Clinical characteristics: Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, and/or immunodeficiency. Ocular findings include nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), and strabismus in many individuals. Hair color ranges from white to brown; skin color ranges from white to olive and is usually at least a shade lighter than that of other family members. The bleeding diathesis can result in variable degrees of bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and/or other surgeries. Pulmonary fibrosis, colitis, and/or neutropenia have been reported in individuals with pathogenic variants in some HPS-related genes. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early 30s and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Diagnosis/testing: The clinical diagnosis of HPS can be established in a proband with hypopigmentation of the skin and hair, characteristic eye findings, and demonstration of absence of platelet delta granules (dense bodies) on electron microscopy. Identification of biallelic pathogenic variants in AP3B1, AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 confirms the diagnosis if clinical features are inconclusive.
Management: Treatment of manifestations: Correction of refractive errors and use of low vision aids; preferential seating in school; low-vision consultant as needed; UV-blocking sunglasses; surgery for strabismus as needed; protection from sun exposure with protective clothing and sunscreen; standard treatment for skin cancer; thrombin-soaked Gelfoam® for skin wounds with prolonged bleeding; medical alert bracelet and bleeding management plan; humidifier to reduce frequency of epistaxis; oral contraceptives and IUD for menorrhagia; DDAVP® (desmopressin acetate) for wisdom tooth extraction and invasive procedures; platelet or red blood cell transfusions for surgery or protracted bleeding; HLA-matched single-donor platelets as needed; maximize pulmonary function with prompt treatment of asthma and pulmonary infections; influenza, pneumococcal, and COVID-19 vaccines; regular moderate exercise; supplemental oxygen for advanced-stage pulmonary fibrosis; lung transplantation for end-stage pulmonary disease; steroids, other anti-inflammatory agents, and/or Remicade® for granulomatous colitis. Immunodeficiency, when present, is lifelong and granulocyte colony-stimulating factor responsive, and affected individuals benefit from an infection prevention plan.
Surveillance: Annual ophthalmologic examination including assessment for refractive errors; annual skin examination for evidence of sun-induced skin damage (e.g., solar keratoses [premalignant lesions], basal cell carcinoma, and squamous cell carcinoma); annual pulmonary function testing in those older than age 20 years; colonoscopy in those with symptoms of colitis (e.g., cramping, mucoid stools, hematochezia, melena); assessment for clinical and laboratory manifestations of immunodeficiency.
Agents/circumstances to avoid: Over-the-counter nonsteroidal anti-inflammatory products, aspirin-containing products, and other anticoagulants unless medically indicated; activities that increase the risk of bleeding; all tobacco and vaping products and inhalation of chemical and physical substances injurious to the lungs; unprotected and direct sun exposure.
Evaluation of relatives at risk: In families with HPS3-, HPS5-, or HPS6-related HPS (milder types of HPS in which hypopigmentation and nystagmus may not be clinically evident), it is appropriate to clarify the status of apparently asymptomatic at-risk sibs in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.
Genetic counseling: HPS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HPS-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HPS-causing pathogenic variants are identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
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