ter), and the authors proposed a founder effect in the Portuguese population [75]. A homozygous deletion of exon 6 has been described in one individual [1]. OMIM also records the 77-year-old patient as homozygous for NM_032122.5:c.177G>A, p.(Trp59Ter), identified by autozygosity mapping, and a 6-year-old Paraguayan boy, without known consanguinity, homozygous for p.(Gln103Ter), with normal mRNA and almost absent dysbindin in fibroblasts; in the databases of the time, this variant appeared in 2 of 120 818 alleles [33, 44, 72]. The presence of p.(Gln103Ter) in a South American patient does not contradict the Portuguese founder effect, but shows that the allele is not exclusive to that population. Huizing 2020 describes an Argentinian boy compound heterozygous for c.307C>T and c.1017_1020del, and it is not possible to determine, from the sources consulted, whether this is a different patient from the Paraguayan one [2, 33]. The association of common DTNBP1 variants with schizophrenia risk was not replicated in a re-evaluation with 38 SNPs in 634 cases, 776 controls and 180 trios of German ancestry; there is no ClinGen curation for schizophrenia, and the OMIM gene entry lists HPS-7 as the only phenotype, referring discussion of the association to the entry for the susceptibility locus SCZD3 (600511), without an established gene–phenotype relationship; a DTNBP1 variant should not be reported as a cause or predictor of schizophrenia [4, 44, 76]. No psychiatric disease has been reported in HPS-7 [2].

HPS-8 (BLOC1S3). The gene is located at 19q13.32, has two exons and encodes a protein of 202 amino acids [2]. The index family, Pakistani and consanguineous, with six affected members, is homozygous for NM_212550.5:c.448del, p.(Gln150ArgfsTer75); Huizing 2020 writes «p.Gly150Argfs*75», but the original paper and VariantValidator indicate glutamine at position 150 [2, 57, 72]. Three additional consanguineous families are homozygous for c.385_403del, c.338_341del (frameshift) and c.444_467del (in-frame deletion), with moderate albinism and bleeding diathesis [77]. OMIM also records a 6-year-old Iranian boy, the son of first cousins, homozygous for NM_212550.5:c.131C>A, p.(Ser44Ter), with mRNA reduced to about 6% in fibroblasts and 4% in melanocytes, easy bruising, mild gingival bleeding and absence of δ granules, without neutropenia, colitis or fibrosis [34, 45, 72]. In the Pakistani proband, silvery hair at birth darkened to golden, there was no history of bleeding at 21 years, and visual evoked potentials showed increased chiasmal decussation; other relatives had bruising, prolonged bleeding from wounds and menorrhagia [34]. The absence of ocular abnormality in the reduced pigmentation mouse, in contrast with the full human ocular phenotype, shows the limits of the murine model for predicting vision [34]. ClinGen gene–disease curation is moderate (2025) [4].

HPS-9 (BLOC1S6). The gene is located at 15q21.1 and encodes pallidin; the MANE Select transcript, NM_012388.4, encodes the 172-amino-acid isoform (NP_036520.1), a value also given by OMIM, and the longer transcript NM_001311255.1, referred to by some of the literature after 2015, encodes the 177-amino-acid isoform (NP_001298184.1) cited by Huizing 2020, which requires attention to numbering [2, 46, 72]. The 17-year-old Italian girl and the 4-year-old Pakistani girl are homozygous for c.232C>T, p.(Gln78Ter), and a 52-year-old Japanese woman for c.285_286dup, p.(His96LeufsTer22) [2, 58]. In 2026, the same p.(Gln78Ter), homozygous in exon 3, was described in a man in his fourth decade with pulmonary fibrosis [70]. OMIM adds two compound heterozygotes, all normalised to NM_012388.4: a Syrian girl with c.200C>G, p.(Ser67Ter), and c.319_320delinsAT, p.(Glu107Met), and a Chinese boy with c.148G>T, p.(Glu50Ter), and c.351dup, p.(Ile118TyrfsTer10), with no detectable pallidin and reduced dysbindin [35, 46, 72]. A 2011 paper describing another child homozygous for p.(Gln78Ter) was retracted after the US federal research integrity office concluded that a figure had been falsified, and it should not be counted among the published cases [35, 46].

HPS-10 (AP3D1). The gene is located at 19p13.3, has 32 exons and encodes the δ subunit of AP-3 (1215 amino acids); the reference transcript indicated is NM_001261826.3 [2, 72]. The index patient, a Turkish boy, was homozygous for c.3565_3566del, p.(Val1189LeufsTer8) (VCV000253144) [2, 59, 73]. Three related siblings were homozygous for c.1978delG, p.(Ala660Argfs*54), a variant that has not been normalised and was not found in ClinVar by text search [2, 4]. A consanguineous family homozygous for the missense p.(Val711Ile) had a milder picture, dominated by sensorineural deafness with neurological signs, mild neutropenia, reduced NK cytotoxicity and brain changes, without albinism; heterozygotes had milder deafness, suggesting a possible semidominant effect in a single family [4]. ClinGen curation is moderate (2025) and OMIM keeps the relationship with HPS-10 as provisional, with the Turkish patient as the only case in the gene entry and without the later families [4, 36, 47]. The index patient's variant affects both isoforms of the gene and prevents assembly of the AP-3 complex [47]. An Indian case from 2025 has been published, with information available only in the title [78].

HPS-11 (BLOC1S5). The gene is located at 6p24.3; the MANE transcript is NM_201280.3, which encodes the longest isoform (187 amino acids), and the transcripts NM_001199322.1 and NM_001199323.1 also exist [71, 72]. The type was established in 2020 in two patients from a French cohort of 230: one homozygous for a 19 063 bp deletion encompassing exons 3 and 4, detected by next-generation sequencing (NGS) read depth and confirmed by array comparative genomic hybridisation in the parents, and the other homozygous for c.345del, p.(Val116SerfsTer19) [60]. These were followed by two siblings from Uzbekistan homozygous for c.113-1G>A [71] and a Chinese patient homozygous for c.181del, p.(Val61Ter) [79]. The two 2020 patients had mild albinism: the French woman, aged 20, had acuity of 20/40 and 20/50, foveal hypoplasia and a bleeding diathesis revealed only by directed history-taking (bruising, week-long epistaxis once or twice a year, gingival bleeding), with reduced aggregation only to low collagen concentrations, low ATP release after TRAP, very low platelet serotonin and almost no δ granules; the Slovenian woman, aged 39, had acuity of 20/33, a normal fovea, numerous pigmented naevi and more marked bleeding (epistaxis in childhood, menorrhagia, excessive blood loss at delivery, in surgery and in dental extraction) [37]. ClinGen gene–disease curation has been definitive since 2023 [4]. The French patient's deletion corresponds to NM_201280.3:c.196-678_384+3483del, was heterozygous in both parents and has its breakpoints in regions of complete homology in introns 2 and 4, compatible with non-allelic homologous recombination; the mutant protein did not restore BLOC-1 stability or function in muted-deficient murine melanocytes [48, 72].

2.5. Normalised variants

Normalisation by VariantValidator (GRCh38, MANE Select) and ClinVar on 27 October 2026; the six rows added from the OMIM entries were normalised in VariantValidator on 28 October 2026 [43–46, 48, 72–74]. For the Bedouin HPS6 variant, the two possible forms of the duplication (c.1065dup and c.1066dup) give different proteins, neither equal to the p.Leu356ArgfsTer11 cited by GeneReviews, so the designation of the original paper is retained [1, 72]. In the 2026 Italian case, the paper states that c.355del is also indexed as «c.561del», a historical numbering that in NM_000195.5 corresponds to another variant and should not be used [72, 80].

2.6. Inheritance, penetrance and genotype–phenotype correlations

All types have autosomal recessive inheritance; heterozygotes are asymptomatic and are not at risk of disease [1]. Penetrance of albinism and δ granule deficiency is complete in the classic types, but expressivity varies: in BLOC-2 deficiency, hypopigmentation may be so subtle that patients are diagnosed with ocular albinism or only appear hypopigmented when compared with their siblings, and in BLOC-1 deficiency some patients may have normal or only reduced dense granules [1, 2]. Pulmonary fibrosis has high penetrance in HPS-1 («virtually all» by middle age, according to Huizing 2020; «all eventually develop it», according to Arif 2026) [2, 68]. Correlations between specific variants of the same gene and the clinical presentation are not convincing, and there is no genotype–phenotype correlation for fibrosis in HPS-1; the useful correlation is the one between the affected complex and the phenotype [1, 14]. The first comparative study, from 1998, illustrates this: among 49 NIH patients, those homozygous for dup16 (25 of 27 Puerto Ricans) were compared with patients without the duplication, a group then lacking a molecular diagnosis and, in the light of current knowledge, genetically heterogeneous; DLCO was below 80% predicted in 9 of 16 adults with dup16 and in none of 10 without it, CT showed fibrosis in 10 of 12 with dup16 (minimal in 8) and only minimal fibrosis in 3 of 8 without it, and IBD occurred in 4 patients in each group, between 3 and 25 years, with no difference in pigmentation [27]. In a 2000 ophthalmological study, the acuity of the better eye did not differ between the groups with and without dup16, and variability prevented vision from being predicted from pigmentation [27].

Heterozygous variants in HPS genes have been found in patients with other phenotypes and are interpreted as possible risk alleles and not as a cause of HPS: HPS1, HPS4 and DTNBP1 in sporadic or familial idiopathic pulmonary fibrosis; AP3B1 in primary immunodeficiency and HLH cohorts, with or without a variant in another gene; AP3D1, HPS3 and HPS4 in autism and schizophrenia [2]. In a surfactant gene panel applied to 221 probands with familial pulmonary fibrosis, 0.5% had HPS1 variants, a figure cited by the 2023 ERS (European Respiratory Society) statement [81]. An isolated heterozygous result in one of these genes does not establish a diagnosis of HPS.

2.7. Allelic disorders, modifiers and gene–disease validity

No other phenotypes caused by germline variants in the 11 genes are known, and the OMIM gene entries list only the respective HPS type [1, 38–48]. The partial exception is the family with the AP3D1 missense p.(Val711Ile) without albinism, which broadens the spectrum of HPS-10 itself [4]. Risk alleles of NOD2 and ATG16L1 and low vitamin D associated with sun avoidance have been proposed as possible modifiers of colitis [2]. In ClinGen curation, the DTNBP1–HPS-7 relationship is definitive (2021), BLOC1S5–HPS-11 definitive (2023), and BLOC1S3 and AP3D1 moderate (2025); there are no ClinGen actionability assertions for AP3B1, HPS3, HPS4, HPS5, HPS6 or BLOC1S3 [4].

3. Clinical Spectrum and Manifestations by System

3.1. Eyes and vision

Almost all children with HPS have nystagmus from birth, usually noticed by the parents and the physician in the first year; there may be periodic alternating nystagmus, erratic eye movements and poor visual attention [1]. Nystagmus is very rapid at first, slows over time and almost always persists throughout life, increasing with lateral gaze, fatigue and anxiety; development of pigment in the iris or retina does not change it [1]. The iris may remain blue or turn green, hazel or brown, and shows complete transillumination or radiating peripupillary streaks; fine granular pigment may appear in the retina [1]. Foveal hypoplasia, present in 94–100% of people with albinism when assessed by optical coherence tomography (OCT), is in HPS always grade 3 or 4 on the Thomas scale, and determines visual acuity, usually between 20/50 and 20/400, typically 20/200, constant after early childhood [1, 82]. Huizing 2020 gives an acuity of 20/60 to 20/400, with slight improvement with lenses, and many patients legally blind (acuity worse than 20/200) [2]. There is photophobia, excessive crossing of optic nerve fibres at the chiasm and alternating strabismus in many patients, generally without amblyopia [1]. Most have significant hypermetropia or myopia and astigmatism [1].

Ocular severity depends on the complex. In BLOC-2 deficiency, acuity is often about 20/100 or better [1]. In a retrospective ophthalmological cohort from Puerto Rico (106 patients), 72.9% had HPS-1 (dup16) and 26.2% HPS-3 (3.9 kb deletion); patients with HPS-3 had significantly better acuity (p<0.005), with no differences in refractive error or in macular volume and thickness on OCT [83]. A systematic review of 186 patients from 112 reports found an association between a diagnosis of ocular albinism and a higher risk of pulmonary fibrosis (OR 9.08; 95% CI 2.26–36.41) and between nystagmus and a lower risk (OR 0.11; 95% CI 0.03–0.42); these associations derive from case literature with publication bias and do not apply to individual risk stratification [84].

3.2. Skin and hair

Hair varies from white to brown and may darken with age; skin ranges from white to olive, generally at least one shade lighter than that of relatives [1]. In BLOC-1 deficiency, hair may be silvery, blond or golden at birth and darken later [1]. Hypopigmentation is more marked in BLOC-3 deficiency than in AP-3 or BLOC-2 deficiencies [2]. Prolonged sun exposure causes skin thickening (pachydermia), premalignant actinic keratoses, naevi, freckles, solar lentigines and basal cell and squamous cell carcinomas; melanocytes are present and melanoma is rare, although Huizing 2020 acknowledges a possible increased risk [1, 2]. In a French albinism series (all forms), 9% of 64 patients had actinic keratoses and 3 adults (4.7%) had skin cancer; a Brazilian albinism series cited in the same guidelines recorded skin cancer in 26% of patients, with a mean age of 47 years, in the context of equatorial sun exposure [21]. In Europe, lesions are often amelanotic, which gives dermoscopy a role [85]. In a dermatological study of 65 NIH patients (3 to 54 years), skin, hair and eye colour varied similarly in dup16 homozygotes and in the others, but signs of actinic damage (multiple freckles, stellate lentigines, actinic keratoses and, at times, basal cell or squamous cell carcinomas) were present in 80% of the former and 8% of the latter, a difference not fully explained by greater proximity to the equator; the same study described melanocytic naevi with atypia, acanthosis nigricans-like lesions in the axillae and neck, and trichomegaly [27]. A case of cutaneous malignant melanoma was reported in a British series of four patients in 1985 [27].

3.3. Bleeding diathesis

Bleeding results from the absence or severe reduction of δ granules, with normal α granules, and varies between and within subtypes [1, 2]. Bruising generally appears with the onset of walking; epistaxis is frequent in childhood and decreases after adolescence; there is gingival bleeding, bleeding on shedding of deciduous teeth, prolonged bleeding after dental extraction, circumcision and other surgery, heavy and irregular menstruation, postpartum haemorrhage and, in patients with colitis, rectal bleeding [1, 14]. Cuts bleed for longer but heal normally, and exsanguination during delivery, trauma or surgery is very rare [1]. Platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal, which leads to the diathesis being underestimated [1]. A review cited by Benvenuto 2022 reports excessive bleeding in 27.3% of patients with HPS undergoing surgery, more frequent without prophylaxis [86]. In an obstetric and gynaecological systematic review (15 women, 29 pregnancies, plus 2 gynaecological patients), 8 of 15 women (53%) had heavy menstrual bleeding, menstrual or postpartum bleeding led to the diagnosis in 5 of 17 (29%), and there was primary postpartum haemorrhage in 12 of 27 viable pregnancies (44%), half of them major [87].

3.4. Pulmonary fibrosis

HPS pulmonary fibrosis (HPS-PF) is a progressive restrictive interstitial lung disease, described in HPS-1, HPS-4 and HPS-2, in one HPS-10 patient and, since 2026, in one HPS-9 patient [1, 2, 70]. There is no convincing evidence of fibrosis in BLOC-2 deficiencies or in the other BLOC-1 types; the absence of reports in a small number of patients does not equate to zero risk [1]. In a 27-year-old HPS-5 man without respiratory symptoms, bronchoalveolar lavage showed foamy alveolar macrophages similar to those of HPS-1, and the authors proposed pulmonary surveillance in this type as well; in the 2004 HPS-5 series, two of the four patients were under 27 years old, an age below which lung disease is rare in any type, which limits the conclusion that fibrosis is absent [31]. In HPS-7, the Portuguese index patient had mild exertional dyspnoea and reduced lung compliance, with otherwise normal tests and HRCT [33]. In HPS-1, symptoms generally appear in the fourth decade, in HPS-4 in middle age and in HPS-2 in childhood or young adulthood [14]. Most patients with BLOC-3 deficiency develop fibrosis between 30 and 50 years and die within about a decade without transplantation [1, 2]; the Oxford textbook places death in the fourth or fifth decade [62].

Adapted from Yokoyama and Gochuico 2021, Table 2 [14]. HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; NSIP, non-specific interstitial pneumonia; DAD, diffuse alveolar damage; DIP, desquamative interstitial pneumonia.

The presentation is progressive exertional dyspnoea or chronic cough, with bibasal inspiratory crackles and, in severe disease, acrocyanosis and digital clubbing [14]. Early forms may have normal function tests; later a restrictive pattern appears with reduced diffusing capacity for carbon monoxide (DLCO), and forced vital capacity (FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC) and DLCO decline to a similar extent [14]. HRCT is more sensitive than radiography, showing bilateral reticulation and basal subpleural septal thickening in early disease and diffuse in severe disease, peribronchovascular thickening, traction bronchiectasis, honeycombing and ground glass, the latter atypical in idiopathic pulmonary fibrosis (IPF); the radiological score correlates inversely with FVC [14]. In the systematic review of 186 patients, ground glass was the most frequent radiological pattern (77.9%) and ceroid deposition the most frequent histological finding (66.7%) [84]. Histology shows UIP and NSIP patterns in HPS-1 and HPS-2 and DIP in children with HPS-2, with foamy macrophages and vacuolated type II cells with giant lamellar bodies [14].

The natural history has been characterised mainly by the NIH cohort and trials. FVC as a function of age, in five-year intervals, has a bimodal distribution, with nadirs at 36–40 and 56–60 years, suggesting a subgroup with early and rapid progression [14]. In the placebo arms, progression was inconsistent in mild to moderate disease: in the 2011 trial, the placebo group lost only 2.5% of predicted FVC per year [88], whereas in severe patients in the placebo arm the annual FVC decline was 12–15% predicted [14]. Three patients aged 37 to 47 years with severe disease survived less than 20 months after reaching an FVC of 50% predicted [14], and O'Brien 2011 summarises that death from HPS-1 PF typically occurs between 40 and 50 years, with an FVC of about 25%, and that an FVC below 50% is associated with death within about two years without transplantation [88]. Acute exacerbations occur in HPS-1 and HPS-4, with rapid dyspnoea, functional decline and diffuse ground glass, and the explant shows UIP with diffuse alveolar damage [14]. Lung transplants in severe HPS-1 have been performed between 27 and 57 years [14].

In HPS-2, the European chILD-EU registry (2009–2017) brought together 6 children with a genetic diagnosis: pulmonary symptoms (dyspnoea, cough, oxygen requirement, clubbing) began 3.3 years before diagnosis, made at a mean of 8.83 years (2–15); all had recurrent lung infections, 3 had spontaneous pneumothorax and 4 scoliosis; all initial CTs had ground glass, with a rapid increase in the reticular pattern and traction bronchiectasis on the following CT, and 3 developed honeycombing and cysts [89]. Biopsy, performed in half, showed cellular NSIP, a UIP-like pattern and DIP [89].

In 2026, the first case of pulmonary fibrosis in HPS-9 was described: a man in his fourth decade with four months of progressive dyspnoea and cough, oculocutaneous albinism and bleeding diathesis, a UIP pattern on HRCT and homozygosity for p.(Gln78Ter) in BLOC1S6; this is an isolated case and does not establish the risk of the subtype [70]. Exertional dyspnoea was reported by 52% of patients with BLOC-3 deficiency and 38% of patients with BLOC-2 deficiency, a non-significant difference in a survey of 85 patients or carers, and about a third report wheezing [90].

3.5. Gastrointestinal tract

The haemorrhagic granulomatous colitis of HPS resembles Crohn's disease, can affect any segment of the gastrointestinal tract, including the gingiva, and is associated with extraintestinal manifestations such as pyoderma gangrenosum [1]. In the retrospective NIH cohort (1995–2019), 37 of 261 patients (14.2%; 12 men and 25 women) had inflammatory bowel disease (IBD), with a median age at onset of 17 years (1–52); symptoms were haematochezia, abdominal pain and loose stools, 30% had fistulae and 22% extraintestinal manifestations [15]. All patients with IBD had biallelic variants of HPS1, HPS3, HPS4 or HPS6, six had very early-onset IBD, HPS-3 had mild IBD, 73% received medical treatment and 35% intestinal resection; histology of three colectomies showed active cryptitis, chronic inflammation, granulomas and ceroid-lipofuscin [15]. GeneReviews indicates severe colitis in about 15% and Huizing 2020 colitis in 10–20% of BLOC-2 and BLOC-3 deficiencies; one adult HPS-7 patient had Crohn's colitis, and the frequency in AP-3 deficiency is unknown [1, 2]. Very early-onset IBD guidelines include HPS 1, 4 and 6 among the monogenic causes [91]. Gastro-oesophageal reflux disease (GORD) was the most frequently reported gastrointestinal symptom (62–69%) in the survey of 85 patients [90] and was coded in 28.6% of patients in US electronic health records [5].

3.6. Immunity and haematology

Immunodeficiency is characteristic of AP-3 deficiency. In HPS-2, neutropenia is the most prevalent immunological feature, responds to granulocyte colony-stimulating factor (G-CSF), which restores neutrophils but does not prevent all recurrent infections, and coexists with a cytotoxic defect of T and NK lymphocytes, with a spectrum ranging from mild recurrent infections to severe HLH [2]. In the largest survey, with 22 HPS-2 patients and 234 patient-years of observation, there was only one additional patient with HLH and two with transient incomplete HLH-like episodes, although cytotoxicity or degranulation was abnormal in all 16 tested; the risk of HLH in HPS-2 is lower than in Griscelli syndrome type 2 and Chédiak-Higashi syndrome [92]. A 2-year-old boy, initially classified as Griscelli, developed fulminant HLH at 3 years, with no identified trigger, refractory and fatal [93]. In this patient, homozygous for R302X (published notation, = NM_003664.5:c.904A>T p.(Arg302Ter), VCV000006376 in ClinVar) [73], haematopoietic cell transplantation had been postponed and G-CSF prevented new bacterial infections before the HLH, and the authors proposed including HPS-2 among the familial haemophagocytic syndromes with a possible indication for transplantation [28, 39]. Huizing 2020 mentions HLH in some HPS-2 patients, fatal in two [2]. Management of HLH follows the protocols for primary haemophagocytic lymphohistiocytosis.

In HPS-10, the index boy had albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalised seizures, ILD and hearing loss, with impaired cytotoxic degranulation without HLH, and died at 3.5 years from septic pneumonia [2, 59]. In BLOC-1 deficiency there have been isolated observations: two HPS-9 patients (Italian and Japanese) with mild thrombocytopenia and recurrent leucopenia or immunodeficiency [2], a Portuguese HPS-7 patient with recurrent bacterial infections and slightly reduced NK degranulation [1] and an HPS-8 patient with nodular lymphocyte-predominant Hodgkin lymphoma [77]. GeneReviews mentions «thrombocytopenia and leukaemia» in the two HPS-9 patients, whereas the mutation review by the same authors describes mild thrombocytopenia and recurrent leucopenia; this article follows the latter, which is more detailed, and the OMIM entries confirm leucopenia and not leukaemia: the Italian adolescent had recurrent skin infections, thrombocytopenia and leucopenia, normal platelet aggregation, no bleeding episodes, a prolonged febrile episode with seizures at 6 years and NK cells with reduced cytotoxicity and increased surface lysosomal markers, and the 52-year-old Japanese woman had leucopenia without recurrent infections and mild thrombocytopenia [1, 2, 35]. The Syrian HPS-9 girl had recurrent respiratory infections and asthma, with normal leucocytes and immunoglobulins and platelets at the lower limit of normal [35]. In HPS-11, the Slovenian patient reported recurrent infections (pneumonia, herpes, conjunctivitis) [37]. In Oman, between 2001 and 2021, three HPS-2 patients had severe neutropenia [94]. In US electronic health records, 23.5% of patients had coded anaemia, with no information on the cause [5].

3.7. Nervous system

HPS-10 is the neurological form: albinism, δ granule deficiency, neutropenia and recurrent infections, profound neurodevelopmental delay, microcephaly, hypotonia, severe generalised seizures or encephalopathy and sensorineural deafness, sometimes hepatosplenomegaly, with onset at birth or in early childhood and death in early childhood in the published cases [4, 13]. In the three siblings homozygous for c.1978delG, the twin girls died before 6 days of age and the brother at 2 years from pneumonia and sepsis [2]. In the index patient, seizures and dystonic movements with axial hypotonia began in the first weeks and progressed to refractory myoclonic and tonic-clonic epilepsy; recurrent infections, with hepatosplenomegaly and severe neutropenia, appeared at 8 months; brain imaging showed telencephalic atrophy, a large posterior fossa arachnoid cyst and deficient myelination; there was microcephaly, Pierre Robin sequence, hypotelorism, large low-set ears and flat acetabula; immunoglobulins and vaccine responses were normal, with elevated IgE and hypersegmented neutrophils in the marrow [36]. There was no clinical bleeding, but platelet function was not studied, so the δ granule deficiency of the index patient is presumed and not demonstrated [36]. The mocha mouse, null for Ap3d1, has pigment dilution, platelet storage pool deficiency, otolith abnormalities with imbalance and progressive deafness, hyperactivity and a hypersynchronised electrocorticographic rhythm, with reduction of the zinc transporter ZnT3 (SLC30A3) in the brain [36]. GeneReviews regards it as unclear whether the neurological features are related to AP3D1 deficiency, whereas Orphanet and GeneGuidance include them in the phenotype; the explanation via the neuronal form of AP-3 and the concordant phenotype of the mocha mouse (seizures, deafness and platelet storage pool deficiency) support this second reading [1, 13, 59]. In BLOC-1 deficiency, a Japanese HPS-9 patient developed schizophrenia at the end of her fifth decade, a Chinese HPS-9 boy had an abnormal EEG and a Syrian HPS-9 girl had recurrent infections, psychomotor delay and dextrocardia [1]. The authors of the Japanese case acknowledge that the schizophrenia may be coincidental, given its frequency in the population, and those of the Syrian girl consider the relationship of the delay and dextrocardia with HPS uncertain [35]. In the Chinese boy, OMIM describes a nearly normal electroretinogram with severely impaired transmission on visual evoked potentials, and not an abnormal EEG; the «EEG» designation in GeneReviews may result from confusion with the electroretinogram [1, 35]. In HPS-7, a 6-year-old Paraguayan boy had motor and language delay, optic nerve hypoplasia and a traumatic intracranial haemorrhage [33]. In 2026 a case of HPS-3 with schizophrenia and Crohn-like colitis was published [95]. In a 2026 HPS-2 case, the child had psychomotor delay, hypertonia and mild dysmorphic features [74].

3.8. Other organs and patient-reported symptoms

Cardiomyopathy and renal failure have been described rarely; end-stage renal failure has been attributed to ceroid deposition in some patients, with renal transplantation as an option [1, 2]. On the 84-question scale applied to 85 patients or carers, hypopigmentation and photosensitivity were present in all with BLOC-2 or BLOC-3 deficiency, nystagmus, low acuity and easy bruising were highly prevalent, and most reported palpitations, imbalance, headaches or migraine and autoimmune-type symptoms (xerophthalmia, rashes, myalgia); GORD, xerophthalmia and headaches were more frequent in adults than in children with BLOC-3 deficiency, and most adults were functionally independent [90]. In US electronic health records, vitamin D deficiency was coded in 16.2%, anxiety in 21.7% and chronic pain in 15.6% [5].

3.9. Synthesis by complex and age

BLOC-3 deficiency (HPS-1, HPS-4) is the most severe: marked albinism and bleeding, symptomatic and potentially fatal pulmonary fibrosis in the fourth decade, colitis in some patients [1, 2]. AP-3 deficiency combines variable hypopigmentation, neutropenia and cytotoxic deficiency, pulmonary fibrosis from childhood in HPS-2 and severe neurological disease in HPS-10 [2, 89]. BLOC-2 deficiency is milder and may go undiagnosed for decades: the oldest published patient, with HPS-5, was diagnosed at 92 years, with light skin and hair, nystagmus, acuity declining with age and a history of bleeding, and another HPS-5 patient at 65 years [1, 2]. According to OMIM, that patient came to attention at 72 years because of prolonged bleeding after resection of a bladder tumour, had a history of bleeding after tonsillectomy at 13 years and of epistaxis requiring cauterisation, had received corticosteroids for «colitis» in middle age and, at 92 years, had hand-motion perception in one eye and light perception in the other, with cataracts and macular staphylomas; OMIM places the first assessment at 72 years, and the sources consulted do not clarify whether the diagnosis was established at that time or only at 92 [31]. In HPS-6, two Japanese sisters without δ granules had no bleeding over 5 years of follow-up, with normal platelet count, bleeding time and von Willebrand factor, and an Italian man was diagnosed only at 44 years, because of digestive symptoms with iron-deficiency anaemia and low vitamin B12 [32]. BLOC-1 deficiency has few cases, with albinism, mild bleeding and isolated observations of colitis, infections, haematological neoplasms and, in one case, fibrosis [1, 70]. Over the lifespan, the usual sequence is nystagmus and hypopigmentation in the first year, bruising with walking, epistaxis in childhood, menorrhagia in adolescence, colitis from the second decade and pulmonary fibrosis in the fourth decade in the at-risk types [1, 14, 15]. The treated presentation differs from this natural history only in lung transplantation and control of colitis, because there is no therapy that alters the progression of fibrosis (section 7) [1].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

HPS should be considered in anyone with oculocutaneous or ocular albinism, because the bleeding diathesis may be mild, unrecognised or underestimated; NGS studies in albinism cohorts have identified variants in HPS genes, and some authors advocate screening all individuals with albinism by platelet studies [1]. Patients present via dermatology, ophthalmology, respiratory medicine, haematology, gastroenterology, immunology or neurology [2]. Suggestive findings are nystagmus, low vision, photophobia and strabismus; skin and hair lighter than those of relatives; easy bruising, epistaxis, gingival bleeding and prolonged bleeding after minor procedures, with normal PT, aPTT and platelet count; and a family history compatible with autosomal recessive inheritance, although the absence of a family history does not exclude the diagnosis [1]. When assessing a child with albinism, the Oxford textbook recommends asking about bruising since the onset of walking (HPS) and about severe or recurrent infections (Chédiak-Higashi) and requesting platelet studies if there are features suggestive of HPS [62].

Sources: GeneReviews, Huizing 2020, Yokoyama and Gochuico 2021, Hengst 2018, Obeng-Tuudah 2021 and Uhlig 2014 [1, 2, 14, 87, 89, 91].

4.2. Emergency signs

Urgent situations are bleeding that does not respond to local measures, particularly postpartum, postoperative or gastrointestinal bleeding in colitis; fever in a patient with neutropenia due to AP-3 deficiency; persistent fever with cytopenias, hepatosplenomegaly, hyperferritinaemia and hypofibrinogenaemia, suggesting HLH in HPS-2; spontaneous pneumothorax, described in 3 of 6 HPS-2 children in the chILD-EU registry; and rapid dyspnoea with functional decline and diffuse ground glass, reflecting acute exacerbation of fibrosis in HPS-1 and HPS-4 [1, 14, 89, 92]. The medical alert bracelet should explicitly describe the functional platelet defect, because routine tests are normal [1].

4.3. Newborn screening

There is no newborn screening programme for HPS. In Puerto Rico, a screening study using pooled DNA from dried blood spots of 12% of annual births, with PCR for the HPS3 founder deletion, found 75 samples with the variant, including 2 homozygous newborns, and a carrier frequency of 1:85 (1.18%) across the island; the authors advocated universal newborn screening in Puerto Rico, a proposal that had not been adopted according to the sources consulted [1, 96].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The clinical diagnosis is established in a proband with oculocutaneous albinism and absence of platelet δ granules [1]. Oculocutaneous albinism is defined by hypopigmentation of the skin and hair, particularly compared with relatives, associated with nystagmus, iris transillumination, reduced retinal pigment and foveal hypoplasia with significantly reduced acuity [1]. The molecular diagnosis requires, in addition to suggestive findings, biallelic pathogenic or likely pathogenic variants in one of the 11 genes; two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1]. Yokoyama and Gochuico define HPS by the combination of oculocutaneous albinism, a bleeding tendency and biallelic variants, regarding the absence of δ granules on electron microscopy as consistent with the diagnosis but available in few laboratories [14]. In the French guidelines, comparing pigmentation with that of the family is difficult in fair-skinned Northern European populations, and OCT is the reference standard for foveal hypoplasia; visual evoked potentials show the asymmetric crossing of the optic pathways [21].

5.2. Platelet function testing

The 2015 guidance of the ISTH (International Society on Thrombosis and Haemostasis) platelet physiology subcommittee proposes a three-step algorithm for inherited platelet function disorders [20]. The first step is clinical: personal and family bleeding history (unexplained or extensive bruising, epistaxis, menorrhagia, bleeding at delivery, after invasive procedures and dental extractions), with the use of a bleeding assessment tool encouraged, although the ISTH-BAT (bleeding assessment tool) has not been sufficiently evaluated in these disorders for a firm recommendation; enquiry about drugs and foods that interfere with platelet function, eczema, recurrent infections and familial myelodysplasia; and physical examination directed at syndromic features, including skin discolouration and ocular involvement [20]. If there are abnormalities, full blood count, PT, aPTT and screening for von Willebrand disease (von Willebrand factor antigen, ristocetin cofactor activity and factor VIII) follow; if these are normal, platelet testing proceeds [20]. First-step tests include a blood film, light transmission aggregometry (LTA) with adrenaline, ADP, collagen, arachidonic acid and ristocetin, a granule release study with ATP/ADP measurement (lumiaggregometry or an alternative) and of at least one α granule marker, and flow cytometry of the major glycoproteins; they require 21–28 mL of blood and can diagnose up to about 40% of these disorders [20]. When secretion is reduced, granule content is measured in the second step, which includes extended LTA, cytometry with additional antibodies, clot retraction, serum thromboxane B2 and transmission electron microscopy for counting α and δ granules; the PFA-100 and bleeding time are not recommended because of insufficient specificity and sensitivity or poor reproducibility [20]. The German S2k guideline of the GTH (Gesellschaft für Thrombose- und Hämostaseforschung), updated in 2025, follows the same logic, with standardised questionnaires, LTA, cytometry, NGS genetics and pre-analytical standards [97], and a 2026 review counts about 60 entities and 75 genes of congenital platelet function disorders [98].

In HPS, aggregometry shows absence or reduction of the secondary wave of aggregation [1]. The reference method is whole mount electron microscopy of intact platelets, not contrast-stained ultrathin sections or scanning microscopy; the 2023 revision of GeneReviews specifically corrected the preferred method [1]. A normal platelet has 4–8 dense bodies and in HPS none [1]; in the French patient with HPS-11 there were fewer than 0.1 dense granules per platelet, compared with 3–8 in controls [60]. This method is semi-specialised and not routinely available; the alternatives are quantification of mepacrine uptake, super-resolution immunofluorescence and absence of the secondary wave on aggregometry [2]. In 2025 a flow cytometry protocol with mepacrine and FluoZin-3 was published, validated in mice and in patients confirmed by electron microscopy: mepacrine uptake was reduced in all models (BLOC-1, BLOC-2, BLOC-3 and AP-3), the FluoZin-3 zinc pattern varied with the complex (increased in BLOC-1, BLOC-2 and AP-3 deficiencies and decreased in BLOC-3 deficiency), and OCA6 albinism showed no changes; the abstract does not give sensitivity or specificity [99]. In the Padua experience, the pathway began with aggregation and transmission electron microscopy and was confirmed by molecular testing [80]. Immunoblotting in fibroblasts or platelet-rich plasma identifies the deficient complex, because the lack of one subunit destabilises the whole complex [2].

The δ granule absence criterion has limitations. In BLOC-1 deficiency, dense granules may be normal or only reduced in some patients, which may exclude them from the classic diagnosis [2]; in the two HPS-11 siblings from Uzbekistan, aggregation was only slightly abnormal and the δ granule secretion defect was evident only on cytometry [71]. In HPS-10, the index patient's platelets were not studied because of the absence of bleeding [59]. A normal platelet study in a patient with albinism reduces the probability of HPS, but does not exclude it.

5.3. Genetic testing

GeneReviews proposes two strategies: a multigene panel with the 11 genes and other differential diagnosis genes, or exome (the most widely used) or genome sequencing when the phenotype is indistinguishable from other disorders with albinism or dense body deficiency [1]. In patients of Puerto Rican, Ashkenazi Jewish or Israeli Bedouin ancestry, targeted analysis of the founder variants may precede the panel [1]. The historical single-gene strategy (HPS1 and HPS4 in the severe phenotype with pulmonary symptoms; HPS3, HPS5, HPS6 and then the BLOC-1 genes in the mild phenotype; AP3B1 and AP3D1 with immunological symptoms) has been replaced by simultaneous testing of all genes [2]. In non-Puerto Ricans with suspected HPS-1, the 2020 review suggests that exons 11 and 13 of HPS1 concentrate the three recurrent variants [2]. The French guidelines regard the NGS panel as the reference standard for subtyping and indicate that about 10.8% of pathogenic albinism alleles are rearrangements, which justifies complementary array comparative genomic hybridisation, and that about 25% of patients with albinism remain without an identified cause [21]. A 2026 review gives a sequencing yield in albinism of about 70% [100]. Another 2026 review counts at least 21 albinism genes, 12 of which are linked to the syndromic forms (Chédiak-Higashi and HPS types 1 to 11), and regards molecular diagnosis by NGS as essential [101].

Adapted from GeneReviews, Table 1, with data up to January 2023 [1, 60]. The method columns indicate the proportion of known variants detected by each technique, and not the clinical sensitivity of the test.

In adults with pulmonary fibrosis, HPS may be diagnosed via respiratory medicine. The 2026 British consensus on familial pulmonary fibrosis includes HPS among the monogenic causes due to altered surfactant biology: variants of HPS1, HPS4 (BLOC-3) and AP3B1 (AP-3) impair lamellar body formation and intracellular trafficking of surfactant components; interstitial disease typically appears in mid-adulthood, earlier in HPS-2, with a mixed inflammatory-fibrosing picture and progressive course [102]. The «Pulmonary fibrosis, familial» panel of the National Genomic Test Directory for England (since 2022; 24 genes and the MUC5B promoter variant, also accessible in Wales, Northern Ireland and Scotland) can be requested directly by the respiratory physician when the patient meets the eligibility criteria; in version 1.18 of the panel in PanelApp (August 2026), HPS1, HPS4 and AP3B1 have the highest level of evidence, whereas the other HPS genes are not part of it [102, 103]. VUS are reported only if they have a reasonable probability of reclassification, predictive testing of unaffected relatives goes through clinical genetics and not the respiratory clinic, and the authors recommend referral to clinical genetics whenever a pathogenic or likely pathogenic variant is identified [102]. A negative pulmonary fibrosis panel therefore does not exclude HPS due to HPS3, HPS5, HPS6 or BLOC-1 genes, which do not cause pulmonary fibrosis but still cause albinism and the bleeding diathesis [1, 103].

The limitations of molecular tests have practical consequences. Sequencing alone without CNV analysis misses the HPS3 founder deletion, the AP3B1 inversion and deletions, the DTNBP1 exon 6 deletion and the BLOC1S5 exon 3 and 4 deletion [1, 60]. Apparent homozygosity may correspond to a deletion of one or more exons on the other allele (false homozygosity) or to uniparental isodisomy, and should be confirmed by parental testing [1]. Deep intronic variants (89 bp pseudoexon in HPS3) and synonymous variants with a splicing effect (HPS1 c.507G>A; HPS5 c.219G>A) escape routine exome interpretation and may require RNA or cDNA studies [2]. In the 2026 HPS-2 case, repeated exomes detected only a heterozygous deletion; long-read sequencing with adaptive sampling identified the SVA insertion on the other allele, confirmed by RNA sequencing, and the authors concluded that a negative or monoallelic exome does not exclude HPS-2 [74]. Some patients with an HPS phenotype have no variants in the known genes, which justifies DNA banking of probands without a molecular diagnosis [1, 2]. Somatic mosaicism has not been described as a mechanism of HPS in the sources consulted; parental mosaicism is considered when only one parent carries the variant (section 8) [1]. A negative molecular result does not exclude HPS in a patient with albinism and absent δ granules.

The report should state the gene, the reference transcript with version (preferably MANE Select: NM_000195.5 for HPS1, NM_003664.5 for AP3B1, NM_032383.5 for HPS3, NM_022081.6 for HPS4, NM_024747.6 for HPS6, NM_032122.5 for DTNBP1, NM_212550.5 for BLOC1S3, NM_012388.4 for BLOC1S6, NM_201280.3 for BLOC1S5), the HGVS c. and p. nomenclature, zygosity, phase confirmation by parental testing and the ACMG/AMP class [1, 72]. For genes with alternative transcripts used in the literature (BLOC1S6, AP3B1) and for variants with historical nomenclature (HPS1 «c.561del», HPS3 «1303+1G>A», HPS6 «c.1065insG»), conversion should be done in VariantValidator or ClinVar, and not by manual calculation [53, 72, 80]. VUS can be reclassified by family segregation, by platelet testing of the proband and siblings and by immunoblotting demonstrating loss of the complex [1, 2]. An isolated heterozygous variant in an HPS gene, found on a familial pulmonary fibrosis, immunodeficiency or IBD panel, does not establish the diagnosis (section 2.6) [2].

5.4. Initial assessment after diagnosis

Adapted from GeneReviews, Table 3, and the French albinism guidelines [1, 21, 92].

5.5. Pulmonary assessment

The diagnosis of HPS pulmonary fibrosis is made by HRCT; lung biopsy is not generally recommended and is relatively contraindicated because of the bleeding risk, and bronchoscopy has no role in diagnosis [14]. The 2022 ATS/ERS/JRS/ALAT (American Thoracic Society / European Respiratory Society / Japanese Respiratory Society / Asociación Latinoamericana de Tórax) guideline includes among the relative contraindications to transbronchial cryobiopsy and surgical biopsy an uncorrectable bleeding risk, FVC below 50% and DLCO below 35% [18]. In a patient in Columbia, a transbronchial biopsy without prior desmopressin and with abnormal aggregometry caused pulmonary haemorrhage of about 700 mL requiring intubation [86]. The same guideline defines progressive pulmonary fibrosis (PPF) in a patient with non-IPF ILD and radiological fibrosis by the presence of at least two of three criteria in the last year, without an alternative explanation: worsening respiratory symptoms; absolute decline in FVC ≥5% predicted or in haemoglobin-corrected DLCO ≥10% predicted within one year; and radiological progression (increase in traction bronchiectasis, new ground glass with traction bronchiectasis, new fine reticulation, increased extent or coarseness of reticulation, new or increased honeycombing, lobar volume loss) [18]. HPS is not mentioned in the guideline; HPS-PF is a fibrosing ILD of known cause that may meet this definition, and its application is an extrapolation [18]. The 2023 ERS statement on familial pulmonary fibrosis is limited to telomere and surfactant genes and expressly refers HPS to its own documents, which do not exist in the sources consulted [81]. The 2026 British consensus on familial pulmonary fibrosis in adults describes a genetic investigation pathway centred on telomeropathies and surfactant disorders, with a panel accessible to respiratory physicians in England; the full text was not obtained [102].

5.6. Assessment of inflammatory bowel disease

In very early-onset IBD, the 2014 diagnostic approach included HPS 1, 4 and 6 among the more than 50 monogenic causes [91]. The 2021 position paper of the Porto group of ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) recommends NGS for monogenic forms, with the indication guided by age at onset, family history, comorbidities and extraintestinal manifestations, using a 75-gene panel, and before any haematopoietic stem cell transplantation (HSCT) [104]. The 2023 BSG/BSPGHAN (British Society of Gastroenterology / British Society of Paediatric Gastroenterology, Hepatology and Nutrition) consensus extends genomic diagnosis of monogenic IBD to children and adults and notes that more than 100 monogenic diseases can present as IBD [105]. Hypopigmentation and a history of bleeding in a patient with granulomatous colitis are the clinical link that points towards HPS.

5.7. Practical algorithm

Built from GeneReviews, Huizing 2020, the ISTH 2015 guidance and Baba 2026 [1, 2, 20, 74].

5.8. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; the Oxford textbook mentions chorionic villus sampling [1, 62]. The decision is personal and views on its use diverge [1]. Without known variants, the sources consulted do not describe a validated phenotypic prenatal method.

6. Differential Diagnosis

6.1. Comparative table

Sources: GeneReviews on HPS, albinism and Chédiak-Higashi; Oxford textbook; Saudubray; ERS 2023; ISTH 2015; De Pace 2026 [1, 20, 61, 62, 66, 81, 82, 106, 107].

6.2. Non-syndromic albinisms

The non-syndromic oculocutaneous albinisms share with HPS the visual changes (nystagmus, iris transillumination, reduced retinal pigment, foveal hypoplasia, abnormal crossing of the optic pathways with strabismus and reduced stereopsis), and the pigmentation of the skin, hair and iris varies with the gene and the variant in all of them [1]. In predominantly European populations, HPS accounts for about 4% of all cases of oculocutaneous albinism, and in the French series of 990 patients with albinism, 46 with HPS were identified [2, 82]. In HPS only grade 3 or 4 foveal hypoplasia is seen, whereas in non-syndromic albinisms it may be grade 1 to 4 [82]. The distinction depends on the bleeding history, platelet testing and a panel that includes the HPS genes; the absence of reported bleeding is not enough to exclude HPS [1]. X-linked ocular albinism has minimal skin manifestations, which makes it resemble BLOC-2 deficiency, but inheritance and platelet testing distinguish them [1].

6.3. Chédiak-Higashi and Griscelli syndromes

Chédiak-Higashi syndrome combines partial albinism, a bleeding diathesis and significantly increased infections in childhood; neutrophils always have giant intracellular granules on the blood film, a finding never present in HPS, about 85% of patients develop the accelerated phase of HLH and all develop neurological disease, including adolescents and adults with the atypical form and children with the classic form after HSCT [1, 106]. Among the HPS subtypes, HPS-2 most closely resembles Chédiak-Higashi, with congenital neutropenia, severe recurrent bacterial infections, pulmonary fibrosis and a lower risk of HLH; the blood film and molecular testing distinguish them [106]. The Griscelli syndromes combine mild hypopigmentation with silvery-grey hair and, in type 2, immunodeficiency and a lymphohistiocytic accelerated phase; type 1 has neurological deficits without immune dysfunction and type 3 has neither neurological nor immunological deficits [1, 82]. Elejalde syndrome is regarded as a type of Griscelli with neurological involvement [1]. Hair microscopy and a peripheral blood film have been proposed as rapid screening in a child with partial albinism and immunodeficiency [4]. A boy with HPS-2 was initially classified as Griscelli because he had a heterozygous RAB27A variant; severe bleeding led to aggregation and dense granule studies, and to the correct diagnosis [93].

6.4. Platelet disorders without albinism

Isolated δ granule deficiency produces the same laboratory defect without visual defects; in the past, patients with HPS and mild hypopigmentation were classified in this way [1]. Glanzmann thrombasthenia and Bernard-Soulier syndrome are distinguished by aggregometry (abnormal with several agonists in the former; abnormal with ristocetin and large platelets on the blood film in the latter) and by glycoprotein cytometry, and the ISTH guidance regards them as the disorders most straightforward to identify [20]. In the 2026 Italian case, aggregation was abnormal and there was reduced expression of CD41a (GPIIb-IIIa), a finding that, in isolation, might have suggested thrombasthenia; electron microscopy and the exome established HPS [80]. In the British ThromboGenomics cohort, 6 of 159 patients with bleeding, thrombotic or platelet disorders had HPS [2].

6.5. Diseases with pulmonary fibrosis, colitis or neurological involvement

In adult familial pulmonary fibrosis, the most frequent monogenic causes are variants in telomere and surfactant genes, with dominant inheritance in most families; HPS is distinguished by albinism, bleeding and ground glass on HRCT, atypical in IPF [14, 81]. The granulomatous colitis of HPS resembles Crohn's disease, and the presence of hypopigmentation and bleeding should prompt a monogenic IBD panel [1, 91]. In HPS-10 with seizures, the differential includes BLOC1S1 disease, with hypomyelinating leukoaxonopathy and epileptic encephalopathy, milder hypopigmentation and ocular albinism and a predominance of BORC deficiency [66]. Familial HLH without albinism (PRF1, UNC13D, STX11, STXBP2) enters the differential diagnosis [107]. Among the causes of generalised hypopigmentation, the Oxford textbook lists phenylketonuria, homocystinuria, Prader-Willi or Angelman syndrome due to a 15q11–q12 deletion with an OCA2 variant on the other allele, Menkes disease and cystinosis, in which the skin and hair are lighter than those of siblings and the 65 kb CTNS deletion is present in 76% of patients of European origin [62]. Waardenburg syndrome (MITF) is another trafficking disorder with hypopigmentation, whose classification as syndromic albinism is debated [61, 82].

7. Treatments and Risk Management Strategies

7.1. Principles and reference documents

There is no HPS-specific clinical practice guideline issued by a scientific society; the available recommendations are from NIH experts, published as reviews (Seward and Gahl 2013, on lifelong care; Huizing 2020; Yokoyama and Gochuico 2021, on pulmonary fibrosis; Wang and Young 2025) and brought together in GeneReviews [1, 2, 14, 16, 17]. There is no cure and no medicine approved by the FDA (Food and Drug Administration) or the EMA (European Medicines Agency) for HPS or its pulmonary fibrosis; treatment is preventive and supportive, ideally multidisciplinary, and all the drugs mentioned below are used off-label, unless otherwise stated [1, 14]. For pulmonary fibrosis, transplantation, platelet testing, monogenic IBD and albinism, guidelines for other conditions apply by extrapolation, which do not mention HPS or mention it only to exclude it from their scope.

Sources: [1, 16, 18–21, 81, 97, 102, 104, 105, 108].

7.2. Eyes

Refractive errors are corrected with appropriate optics; low vision aids include hand-held magnifiers and bioptic lenses, and at school preferential seating and support from a low vision consultant are needed [1]. Sunglasses blocking ultraviolet radiation help with photophobia, but many patients prefer not to wear them because they reduce vision; opaque or very dark contact lenses do not generally improve visual function [1]. Strabismus surgery is reserved for misalignments not corrected by medical measures, is rarely needed and not always effective [1]. The 2026 ophthalmological review includes amblyopia screening, cycloplegic refraction with full correction, management of nystagmus (contact lenses, prisms, surgery), spectral filters and low vision aids [109]. In the two German HPS-11 siblings, uncorrected visual impairment was the main problem, and tinted lenses with 20% absorption indoors and 80% outdoors were fitted [71].

7.3. Skin

Sun protection includes clothing (wide-brimmed hat, long sleeves, trousers, socks) for prolonged exposure and high sun protection factor (SPF) sunscreen, 45–50 or higher in very sensitive people and 15 or higher in less sensitive people; in the very sensitive, 5–10 minutes of sun may be harmful, and in the less sensitive 30 minutes or more [1]. The Oxford textbook recommends broad-spectrum sunscreen with SPF ≥45, sunglasses and wide-brimmed hats [62]. Routine dermatological examination and removal of suspicious lesions are part of care, and skin cancer is treated by the usual methods [1, 14]. The French guidelines recommend screening for and treating vitamin D deficiency from 5 years, with lifelong maintenance therapy, without a consensus on dose [21].

7.4. Bleeding

Bleeding management rests on a plan coordinated by haematology with the school, family and primary care, and on a medical alert bracelet describing the functional platelet defect [1]. For minor wounds that do not clot, gelatin sponge soaked in thrombin is used; humidifiers may reduce the frequency of epistaxis [1]. To limit alloimmunisation, which compromises future candidacy for lung transplantation, procoagulants are preferred for mild bleeding and transfusion is reserved for situations in which it is needed, with single-donor, irradiated and leucoreduced platelets, and in some cases HLA-matched [14, 110]. For elective surgery with moderate or greater estimated blood loss, GeneReviews recommends single-donor HLA-matched platelets, and platelets on standby for all surgery with significant bleeding risk [1].

Desmopressin. Desmopressin (desmopressin acetate; Ddavp Desmopressin® solution for injection in Portugal; DDAVP® injection in the USA and Brazil) is a synthetic vasopressin analogue that, at haematological doses of 0.3–0.4 µg/kg, increases plasma concentrations of factor VIII and von Willebrand factor 3- to 4-fold and releases tissue plasminogen activator [111]. The reference dose in HPS is that of GeneReviews: 0.3 µg/kg in 50 mL of normal saline, as an intravenous infusion over 30 to 60 minutes immediately before the procedure, for more invasive trauma such as wisdom tooth extraction [1]. The Columbia centre used 0.3 µg/kg IV before transplant surgery and transbronchial biopsy [86]. Not all patients respond, and a prior response test is recommended [1]; Merideth 2020 describes a variable response [110]. In Portugal, the SmPC includes in the indication the shortening or normalisation of bleeding time before invasive procedures and the control of bleeding in patients with congenital platelet dysfunction, which covers HPS; the dosage is 0.3 to 0.4 µg/kg, diluted in 50 to 100 mL of normal saline, infused over 15 to 30 minutes, reduced to 0.2 µg/kg in the elderly or those with cardiovascular disease, given immediately before surgery and repeated every 12 hours if needed [111]. The FDA label indicates desmopressin in haemophilia A with factor VIII above 5% and in type 1 von Willebrand disease, at a dose of 0.3 µg/kg of actual body weight, with a maximum of 20 µg, infused over 15 to 30 minutes, 30 minutes before the procedure, repeatable after 8–12 hours and then once a day, with tachyphylaxis on repeated doses and efficacy established from 3 months of age [112]. The 30–60 minute infusion of GeneReviews is slower than that of the labels, and the 20 µg maximum appears only in the US label. The main adverse effects are fluid retention and hyponatraemia (boxed warning in the FDA label), with seizures in severe cases: fluid intake should be restricted from 1 hour before to 8 hours after (maximum 0.5 L according to the Portuguese SmPC), sodium measured before, at one week and at about one month with repeated use, and the drug avoided with current or previous hyponatraemia, creatinine clearance below 50 mL/min, polydipsia, loop diuretics or glucocorticoids; there is also hypotension or hypertension and thrombosis in type IIB von Willebrand disease [111, 112]. In children, fluid restriction requires extra care [112]. Use in HPS dates back to 1989, when desmopressin corrected the bleeding time in some patients and the authors suggested combining it with an antifibrinolytic, because it also increases plasminogen activator activity; vitamin E, used previously for the same purpose, has no demonstrated efficacy and is not part of current recommendations [1, 27].

Antifibrinolytics. Tranexamic acid and aminocaproic acid can reduce the severity of menorrhagia and are used in mucosal and dental bleeding, with no HPS-specific dose in the sources consulted; the doses below are those of the labels for analogous indications, by extrapolation [1]. Oral tranexamic acid (Tafixyl® 500 mg in Portugal; Transamin® in Brazil) has, in the Portuguese SmPC, for menorrhagia, a dose of 1–1.5 g 3 to 4 times a day for 3 to 4 days, started with profuse bleeding, and for dental extraction in patients with coagulation disorders, after an intravenous dose, 25 mg/kg orally 3 to 4 times a day for 6 to 8 days; in children, 25 mg/kg per dose with limited data; the SmPC limits the indication to adults and states that there is no experience below 15 years in menorrhagia [113, 114]. The US tablet label indicates 1300 mg 3 times a day (3900 mg/day) for a maximum of 5 days per cycle, and contraindicates the combination with combined hormonal contraception and active thromboembolic disease or intrinsic risk of thrombosis [115], which is relevant to patients with HPS who use combined oral contraceptives. Intravenously, the FDA label indicates 10 mg/kg of actual body weight immediately before dental extraction and then 10 mg/kg 3 to 4 times a day for 2 to 8 days, at a maximum rate of 1 mL/min, and the Portuguese SmPC for the solution for injection indicates 0.5–1 g 2 to 3 times a day for local fibrinolysis and about 20 mg/kg/day in children from 1 year, with limited paediatric data; neither defines a maximum daily dose for the intravenous route [116, 117]. Both require reduction in renal impairment (in the Portuguese oral SmPC, 15 mg/kg twice a day with creatinine 120–249 µmol/L, 15 mg/kg per day with 250–500 µmol/L and 7.5 mg/kg per day above 500 µmol/L) and are contraindicated in subarachnoid haemorrhage and active intravascular coagulation [113, 116]. Aminocaproic acid (Ipsilon® in Brazil) has, in the US label, for bleeding due to increased fibrinolysis, 5 g in the first hour and then 1 g/h (tablets) or 1.25 g/h (oral solution) for about 8 hours or until control, with no maximum dose defined in the source, which mentions prolongation of bleeding time with continuous infusions above 24 g/day, and it is contraindicated in active intravascular coagulation [114, 118]; it was used by infusion as prophylaxis for a lung transplant and to treat a retroperitoneal haemorrhage under anticoagulation [86, 119].

Menorrhagia. GeneReviews mentions oral contraceptives and intrauterine devices, the description of treatment with a levonorgestrel intrauterine system and with recombinant factor VIIa, and antifibrinolytics [1]. In an HPS-11 patient, menorrhagia improved with hormonal contraception [60].

Recombinant factor VIIa. Eptacog alfa (NovoSeven®) was used for menorrhagia in HPS in a report cited by GeneReviews, with no dose stated [1]. In the analogous labelled condition, Glanzmann thrombasthenia refractory to platelet transfusions, with or without antiplatelet antibodies, the FDA dose, in adults and children, is 90 µg/kg IV every 2–6 hours until haemostasis in severe bleeding, with no maximum dose defined in the source, and 90 µg/kg immediately before surgery, repeated every 2 hours during the procedure and then every 2–6 hours; the label carries a boxed warning of arterial and venous thrombosis [120]. Use in HPS is an extrapolation, and the label regards platelets as the primary treatment when there is no refractoriness [120].

Sources: [1, 14, 86, 111–118, 120].

7.5. Pulmonary fibrosis

Prevention and support. Before fibrosis appears, maximising lung function is recommended: prompt treatment of asthma and respiratory infections, optimisation of reactive airway disease, vaccination against influenza, pneumococcus and COVID-19, regular moderate exercise, balanced nutrition, weight control and treatment of comorbidities [1, 14]. Patients should avoid tobacco, vaping and all recreational inhaled products, exposure to organic and inorganic fibres, volatiles and polluted environments, and drugs associated with iatrogenic pulmonary fibrosis (methotrexate, bleomycin, amiodarone, nitrofurantoin) [1]. These preventive measures apply to asymptomatic individuals of the at-risk types (HPS-1, HPS-2, HPS-4 and possibly HPS-10) [14]. In established disease, pulmonary rehabilitation and oxygen therapy for hypoxaemia are the mainstay of support; oxygen therapy is vital in advanced disease and helps delay secondary pulmonary hypertension [1, 14]. Corticosteroids have often been tried without apparent benefit and are not recommended [1, 14]. The 2025 review by Wang and Young maintains this position and adds that there are case reports of high-dose corticosteroids in a presumed acute exacerbation; it recommends annual influenza and pneumococcal vaccination according to chronic lung disease standards, periodic assessment of oxygen needs by exercise testing and referral of symptomatic patients to pulmonary rehabilitation; secondary spontaneous pneumothorax, described mainly in HPS-2 in childhood and adolescence, may recur and eventually require pleurodesis [17].

Antifibrotics. No antifibrotic is approved for HPS-PF, and the two randomised trials of pirfenidone were inconclusive (section 7.10) [1, 14]. Pirfenidone was well tolerated in those trials and was continued on a compassionate-use basis case by case in NIH patients [14, 121]. The 2022 ATS/ERS/JRS/ALAT guideline suggests nintedanib in PPF in patients who have failed standard management of a non-IPF fibrosing ILD (conditional recommendation, low-quality evidence; 62% of votes conditional, 29% strong) and leaves pirfenidone in PPF as a research recommendation [18]. The 2023 ERS statement agrees with the use of antifibrotics in IPF and PPF, including in patients with known monogenic disease, although it excludes HPS from its scope [81]. Application to HPS-PF is an extrapolation: HPS-PF may meet the definition of PPF, but nintedanib has not been studied in HPS, and its label identifies bleeding risk as a precaution, which in HPS is a theoretical concern [14, 122, 123]. The 2025 review by Wang and Young diverges on this point: it regards nintedanib as contraindicated in HPS because of the potential for increased bleeding complications, without citing clinical data in the disease, and allows pirfenidone case by case in patients with CT-documented fibrosis and demonstrated progression, by extrapolation from experience in progressive fibrosing ILD, acknowledging that it is well tolerated but of uncertain efficacy in HPS; no label, neither the FDA nor the European one, lists HPS or platelet diatheses as a contraindication to nintedanib, where they appear as a precaution [17, 122, 123]. In the systematic review of published cases, survival was better with an antifibrotic or transplantation (log-rank p=0.042), with no independent prognostic factor on multivariate analysis; this is low-quality observational evidence [84]. In US electronic health records, pirfenidone was prescribed to 2.5–2.7% of patients with HPS and nintedanib to fewer than 10 patients (1.3%) [5]. The 2026 British consensus, which groups HPS with the surfactant biology disorders, considers that these have no specific treatment: immunomodulation is decided case by case, especially in children with an inflammatory phenotype; in adults with fibrosing disease antifibrotics are appropriate, although without dedicated studies and with only a small observational study suggesting stabilisation; lung transplantation is the only definitive treatment, and referral to specialised centres is recommended [102].

Pirfenidone (Esbriet® in the USA and the EU; generics in the EU; Esdona® and generics in Brazil). In alveolar macrophages from HPS-1 patients, it reduced activation in vitro [14]. The dose used in the HPS trials was 801 mg (3 tablets of 267 mg) 3 times a day, after weekly escalation (267 mg 3 times a day in the first week and 534 mg in the second), in the 2011 trial, and 800 mg 3 times a day in the 2002 trial [88, 124]. This matches the label dose for IPF in adults: titration over 14 days to 801 mg 3 times a day (2403 mg/day), with food, without doses above 2403 mg/day; the European SmPC requires titration to be restarted after 14 or more consecutive days without a dose, reduction to 267–534 mg 2 to 3 times a day for gastrointestinal effects and to 267 mg 3 times a day for mild to moderate photosensitivity [125, 126]. The labelled indication is IPF in adults, and paediatric safety and efficacy have not been established [125, 126]. Adverse effects include drug-induced liver injury, including fatal cases after marketing, which requires liver tests (ALT, AST, bilirubin) before and during treatment; photosensitivity and rash, to be prevented with daily sun avoidance, sunscreen and clothing; severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS); nausea, dyspepsia, GORD and diarrhoea [125]. In the 2011 trial, dyspepsia and heartburn affected about half of each group and responded better to proton pump inhibitors than to H2 antagonists, and there was photosensitivity rash and possible elevation of creatine kinase with pirfenidone [88]. In HPS, photosensitivity adds to the skin vulnerability of albinism.

Nintedanib (Ofev® in the USA, the EU and Brazil; generics in the EU and Brazil). A tyrosine kinase inhibitor whose targets include the vascular endothelial growth factor receptor (VEGFR) [123]. In adults, the dose is 150 mg orally 2 times a day, about 12 hours apart and with food, reduced to 100 mg 2 times a day for adverse effects or mild hepatic impairment (Child-Pugh A), with a maximum of 300 mg/day [122, 123]. In the EU, between 6 and 17 years, the dose is weight-based, 2 times a day: 13.5–22.9 kg 50 mg (reduced 25 mg); 23.0–33.4 kg 75 mg (50 mg); 33.5–57.4 kg 100 mg (75 mg); ≥57.5 kg 150 mg (100 mg); it is not recommended below 6 years or 13.5 kg, and requires monitoring of growth, annual bone imaging of the growth plates while the epiphyses are open and dental examination at least every 6 months [123]. In the USA, paediatric safety and efficacy have not been established, and efficacy was not demonstrated in a trial of 26 patients aged 6 to 17 years [122]. Bleeding events occurred in 10% versus 7% (IPF), 11% versus 8% (systemic sclerosis-associated ILD) and 11% versus 13% (progressive ILD), mainly epistaxis, and after marketing there were serious bleeds, some fatal; the FDA label recommends using nintedanib in patients with known bleeding risk only if the anticipated benefit outweighs the risk, and the European SmPC stresses that patients with a hereditary predisposition to bleeding were not included in the trials [122, 123]. Diarrhoea affected 67% versus 24% in the progressive ILD trial; liver tests and, in women, a pregnancy test are required before starting [122]. The European paediatric indication in clinically significant progressive fibrosing ILD is relevant to paediatric HPS-2, but there are no data in HPS [89, 123].

Nerandomilast (Jascayd®). A phosphodiesterase 4 (PDE4) inhibitor, approved by the FDA on 7 October 2025 for IPF in adults (new molecular entity, priority review, orphan designation), with the PPF indication in adults added in December 2025; in the EU, the European Commission authorisation of 15 July 2026 covers IPF and PPF in adults [127–129]. The dose is 18 mg orally 2 times a day, with or without food, reduced to 9 mg 2 times a day for intolerance (diarrhoea, weight loss), except with pirfenidone or CYP3A inducers, when 18 mg is maintained; the EU requires 9 mg 2 times a day with strong CYP3A inhibitors; pirfenidone reduces exposure to nerandomilast by about 50% [128, 129]. It is not recommended with an estimated glomerular filtration rate below 15 mL/min/1.73 m² [128]. Adverse effects include diarrhoea (42%, 31% and 17% with 18 mg, 9 mg and placebo), depression in an aggregate that includes suicidal ideation (12%, 11% and 10%), weight loss and, in FIBRONEER-ILD, neoplasms more frequent with the drug (5% and 5% versus 3%); the trials excluded severe depression and suicidal behaviour or ideation [128]. There are no data at all in HPS, and its use in HPS-PF would be an extrapolation from the PPF indication [128].

7.6. Lung transplantation

Single or double lung transplantation is the option in end-stage fibrosis, with reports of success, and the 2025 review regards early referral to a transplant centre as critical in HPS-1 and HPS-4 patients [1, 14, 17]. The 2021 ISHLT (International Society for Heart and Lung Transplantation) consensus recommends referral of any ILD at diagnosis of histological UIP or a probable or definite UIP pattern on CT, even while therapy is being started; of any fibrosis with FVC below 80% or DLCO below 40% predicted; in the presence, in the last 2 years, of a relative decline in FVC ≥10%, DLCO ≥15% or FVC ≥5% with worsening symptoms or radiological progression; with an oxygen requirement at rest or on exertion; and early in familial pulmonary fibrosis, because of the extrapulmonary manifestations [19]. Listing is indicated in the presence, in the last 6 months and despite treatment, of an absolute decline in FVC above 10%, DLCO above 10%, or FVC above 5% with radiological progression; desaturation below 88% or a decline of more than 50 m on the 6-minute walk test; pulmonary hypertension; or hospitalisation for respiratory decline, pneumothorax or acute exacerbation [19]. The consensus expressly mentions HPS among the ILDs that require special consideration because of extrapulmonary manifestations, allows pirfenidone and nintedanib to be continued until transplantation, and considers that intractable haematological diseases, including bleeding diathesis, allow transplantation only in very selected cases [19]. The HPS series diverge from this formulation: the Columbia centre concludes that HPS should not be considered a contraindication, and the NIH recommend an individualised haematological plan [86, 119]. The 2025 review recalls that the bleeding diathesis was considered a contraindication to transplantation until the first successful transplant, in 2005, and cites an estimate from the patient network (HPS Network), obtained by personal communication in April 2024, of 49 patients with HPS who have received lung transplants worldwide; the estimate does not come from a registry [17].

At Columbia (2003–2021), of 11 candidates (median age 48 years at referral, 8 Puerto Ricans with confirmed HPS-1, 4 former smokers), 7 underwent transplantation, 3 double and 4 single lung, with 3 patients on extracorporeal membrane oxygenation (ECMO) as a bridge [86]. Survival was 85.7% at 30 days and 83.3% at 1 and 2 years; median blood loss was 400 mL (125–750), with one massive intraoperative haemorrhage of 4043 mL despite desmopressin and a previous surgical biopsy without bleeding, and one death at 72 hours due to dislodgement of a venoarterial ECMO cannula with massive transfusion [86]. There was primary graft dysfunction in 3 of 7 (grade 3 at 72 hours in 2), mild acute rejection at 9 and 12 months in 2 patients, both with chronic graft dysfunction, and one death at 82 months after de novo donor-specific antibodies; there was no recurrence of fibrosis in the graft [86]. Prophylaxis was given in 6 of 7 patients (mainly desmopressin; one with aminocaproic acid infusion; one with 2 units of preoperative platelets), and the centre recommends prior haematological consultation, a massive transfusion plan, desmopressin 0.3 µg/kg IV and platelets immediately before surgery, desmopressin before bronchoscopic biopsies and single lung transplantation as an option with less dissection and shorter operating time [86].

At the NIH and two regional centres, 6 HPS-1 patients with fibrosis (median age 41.5 years) were assessed for transplantation: 3 died without transplantation, one referred with FVC of 14%, pulmonary artery pressure of 47 mmHg and a lung allocation score of 91, and two without compatible donors because of transfusional sensitisation (calculated panel reactive antibody of 41% and 100%; one with antibodies against 100% of donors after platelet transfusions 2, 9 and 10 years earlier) [119]. The 3 bilateral transplant recipients had, respectively, continuous desmopressin infusion for about 14 hours without platelets and more than 6 years without chronic dysfunction; leucoreduced platelets for mild bleeding and treated acute rejection; and venovenous ECMO for 11 days with heparin, mild diffuse bleeding treated with prothrombin complex concentrate, platelets and desmopressin, and a retroperitoneal haemorrhage on enoxaparin treated with aminocaproic acid [119]. The authors recommend an individualised plan, platelets immediately available for all patients even with desmopressin, limiting alloimmunisation, early haematological assessment, perioperative desensitisation in sensitised patients and genetic testing to identify patients at risk [119]. ECMO with full anticoagulation has been used successfully in listed patients, and surveillance bronchoscopies with biopsy after transplantation may require bleeding prophylaxis [14]. In a 2026 Chinese case, a 47-year-old man with HPS-PF, right-sided aortic arch, a MUC5B variant and early-stage lung cancer underwent double lung transplantation, returned to work within 1 month and had no recurrence at 1 year [130].

7.7. Granulomatous colitis

Colitis responds to corticosteroids and other anti-inflammatory drugs, immunomodulators and tumour necrosis factor α antagonists (anti-TNF-α), and partial or total colectomy is reserved for severe refractory disease [1, 2]. In the NIH cohort, 73% of patients with IBD received medical treatment and 35% intestinal resection, and 7 of 13 patients treated with anti-TNF had a prolonged clinical response [15]. In a Turkish series of 4 patients on anti-TNF (2008–2013), with a mean follow-up of 7.5 years, 2 improved significantly and 2 had an unfavourable course, and the authors considered the response apparently inferior to that in Crohn's disease [131]. A 24-year-old Puerto Rican man with infliximab-resistant colitis and symptomatic sigmoid stricture was treated with laparoscopic low anterior resection and a defunctioning ileostomy, after haematological optimisation; the specimen showed transmural inflammation, a fistulous tract and ceroid [132]. An NIAID (National Institute of Allergy and Infectious Diseases) study of stepwise therapy for colitis (mesalazine, corticosteroids, infliximab, 6-mercaptopurine, adalimumab, tacrolimus) was withdrawn without enrolment [133].

Infliximab (Remicade® in the USA, the EU and Brazil; biosimilars) is the anti-TNF cited by GeneReviews as used with benefit, with no dose indicated for HPS [1]. The label dose for the analogous condition, Crohn's disease, is 5 mg/kg IV at weeks 0, 2 and 6 and then every 8 weeks, with 10 mg/kg every 8 weeks in adults who lose response, the highest dose provided in the label for Crohn's disease; in paediatric Crohn's disease from 6 years, 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks, with no escalation defined in the label [134]. Use in HPS colitis is an extrapolation [15, 134]. Rectal bleeding from colitis aggravates the diathesis, and surgery requires the haemostatic plan described in section 7.4 [1, 132].

7.8. Immunodeficiency and haemophagocytic lymphohistiocytosis

The neutropenia of AP-3 deficiency generally responds to G-CSF, which should be part of an infection prevention plan with infectious diseases, the school, the family and primary care [1]. Filgrastim (Neupogen® in the USA; Granulokine® and Zarzio® in Brazil; biosimilars) has, in the US label, for congenital neutropenia, a starting dose of 6 µg/kg subcutaneously 2 times a day, adjusted to response, with doses of 100 µg/kg/day or more rarely required and no maximum dose defined in the source [114, 135]. In HPS-2, G-CSF restores neutrophils but does not prevent all recurrent infections [2]; it prevented bacterial infections in a 2-year-old boy [93] and, in the child with the SVA insertion, given from 2 years of age, it improved neutrophils and prevented severe infections [74]. Use in HPS is an extrapolation from congenital neutropenia. The sources consulted did not include the European or Portuguese SmPC for filgrastim.

Given the low risk of HLH in HPS-2 (one additional patient with HLH in 234 patient-years), preventive HSCT does not appear justified; HSCT should be considered after a severe episode of HLH [2, 92]. The diagnosis and treatment of HLH follow the protocols for primary haemophagocytic lymphohistiocytosis. ESID (European Society for Immunodeficiencies) maintains a registry that includes these patients [1].

7.9. Comparative regulatory status

Sources: Drugs@FDA, FDA labels, EMA EPARs, Infomed and ANVISA open data («active» status and date of completion of the process, which is not necessarily the date of first registration) [111–116, 118, 120, 122, 123, 125–129, 134, 135]. The EMA has no orphan designations for HPS in the public list of designations (3310 records consulted) [136]; in the FDA Office of Orphan Products Development (OOPD) orphan designation database, searches for the term «Hermansky» in the designation text, carried out on 27 and 28 October 2026 over the whole period since 1983, returned no records [137]. As the search covers only the designation text, a designation worded with another name (for example, pulmonary fibrosis associated with a genetic disease) would not be found, so the negative result does not prove the absence of designations. No medicine has an approved indication for HPS in any of the jurisdictions.

7.10. Clinical trials

Sources: [88, 121, 124, 133, 138–141].

The HPS-PF trials are small, conducted almost only in Puerto Ricans with HPS-1, and do not allow indirect comparison with each other or with IPF trials. The 2002 trial gave opposite results depending on the statistical model, and the 2011 trial was stopped because progression in the placebo arm (2.5% of predicted FVC per year) made it impossible to demonstrate benefit even with complete arrest of decline [88, 124]. The registry data from the 2011 trial show numerically greater declines with pirfenidone, with standard deviations larger than the means and a placebo arm of 3 patients at 36 months, which precludes any conclusion [138]. The 2018 open-label series compares 3 patients with historical controls and is subject to selection and survival bias [121]. The heterogeneity of progression (bimodal FVC nadirs) and the scarcity of patients are the reasons why the NIH sought, in 2026, specialist support to define outcomes and designs for future trials [14, 142]. The FIBRONEER trials of nerandomilast showed, in IPF (n=1177), an adjusted FVC decline of −106 mL (18 mg) and −122 mL (9 mg) versus −170 mL with placebo, differences of 64 mL (95% CI 25–102) and 48 mL (10–86), and in PPF (n=1178) of −86 mL and −69 mL versus −152 mL, differences of 65 mL (30–101) and 83 mL (48–118); these results do not translate directly to HPS, which was not represented [128].

7.11. Developments in the last 12 months

Gene therapy remains preclinical: a lentiviral vector with HPS1 corrected HPS-1 dermal melanocytes, HPS1 transfection normalised galectin-3 in lung fibroblasts, transgenic correction of Ap3b1 in type II cells protected against bleomycin fibrosis in the mouse, and SpCas9 editing corrected the HPS1 dup16 in B lymphoblasts; there is no registered human trial [14, 144]. A 2025 review describes cell and gene therapies explored for melanosomes and the epithelium, less well known for platelets and the endothelium, and induced pluripotent stem cell models [67]. On ClinicalTrials.gov, consulted on 27 October 2026, there were no active interventional trials for HPS; the 12 registered studies were completed, terminated, withdrawn or of unknown status, with the exception of the observational studies [143]. The NIH notice was read on a public tenders aggregator and was not confirmed on the official SAM.gov portal [142]. A negative search does not prove the absence of unregistered studies.

7.12. Agents and circumstances to avoid

All non-steroidal anti-inflammatory drugs (NSAIDs) and products containing acetylsalicylic acid should be avoided, as should anticoagulants at therapeutic doses unless clinically indicated, high-impact sports and activities with a risk of bleeding, tobacco and vaping, pulmonary toxicants (fibres, volatiles, polluted environments), drugs associated with pulmonary fibrosis (methotrexate, bleomycin, amiodarone, nitrofurantoin) and unprotected sun exposure [1]. Diagnostic lung biopsy is not recommended [14]. Systemic corticosteroids are not recommended for fibrosis [14]. In the 2026 Italian case, methotrexate for rheumatoid arthritis was contraindicated because of renal and hepatic disease, and its pulmonary toxicity adds a reason to avoid it in HPS [1, 80].

7.13. Pregnancy and lactation

Pregnancy proceeds normally when the mother or the fetus is affected, but delivery carries a bleeding risk in a woman with HPS, and a haematology appointment should be made as soon as the pregnancy is confirmed, to plan delivery [1]. In the obstetric systematic review, primary postpartum haemorrhage occurred in 44% of viable pregnancies; among 17 pregnancies with a prior diagnosis, major postpartum haemorrhage occurred in 3 of 9 (33%) with desmopressin cover and in none of the 8 with platelets, and the authors recommend multidisciplinary obstetric and haematological management [87]. The comparison is observational and based on few cases. The Portuguese SmPC for injectable desmopressin regards the experience in pregnancy as insufficient, whereas the FDA label mentions decades of use without an identified risk of malformations [111, 112]. Tranexamic acid crosses the placenta and should be avoided in pregnancy unless absolutely necessary; it passes into milk at about one hundredth of the maternal blood concentration, and the Portuguese SmPC recommends not using it during breastfeeding unless absolutely necessary [113]. Nintedanib is contraindicated in pregnancy, requires highly effective contraception until 3 months after the last dose and a pregnancy test, and there are no data on excretion in human milk [123]. There are no data on pirfenidone in human pregnancy, and in animals there is placental transfer and excretion in milk [126]. Nerandomilast may cause pregnancy loss in animal studies and is excreted in rat milk [129].

7.14. Dental procedures and surgery

The perioperative plan is individual and coordinated with haematology: prior desmopressin response test, desmopressin 0.3 µg/kg IV immediately before invasive procedures (maximum of 20 µg in the US label [112]), antifibrinolytics for mucosal and dental procedures, platelets on standby for all surgery with significant bleeding risk and single-donor HLA-matched platelets for surgery with moderate or greater estimated blood loss [1, 86]. In transplant candidates, limiting alloimmunisation weighs on the choice between procoagulants and platelets [14, 119]. Bronchoscopic biopsy should be preceded by desmopressin [86]. The UKHCDO published in 2006 guidance on bleeding, surgical and obstetric management for inherited platelet disorders, the full text of which was not read [108].

7.15. Transition to adulthood

Needs change with age: in childhood, low vision, school adaptation, bruising and epistaxis predominate; in adolescence, menorrhagia; in young adulthood, colitis and the start of pulmonary surveillance; and from the fourth decade, fibrosis in the at-risk types [1, 16]. Most adults are functionally independent [90]. Transition should ensure that the adult knows their subtype, the bleeding plan and the need for function tests from 20 years (or from late adolescence, according to the 2025 review) [17], and that they remain abstinent from tobacco and avoid unnecessary alloimmunisation, conditions that preserve future candidacy for transplantation [1, 14]. The sources consulted do not describe a structured HPS-specific transition programme.

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

HPS is transmitted in an autosomal recessive manner in all types [1]. The parents of a proband are presumed heterozygous and should both be tested when there is a molecular diagnosis; if only one carries the variant, once paternity and maternity have been confirmed, a de novo variant in the proband or a post-zygotic de novo variant in a mosaic parent is considered [1]. Apparent homozygosity requires exclusion of a deletion of one or more exons not detected by sequencing (false homozygosity) and of uniparental isodisomy [1]. Heterozygotes are asymptomatic and are not at risk of disease [1].

The Oxford textbook gives a carrier frequency of 1/18 in Puerto Rico, without specifying the gene or region [62].

8.2. Cascade testing and carriers

Carrier detection requires prior identification of the familial variants [1]. Testing of the partners of carriers and affected individuals is recommended, especially if they are of the same ethnic origin, because there are founder variants in Puerto Ricans, Ashkenazi Jews, Europeans, Japanese, Swiss and Israeli Bedouins [1]. For the HPS3 deletion there is an allele-specific assay that distinguishes heterozygotes and homozygotes [52]. In HPS-1 and HPS-4, the diagnosis of an affected sibling is apparent from hypopigmentation and nystagmus; in the other nine genes, in which there are mild forms without obvious hypopigmentation or nystagmus, apparently asymptomatic siblings should be clarified by molecular testing when the variants are known or, if not, by platelet electron microscopy [1]. Early clarification of an affected sibling allows a bleeding plan before surgery or delivery and, in the at-risk types, pulmonary surveillance and tobacco abstinence.

8.3. Prenatal and preimplantation diagnosis

Once the familial pathogenic variants have been identified, prenatal diagnosis, for example by chorionic villus sampling, and preimplantation genetic testing are possible [1, 62]. Views on their use differ between professionals and families, and the decision is personal [1]. In probands without a molecular diagnosis, DNA banking preserves the possibility of future diagnosis [1].

8.4. Content of counselling

Counselling should ideally precede pregnancy and be directed at young adults who are affected, carriers or at risk of being carriers [1]. The content includes the subtype and its prognosis (pulmonary fibrosis in BLOC-3 and AP-3 deficiencies, immunodeficiency in AP-3, mild phenotype in BLOC-2), recurrence risks, obstetric bleeding risk and the delivery plan, avoidance of tobacco and pulmonary toxicants, and interpretation of isolated heterozygous results found on panels for other diseases [1, 2, 87]. Testing of asymptomatic minors is justified in this disease because the result has immediate consequences for the bleeding plan, sun and visual protection and surveillance; determination of carrier status in minors without clinical consequences should await the age at which they can decide, a general counselling principle that the sources consulted on HPS do not specifically discuss. In families with a DTNBP1 variant, it should be explained that the gene is not a predictor of schizophrenia [4].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The figures refer to different measures and are not comparable with each other. The Orphanet worldwide estimate is not validated; the North American data count coded diagnoses not confirmed genetically, and are not a validated population prevalence [3, 5]. In the US records, the mean age was 35 ± 22 years, 59% were women, 25.6% were aged 18 or under, 68.3% were white, 6.2% black, 3.7% Asian and 45.2% Hispanic; albinism was coded in 26.9%, platelet defects in 26.3%, nystagmus in 20.1%, legal blindness in 16.6% and unspecified pulmonary fibrosis in 5.24% (incidence) to 14.9% (prevalence) [5]. The French guidelines give for HPS-1 «1/800 in Puerto Rico», a value that diverges from the 1/1800 of the other sources [21].

9.2. Founder populations and geography

Puerto Rico concentrates two founders: the HPS1 dup16 in the north-west and the 3.9 kb HPS3 deletion in the centre [1, 2]. Homozygosity for dup16 was found in about 80% of patients of Puerto Rican ancestry in a series cited by GeneReviews; by 2023, about 260 Puerto Rican patients homozygous for dup16 represented about 33% of all published patients, and about 70 homozygous for the HPS3 deletion about 9% [1]. By 2019, about 333 Puerto Ricans and about 385 patients of other ethnicities had been reported [2]. In the USA, coded diagnoses are concentrated on the East Coast and in Texas, Ohio and Illinois, consistent with the Puerto Rican diaspora, and the authors raise the hypothesis of an undescribed founder in Native Americans [5].

In Europe, the isolate of a Swiss Alpine village has the HPS1 variant c.972dup, which is also frequent in other Europeans, and HPS4 c.2089_2093dup is the recurrent European variant [1, 2]. In France, in a screening of 990 patients with albinism, 46 had HPS, and the Bordeaux cohort of 230 patients without a molecular diagnosis gave rise to the description of HPS-11 [2, 60]. In the United Kingdom, 6 of 159 patients in the ThromboGenomics project with bleeding, thrombotic or platelet disorders had HPS [2]. The 2026 European review regards the prevalence of albinism as probably underestimated in Europe, because of mild phenotypes in fair-skinned populations, and the risk of skin cancer as lower than in equatorial regions [85]. The other founder populations are Ashkenazi Jews (HPS3), Israeli Bedouins (HPS6, about 20 affected in one family) and Japan (HPS1 c.398+5G>A; HPS6 c.2038C>T) [1, 2]. Outside these, HPS has been described in China, India, the Middle East, South America and Western and Eastern Europe [1]; in albinism panels, 10 patients with HPS were identified among 21 Arabs with ocular hypopigmentation, 9 among 46 Japanese negative for OCA1 and HPS1, and 10 in a Chinese cohort [2]. In Oman, between 2001 and 2021, 8 patients were diagnosed (3 HPS-2, 1 HPS-3, 4 HPS-6), with three novel variants [94]. Eight Chinese children adopted in the USA were genotyped at the NIH because of albinism and easy bruising [145].

9.3. Portugal and Brazil

HPS-7 was first described in a 48-year-old Portuguese woman homozygous for DTNBP1 p.(Gln103Ter), and by 2020 four more Portuguese individuals homozygous for the same variant had been reported, including two siblings [2, 56]. In 2024, Rodrigues and colleagues published the case of a 69-year-old Portuguese woman, the daughter of first cousins, with severe visual impairment, photophobia, esotropia, pendular nystagmus, iris transillumination, a hypopigmented fundus and recurrent epistaxis, whose sister had died young with albinism and epistaxis; she was homozygous for the same variant, and the authors propose a founder effect in the Portuguese population [75]. A Portuguese HPS-7 patient had recurrent bacterial infections and slightly reduced NK degranulation [1]. There are no prevalence estimates for HPS in Portugal in the sources consulted. For Brazil, the sources consulted contain no prevalence data or HPS series; the French guidelines cite a Brazilian albinism series with skin cancer in 26% and a mean age of 47 years, which is not specific to HPS [21]. The lack of data in the sources consulted does not demonstrate that none exist.

9.4. Special populations

In children, assessment should include vision and school adaptation, the bleeding plan and, in AP-3 deficiency, the infection plan; in HPS-2, ILD may begin in early childhood [1, 89]. In women, menorrhagia and postpartum haemorrhage are the main bleeding manifestations and a frequent route to diagnosis (29% of women in the obstetric review) [87]. In the elderly, BLOC-2 deficiency may only be recognised in the ninth decade, and the cumulative skin risk increases [1, 2]. In fair-skinned Northern European patients and in families with red or blond hair, BLOC-2 deficiency, with a relative increase in pheomelanin, may go unnoticed; AP-3 deficiency may escape diagnosis because immunodeficiency dominates the picture, and BLOC-1 deficiency may not meet the classic platelet criterion [2].

9.5. European networks and patient associations

The relevant European Reference Networks are ERN-Skin (genodermatoses, including albinism), EuroBloodNet (rare haematological diseases, including platelet disorders), ERN-LUNG (rare lung diseases, including ILD), ERN-EYE (rare eye diseases) and ERN RITA (immunodeficiencies, autoinflammatory and autoimmune diseases, relevant to HPS-2 and HPS-10) [22–26]. The Hermansky-Pudlak Syndrome Network (USA) is the patient association partnering the NIH studies; NOAH (National Organization for Albinism and Hypopigmentation, USA), the Albinism Fellowship (United Kingdom) and Genespoir (France) support people with albinism [146–149]. The ESID registry and the National Eye Institute's eyeGENE collect patient data [1]. In the sources consulted, no HPS-specific association was identified in Portugal or Brazil, although no targeted geographical search was carried out.

10. Illustrative Clinical Case

Giulianelli and colleagues published in 2026 the case of a 62-year-old Italian woman, referred in July 2024 to Padua for progressive pulmonary fibrosis followed locally since 2019 [80]. She was a former heavy smoker of conventional and electronic cigarettes (21 pack-years), with no occupational exposure or family history of lung disease, and had severe chronic kidney disease of unknown cause, mild hepatic steatosis and rheumatoid arthritis diagnosed in 2022 (ACR/EULAR 2010 criteria with a score of 8; very high rheumatoid factor and anti-CCP antibodies, with peaks of 2098 and 172 kU/L), for which methotrexate was contraindicated because of renal and hepatic disease and which was treated with abatacept, prednisone and hydroxychloroquine (DAS28 of 4.65) [80]. On examination she was eupnoeic, with SpO2 of 96% on room air, bibasal crackles and clubbing of the toenails; she had had oculocutaneous albinism since birth, with iris transillumination, nystagmus, non-traumatic bruising on the arms and a lifelong bleeding tendency [80]. Figure 1 of the paper shows the albinism from childhood to the present, alongside her mother and sister, and bruising after venepuncture, minor trauma and eye rubbing (https://pmc.ncbi.nlm.nih.gov/articles/PMC13158218/figure/f1/) [80].

FVC fell from 2.73 L (86% predicted) in 2021 to 2.07 L (61%) in 2024, with a loss of 9% in the last year, and DLCO from 60% to 37%, with a loss of 12% in the last year; there was marked desaturation on the 6-minute walk test [80]. HRCT showed reticulation, mild ground glass, multiple traction bronchiectases and honeycombing with an apicobasal gradient, in a UIP pattern with progression between 2019 and 2024 (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC13158218/figure/f3/) [80]. Platelet count was normal, aggregation was reduced with decreased expression of GPIIb-IIIa (CD41a), and transmission electron microscopy of platelets (Karnovsky fixation, Epon embedding) showed rarefaction to absence of δ granules (Figure 4, with the sequencing read of the deletion: https://pmc.ncbi.nlm.nih.gov/articles/PMC13158218/figure/f4/) [80]. Exome sequencing identified the homozygous variant NM_000195.5(HPS1):c.355del, p.(His119ThrfsTer5), classified in the paper as likely pathogenic and in ClinVar as pathogenic (VCV000021103), establishing HPS-1 [73, 80]. The figures were consulted via their legends and public addresses; the images were not analysed visually.

Management included discontinuing abatacept and starting rituximab, for the arthritis and the possible contribution of rheumatoid arthritis to the lung disease, with preserved immunoglobulins and a clonal CD8+ T lymphocytosis attributed to the arthritis; low-dose prednisone and hydroxychloroquine were continued [80]. Nintedanib and pirfenidone were not started, because of renal function and the limited evidence in HPS, and lung transplantation was considered unfeasible because of renal failure and active arthritis; the patient received ambulatory oxygen, vaccines against influenza, SARS-CoV-2 and pneumococcus, pulmonary rehabilitation and smoking cessation support [80]. The joint course was good on rituximab, with regular respiratory follow-up, and the patient described the diagnosis as the formal recognition of a condition she had lived with for 60 years without knowing its name [80].

The case shows the diagnostic delay that is possible when bleeding is accepted as a personal trait and albinism is not integrated into the assessment of an ILD, the value of electron microscopy and the exome when aggregation and cytometry suggest another thrombocytopathy, and the overlap of an autoimmune disease with HPS fibrosis [80]. The choices in the report are not routine: rituximab was chosen for the rheumatoid arthritis and not for HPS, and the non-use of an antifibrotic resulted from renal function and the scarcity of evidence, in a context in which the PPF guideline suggests nintedanib in progressive fibrosing ILD by extrapolation [18, 80]. The patient's functional progression (loss of 9% of FVC and 12% of DLCO in one year) met the functional criteria for PPF and the ISHLT referral criteria, which in this case were limited by comorbidities [18, 19].

Other published cases illustrate different subtypes: the 69-year-old Portuguese HPS-7 patient [75]; an Austrian child with HPS-4 genetically diagnosed at 8 months after ophthalmological referral at 7 weeks, stable at 2 years and 5 months without pulmonary or gastrointestinal involvement [150]; the two HPS-11 patients from France and Slovenia [60]; and the HPS-2 child with the SVA insertion, with nystagmus at 8 weeks, febrile neutropenia at 11 months (absolute neutrophil count 0 to 360/µL), psychomotor delay, abnormal NK degranulation (ΔCD107a <5%) and prolonged bleeding after dental surgery [74].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on the subtype. In BLOC-3 deficiency, pulmonary fibrosis is the main determinant: symptomatic in the fourth decade, it leads to death within about a decade without transplantation, typically between 40 and 50 years with an FVC of about 25%, and an FVC below 50% is associated with death within about two years without transplantation [1, 2, 88]. The Oxford textbook places death from fibrosis in the fourth or fifth decade [62]. The 2025 review identifies progressive fibrosis and respiratory failure as the main cause of death in HPS-1 and HPS-4 [17]. After transplantation, survival in the Columbia series was 83.3% at 1 and 2 years, with no recurrence of fibrosis in the graft [86]. In HPS-2, fibrosis begins in childhood and progresses rapidly, and HLH, although rare, was fatal in two patients [2, 89]. In HPS-10, the published cases died in early childhood [2, 4]. In BLOC-2 and BLOC-1 deficiencies, fibrosis has not been described (with the exception of the 2026 HPS-9 case), and there are patients diagnosed at 65, 77 and 92 years; the absence of events in small series does not equate to zero lifetime risk [1, 2, 70]. Visual acuity is stable after early childhood [1]. Colitis requires intestinal resection in about a third of patients with IBD [15]. The serum biomarkers CCL22 and choline were associated with functional decline and had high accuracy on ROC curves for predicting fibrosis in HPS-1, with no values given in the abstract and without validation for clinical use [68].

11.2. Surveillance

In the NIH trials, function tests were performed every 4 months with annual HRCT, a research schedule and not a clinical recommendation [88]. The age at which pulmonary surveillance should begin has no formal guidance and the sources diverge: GeneReviews indicates function tests from 20 years and HRCT at around 30, whereas the 2025 review by Wang and Young proposes pulmonary examination, thin-section non-contrast CT and baseline function tests in late adolescence in HPS-1, HPS-2 and HPS-4 patients, before symptoms, to establish the baseline and rate of progression, with annual function tests thereafter, the interval to the next CT defined by the initial extent and the functional course, and assessment as early as childhood in HPS-2; surgical lung biopsy and routine bronchoscopy are not recommended, because of the bleeding risk and the little they add in a genetic disease of known fibrosis [1, 17]. HPS-PF may be asymptomatic with normal tests in the early stages, which justifies surveillance from 20 years in the at-risk types [1, 14]. The sequence of thresholds (PPF definition to decide on antifibrotic therapy by extrapolation; ISHLT criteria for referral and listing) is the same as that given in section 7.

12. Summary and Final Considerations

Hermansky-Pudlak syndrome is a class of eleven autosomal recessive disorders of the biogenesis of lysosome-related organelles, caused by loss of function of subunits of the AP-3, BLOC-1, BLOC-2 and BLOC-3 complexes. All patients have oculocutaneous albinism, with nystagmus and foveal hypoplasia, and a bleeding diathesis due to absent δ granules with normal platelet count, PT and aPTT; the affected complex determines the rest of the phenotype, with fatal pulmonary fibrosis in middle age in BLOC-3 deficiency, immunodeficiency and fibrosis in childhood in HPS-2, severe neurological disease in HPS-10, granulomatous colitis in BLOC-2 and BLOC-3 deficiencies, and mild presentations in BLOC-2 and BLOC-1 deficiencies, which may remain undiagnosed into old age.

The diagnosis should be considered in all people with albinism, in women with menorrhagia or postpartum haemorrhage and hypopigmentation, in children with partial albinism and neutropenia, in patients with early-onset IBD and in adults with ILD and albinism. It rests on the combination of albinism and absence of δ granules on whole mount electron microscopy and is confirmed by a panel or exome that includes the 11 genes and CNV analysis, because founder deletions such as that of HPS3 escape sequencing, and a negative result does not exclude the disease. Puerto Rico concentrates two founders, and there are Swiss, Japanese, Ashkenazi, Bedouin and, probably, Portuguese (DTNBP1 p.(Gln103Ter)) founders.

There is no approved medicine for HPS. Treatment combines ocular and skin protection, a haemostatic plan with desmopressin (included in the Portuguese SmPC indication for congenital platelet dysfunction), antifibrinolytics and single-donor platelets, limitation of alloimmunisation, avoidance of tobacco, NSAIDs and pulmonary toxicants, annual pulmonary surveillance from 20 years (or from late adolescence, depending on the source) and early referral for lung transplantation, which in a series of seven patients with an individualised haematological plan had a survival of 83.3% at one and two years [86]. The pirfenidone trials were inconclusive, nintedanib and nerandomilast apply only by extrapolation from progressive pulmonary fibrosis, and gene therapy remains preclinical; the NIH are preparing the design of future trials in HPS pulmonary fibrosis.

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