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PubMed This is a summary of 19 peer-reviewed journal articles Updated
Medical Genetics

Confirming the Diagnosis: Science and Certainty

At a Glance

Hermansky-Pudlak syndrome can be present even when platelet counts and routine clotting tests are normal. Diagnosis usually combines the pattern of light coloring and bleeding with specialized platelet microscopy and genetic testing to identify the condition and its subtype.

Diagnosing Hermansky-Pudlak Syndrome (HPS) is often a journey of “connecting the dots” between two seemingly unrelated symptoms: light coloring (albinism) and a tendency to bleed easily [1]. Because HPS is rare, the diagnostic process requires specialized tests that go far beyond routine blood work.

The Biological “Shipping” Glitch

To understand why HPS happens, it helps to think of your cells as busy factories. Inside these factories, specialized “containers” called lysosome-related organelles (LROs) must be built and shipped to the right locations [2]. These containers include melanosomes, which carry pigment to your skin and eyes, and dense granules, which carry “emergency supplies” inside your platelets to help your blood clot [2][3].

In HPS, the “shipping crews”—protein complexes known as BLOC-1, BLOC-2, BLOC-3, and AP-3—are defective [4].

  • BLOC-3 (HPS-1, HPS-4): Acts like a master switch for maturing pigment containers [5].
  • BLOC-2 (HPS-3, HPS-5, HPS-6): Helps guide containers to their final destination [6].
  • AP-3 (HPS-2, HPS-10): Responsible for sorting specific cargo into the containers [7].
    When these crews fail, the containers are either not made correctly or never arrive where they are needed, leading to the symptoms of HPS [8][9].

Why Standard Bleeding Tests Fail

If you have HPS, your routine blood tests—like a Platelet Count, PT (Prothrombin Time), or PTT (Partial Thromboplastin Time)—will almost always look perfectly normal [9][10]. This is because these tests check for enough platelets and the right “clotting factors” in your liquid blood [11].

HPS is different. You have enough platelets, and your liquid blood factors are fine. The problem is inside the platelets [12]. Your platelets are missing their dense granules, which normally store chemicals like serotonin and ADP [9]. Without these granules, when you get a cut, your platelets can’t “call for backup” to create a strong, lasting clot [11].

The Core Diagnostic Tests

Because routine tests miss HPS, doctors integrate your clinical symptoms with two specialized, complementary tools to confirm the diagnosis:

  1. Platelet Whole-Mount Electron Microscopy (WM-EM): A specialist uses a powerful microscope to look at your platelets. Normally, platelets look like they are filled with small “black dots” (the dense granules) [12]. In someone with HPS, these black dots are absent or markedly reduced [1][12].
  2. Molecular Genetic Testing: A blood or saliva sample is sent to a lab to look for mutations in the 11 known HPS genes [13]. This identifies your specific subtype, which is vital for understanding your future health risks [14].
    Note: Sometimes a genetic test comes back negative or identifies a “Variant of Uncertain Significance” (VUS) even if electron microscopy shows HPS. In these cases, working with a medical geneticist can help interpret the findings or order more complex testing.

Distinguishing HPS from “Look-Alikes”

Since albinism can occur in many conditions, doctors must rule out other disorders that may look similar to HPS but require different care:

  • Non-Syndromic Oculocutaneous Albinism (OCA): This is “isolated” albinism. People with OCA have light skin, hair, and eyes, but they do not have the bleeding problems or lung risks associated with HPS [15]. Their platelets will show normal dense granules under a microscope [12].
  • Chediak-Higashi Syndrome (CHS): Like HPS, this includes albinism and bleeding. However, CHS also causes severe immunodeficiency (frequent infections) and progressive nerve problems [16]. Under a microscope, doctors can see “giant” granules in white blood cells that are never found in HPS [17].
  • Griscelli Syndrome (GS): This also causes light coloring and immune or nerve issues [18]. Doctors distinguish it from HPS by looking at hair shafts under a microscope; GS shows large, irregular clumps of pigment, whereas HPS hair typically looks more uniform [19].

By using these specialized tests, your medical team can move past the “look-alikes” to provide the specific monitoring and care that Hermansky-Pudlak Syndrome requires.

Common questions in this guide

How is Hermansky-Pudlak syndrome confirmed?
Doctors usually combine a history of albinism and unusual bleeding with specialized platelet testing and genetic testing. Whole-mount electron microscopy can show that platelet storage granules are missing or greatly reduced, while genetic testing can identify the HPS subtype. A normal platelet count or normal PT and PTT do not rule out HPS.
What does platelet whole-mount electron microscopy show in HPS?
Under this specialized microscope, healthy platelets contain small dark dense granules. In HPS, these granules are absent or markedly reduced, helping explain why platelets do not form a strong, lasting clot. The sample usually needs to be sent to a specialized laboratory.
Can genetic testing be negative even when HPS is suspected?
Yes. Standard testing may miss some DNA changes, or it may find a variant of uncertain significance, meaning the laboratory cannot yet tell whether the change causes disease. A medical geneticist can review the result and consider copy-number analysis, which looks for missing or duplicated DNA segments, or other testing when platelet microscopy supports HPS.
Why can PT and PTT be normal in Hermansky-Pudlak syndrome?
PT and PTT measure clotting proteins in the liquid part of blood, and a platelet count measures how many platelets are present. In HPS, those results are often normal because the problem is inside the platelets: their storage granules are missing, so they cannot release signals that recruit more platelets to a cut. Normal results therefore do not exclude HPS.
How do doctors tell HPS apart from other albinism syndromes?
Non-syndromic oculocutaneous albinism usually does not cause the bleeding pattern or platelet granule changes seen in HPS. Chediak-Higashi syndrome may cause immune problems and large granules in white blood cells, while Griscelli syndrome can show irregular pigment clumps in hair. Blood-cell and hair examination, together with genetic testing, can help distinguish these conditions.
What can an HPS gene result tell me about care?
Genetic testing can identify the HPS subtype and the affected cell-shipping protein group, such as BLOC-1, BLOC-2, BLOC-3, or AP-3. This information can help the care team understand which health risks to monitor. The result should be interpreted with a medical geneticist.

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Has my (or my child's) blood been sent for platelet whole-mount electron microscopy at a specialized lab?
  2. 2.Since routine blood clotting tests like PT and PTT are often normal in HPS, what other tests will you use to monitor bleeding risk?
  3. 3.Does our genetic testing include 'copy-number analysis' to look for missing pieces of DNA that standard sequencing might miss?
  4. 4.Based on the genetic results, which protein complex (BLOC-1, 2, 3, or AP-3) is affected, and what does that mean for our care plan?
  5. 5.Can we review the peripheral blood smear or hair sample results to definitively rule out Chediak-Higashi or Griscelli syndrome?

References

References (19)
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    A novel likely pathogenic variant in a patient with Hermansky-Pudlak syndrome.

    Lansdon LA, Chen D, Rush ET, et al.

    Cold Spring Harbor molecular case studies 2021; (7(5)) doi:10.1101/mcs.a006110.

    PMID: 34362826
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    A Novel Likely Pathogenic Variant in the BLOC1S5 Gene Associated with Hermansky-Pudlak Syndrome Type 11 and an Overview of Human BLOC-1 Deficiencies.

    Boeckelmann D, Wolter M, Käsmann-Kellner B, et al.

    Cells 2021; (10(10)) doi:10.3390/cells10102630.

    PMID: 34685610
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    New insights into the pathogenesis of Hermansky-Pudlak syndrome.

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    Pigment cell & melanoma research 2022; (35(3)):290-302 doi:10.1111/pcmr.13030.

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    Defective AP-3-dependent VAMP8 trafficking impairs Weibel-Palade body exocytosis in Hermansky-Pudlak Syndrome type 2 blood outgrowth endothelial cells.

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    Coexistence of Hermansky-Pudlak syndrome and JAK2V617F-positive essential thrombocythemia.

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    Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing.

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This page is for informational purposes only and does not constitute medical advice. A hematologist or medical geneticist should interpret your Hermansky-Pudlak syndrome results and recommend next steps.