Hermansky-Pudlak Syndrome

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 R 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 R (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 R 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. Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

Virucidal activity of formaldehyde solutions used for preservation of allograft tympano-ossicular systems

Objective: Allograft tympano-ossicular systems (ATOS) can provide superior outcomes in particular circumstances, for example, in case of a need for total reconstruction of the eardrum and chain. ATOS are preserved in a 2.7%–4% formaldehyde solution after procurement at room temperature (15-25°C) for 2–5 days, followed by 4 °C for a total storage of at least 14 days. This study aimed to review the literature on the virucidal effect of formaldehyde on viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Narrative review of the literature available on the virucidal effect of formaldehyde, as searched in the scientific database PubMed. Results: Both free and intracellular HIV as well as HBV and HCV are significantly reduced at low concentrations of formaldehyde and short exposure time. Factors increasing the effectivity of formaldehyde solutions are high concentration, long exposure time, and high temperature. It has been demonstrated that HIV-infected allografts are disinfected by formaldehyde preservation. No case of HIV, HBV, or HCV transmission through ATOS has been reported. Coronaviruses closely related to SARS-CoV-2, such as SARS-CoV and MERS-CoV, are inactivated by low concentrations of formaldehyde solution, even at short exposure times. Conclusion: These findings indicate that formaldehyde is effective in inactivating HIV, HBV, HCV, and coronaviruses. ATOS are stored in a high concentration formaldehyde solution for a long period. The applied preservation method of ATOS, including temporary storage at room temperature, should be maintained for effective inactivation. The formaldehyde preservation method in combination with donor screening and serological and nucleotide amplification testing make ATOS a very safe reconstruction material.

Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.