Hermansky-Pudlak Syndrome: Albinism, Bleeding & Lung Disease

Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder that bundles together an unusual trio of problems: a form of albinism that affects the skin, hair, and eyes; a bleeding tendency caused by malfunctioning platelets; and, in certain subtypes, progressive scarring of the lungs or inflammatory bowel disease. At least nine genetically distinct subtypes have been identified, each caused by mutations in a different gene, and all inherited in an autosomal recessive pattern, meaning a child must receive a defective copy from both parents to be affected. Although rare worldwide, HPS reaches striking prevalence in parts of Puerto Rico, and its complications range from manageable to life-threatening depending on which subtype a person carries.

Why One Defect Causes So Many Problems

The genes behind HPS all participate in building and loading a family of tiny compartments inside cells called lysosome-related organelles. These compartments include melanosomes (which produce and store pigment), platelet dense granules (which store the small molecules platelets release to form clots), and certain types of lysosomes involved in recycling cellular waste. The proteins encoded by HPS genes assemble into multi-protein complexes, referred to by researchers as BLOCs (biogenesis of lysosome-related organelles complexes) and an adaptor complex called AP-3. When any one of these protein subunits is missing or broken, the complex it belongs to falls apart, and the organelles it helps build either form incorrectly or fail to get loaded with the right cargo.

For example, the HPS1 and HPS4 proteins are both essential subunits of BLOC-3. Loss of either one destabilizes the whole complex, disrupting the transport of proteins needed for melanosomes to mature and for dense granules to form properly.¹ Research on cells from people missing either HPS1 or HPS4 has shown that lysosomes and late endosomes end up scattered abnormally throughout the cell instead of clustering near the nucleus where they normally concentrate.² Different subtypes affect different steps in the process. In studies of human melanocytes from people with HPS types 1, 2, and 3, each subtype showed a distinct pattern of cargo-trafficking failure, explaining why the severity of albinism and other features can vary from one subtype to another.³

Albinism and Eye Findings

Every person with HPS has some degree of oculocutaneous albinism, though how light the skin and hair appear varies considerably. Some individuals are very fair, while others retain enough pigment to look only somewhat lighter than their unaffected family members. The eye-related problems tend to be more consistent and often more disabling than the skin changes. Nystagmus, the involuntary back-and-forth movement of the eyes, is present in essentially all patients. Visual acuity typically falls between roughly 20/60 and 20/400, with correction of refractive error offering only modest improvement.⁴ Foveal hypoplasia, where the central pit of the retina that normally allows sharp central vision fails to develop fully, is a universal finding.⁵ Because the fovea is structurally underdeveloped rather than damaged after the fact, corrective lenses and surgical procedures aimed at the external eye cannot fully restore the sharpness of central vision.

The degree of iris translucency and retinal pigmentation varies from person to person, even within the same subtype. Some patients have blue or gray irises that transilluminate brightly during an eye exam, while others retain enough iris pigment to appear brown. This variability is one reason the diagnosis is sometimes delayed: a child with brown eyes and moderately light skin may not raise immediate suspicion of an albinism-related syndrome.

The Bleeding Tendency

The second hallmark of HPS is a bleeding diathesis caused by a platelet storage pool deficiency. Platelets in people with HPS lack dense granules, the tiny storage packets that normally release serotonin, ADP, and calcium during clot formation. Without dense granules, platelets stick to a wound but cannot effectively recruit and activate their neighbors, so clots are slow to form and fragile once they do. The most reliable laboratory finding for diagnosis is the near-total absence of platelet dense bodies on whole-mount electron microscopy.⁶

In everyday life, this translates to easy bruising, prolonged bleeding from cuts, heavy menstrual periods, and nosebleeds. The bleeding is not usually as severe as what you would see in classic hemophilia, but it becomes a serious concern during surgery, dental procedures, and childbirth. A systematic review of obstetric outcomes found that primary postpartum hemorrhage occurred in about 44% of viable pregnancies in women with HPS, and half of those episodes qualified as major hemorrhage.⁷ This is one reason that pregnancy in a person with HPS requires careful coordination between obstetricians and hematologists well before delivery.

Pulmonary Fibrosis and Why Subtype Matters

The most life-threatening complication of HPS is progressive pulmonary fibrosis, but it does not affect everyone with the syndrome equally. Subtypes HPS-1, HPS-2, and HPS-4 are the ones associated with lung scarring, and the risk is highest in HPS-1. In Puerto Rico, where long-term follow-up data are most robust, essentially all patients with HPS-1 eventually develop pulmonary fibrosis.⁸ The fibrosis typically begins in the third or fourth decade of life, progressing in a pattern that resembles idiopathic pulmonary fibrosis (IPF), with worsening shortness of breath, declining lung function, and eventually respiratory failure. People with other HPS subtypes, such as HPS-3 or HPS-5, appear to be spared from significant lung disease, which makes genetic subtyping a crucial piece of medical management.

Research into why some subtypes scar the lungs points toward problems in the type 2 alveolar epithelial cells, the cells responsible for producing surfactant and repairing lung tissue. In HPS-1, loss of the HPS1 protein leads to impaired autophagy, the cell’s housekeeping process for clearing out damaged components. The resulting buildup of surfactant and lysosomal stress pushes these cells toward self-destruction, triggering a cycle of injury and scarring.⁹ A systematic review found that patients who received antifibrotic drugs or lung transplantation had significantly improved survival compared to those who did not.¹⁰

Granulomatous Colitis and Immune Complications

Some people with HPS develop a bowel inflammation that closely resembles Crohn’s disease, complete with deep ulcerations and granulomas (clusters of immune cells that form in response to chronic irritation). This complication has been most commonly associated with HPS types 1 and 4. Biopsy samples from affected patients show chronic inflammation with deep ulcers and granulomas without caseating necrosis, a pattern nearly indistinguishable from Crohn’s disease on a slide.¹¹ Whether this colitis is truly a form of Crohn’s disease triggered by the underlying HPS genetic susceptibility, or a separate process driven by the accumulation of ceroid-like pigment in intestinal macrophages, remains an open question.¹² The practical relevance is that the colitis often responds to the same anti-TNF-alpha therapies used for Crohn’s disease, which is reassuring for clinicians trying to manage it.¹³

HPS type 2 carries its own distinct set of immune problems. Because the AP-3 adaptor complex affected in HPS-2 also plays a role in immune cell function, people with this subtype can have defective natural killer (NK) cells. In one study, NK cells from HPS-2 patients showed poor ability to kill tumor cell lines, including Hodgkin lymphoma lines, and produced less of the signaling molecule IFN-gamma. This combined defect in innate and adaptive immunity may explain the increased susceptibility to infections and lymphoma seen in some HPS-2 patients.¹⁴

The Puerto Rico Founder Effect

Worldwide, HPS is quite rare, but in northwestern Puerto Rico it occurs at a frequency of about 1 in 1,800 people, making it one of the most common genetic disorders in that population. This is the result of a founder effect: a small founding population carried the mutation, and over generations in a relatively isolated community, the carrier frequency climbed to high levels. Notably, two different founder mutations causing HPS exist on the island, each associated with a different subtype.¹⁵ Much of the clinical research on HPS has emerged from studying this population, which is why Puerto Rican clinicians have historically been among the most experienced in managing the disorder. For the same reason, carrier screening for HPS mutations is sometimes recommended for people of Puerto Rican descent who are planning to have children, even if they have no family history of the condition.

Getting to a Diagnosis

Diagnosis of HPS is sometimes delayed because the albinism can be subtle and the bleeding tendency mild enough to be attributed to other causes. The condition should be considered in anyone who presents with some degree of oculocutaneous albinism alongside unexplained bruising or prolonged bleeding. The fastest confirmatory test is whole-mount electron microscopy of a platelet sample, which reveals the absence of dense bodies. This technique is both accurate and relatively quick compared to more elaborate genetic testing.¹⁶ Standard platelet function tests like platelet aggregation studies will show an abnormal pattern, but they are not specific to HPS. Genetic testing through high-throughput sequencing is needed to pin down the exact subtype, which matters for prognosis: knowing whether someone has HPS-1 versus HPS-5, for instance, determines whether they need aggressive lung monitoring or can be largely reassured on that front. In one cohort of 11 patients from eight unrelated families diagnosed between 2016 and 2024, the average age at diagnosis was about six years, though it ranged from four months to eighteen years.¹⁷

Managing the Bleeding Risk

Because HPS bleeding stems from missing platelet granule contents rather than from missing clotting factors, the management strategy differs from what you would use in hemophilia. Desmopressin (DDAVP), a synthetic hormone that boosts clotting activity, is often the first-line treatment attempted before procedures. However, the response to DDAVP is unpredictable. In a series of nine HPS patients tested, four showed a clear shortening of bleeding time, one had an equivocal response, two improved only modestly, and two did not respond at all.¹⁸ For this reason, each patient should ideally be trial-tested with DDAVP well before an elective procedure, so the clinical team knows whether it will work for that individual.

When DDAVP alone is insufficient, platelet transfusions become the fallback. HLA-matched platelets are preferred when available to reduce the risk of alloimmunization, a problem where the body develops antibodies against donor platelets that make future transfusions less effective. In more complex surgical situations, recombinant activated factor VII (rFVIIa) has been used successfully. In one case report, a single pre-operative dose of rFVIIa allowed a tooth extraction in an HPS-1 patient to proceed without any bleeding events.¹⁹ Combination approaches, using DDAVP together with HLA-matched platelets and local hemostatic packing, have also been reported to achieve sustained clot control for dental surgery.²⁰

Lung Transplantation for End-Stage Fibrosis

For patients with HPS subtypes that progress to severe pulmonary fibrosis, lung transplantation is the only option that can meaningfully extend life once the disease reaches its later stages. Understandably, transplant teams have been cautious about offering this procedure to people with a known bleeding disorder. But accumulating experience has shown that HPS should not be considered a contraindication. A review concluded that while patients with HPS may face an increased risk of massive hemorrhage during the transplant surgery itself, this risk is unpredictable and can be mitigated with careful planning involving hematology consultation, prophylactic platelet transfusion, and desmopressin.²¹

In a series of six HPS patients evaluated for lung transplant, three ultimately received bilateral lung transplants. Among those three, no excessive bleeding was encountered, and no recurrence of HPS-related pulmonary fibrosis was detected for up to six years after transplant.²² One significant barrier is alloimmunization: because many HPS patients receive platelet transfusions earlier in life for bleeding episodes, they may develop antibodies that complicate the transplant matching process. The recommendation from transplant specialists is to limit unnecessary platelet transfusions in HPS patients known to be at risk for pulmonary fibrosis, specifically to preserve their candidacy for a future transplant.²³

Mouse Models and Why They Matter

Much of what we know about HPS at the cellular level comes from mice. There are at least 16 mouse strains with mutations in HPS-related genes, far more than the nine human subtypes identified so far, and these mice have been invaluable for teasing apart which gene does what. Mouse studies have defined the specific granule abnormalities in HPS and revealed that the disease affects a surprisingly wide range of tissues beyond the obvious trio of skin, platelets, and lungs.²⁴ Detailed analysis of pigment cells from five different mouse HPS strains showed that most had defects in how melanosomes form in the first place, while one strain (called “ashen”) had normal melanosome formation but could not secrete them from the cell, which makes it functionally lighter even though the pigment granules themselves are fine.²⁵ These distinctions help researchers understand which stage of organelle life is disrupted in each human subtype and point toward different therapeutic windows.

Experimental Therapies on the Horizon

There is no cure for HPS today, but several lines of research offer some hope. Gene therapy has been explored in laboratory settings: researchers have used lentiviral vectors to deliver a working copy of the HPS1 gene into melanocytes cultured from patients with HPS-1. The treated cells showed corrected expression and function of the HPS1 protein, a proof of concept that the defect is fixable at the genetic level, at least in a dish.²⁶ Translating this into a clinical therapy, especially for the lung fibrosis that poses the greatest threat to life, remains a major challenge, since you would need to efficiently deliver the corrected gene to lung epithelial cells in a living person.

A separate avenue of research uses three-dimensional lung organoids, miniature lung-like structures grown from stem cells, to study how fibrosis develops in HPS. Scientists have shown that introducing the HPS mutations associated with lung fibrosis into these organoids causes them to develop fibrotic changes, while deleting HPS8 (a subtype not linked to lung disease in humans) does not. The organoid work identified a signaling molecule called interleukin-11 (IL-11) as a key driver: IL-11 was upregulated in the epithelial cells of the fibrotic organoids, and when the IL-11 gene was deleted from HPS4-mutant organoids, the fibrosis did not develop.²⁷ IL-11 is already being investigated as a therapeutic target in other fibrotic diseases, so there is an existing drug-development infrastructure that HPS research could potentially piggyback on. These are still early days, but the organoid platform gives researchers a faster way to screen potential treatments than waiting for results in mouse models alone.

Living with HPS Across the Lifespan

Because HPS affects multiple organ systems and the complications unfold over decades, coordinated care from a team that includes dermatology, ophthalmology, hematology, pulmonology, and gastroenterology is the standard recommendation. Children with HPS need sun protection guidance, low-vision support in the classroom, and awareness among school staff that nosebleeds and bruising may be more frequent and prolonged than in other children. Adolescents, especially girls, often need a hematology plan for menstrual bleeding management before menarche arrives.

For adults with the high-risk subtypes, regular pulmonary function testing and high-resolution chest CT scans become the most important screening tools, aimed at catching fibrosis early enough to start antifibrotic therapy or begin the often lengthy process of evaluation for lung transplant. Reproductive counseling is relevant for any couple where both partners could be carriers, and pregnancy in an affected woman requires advance planning for the heightened risk of postpartum hemorrhage.²⁸ The lifespan in HPS varies widely by subtype. People with subtypes that do not develop lung disease can live a normal or near-normal lifespan with appropriate bleeding precautions, while those with HPS-1 face a significantly shortened life expectancy driven primarily by the progression of pulmonary fibrosis.