Clinical and genetic characterization of Hermansky-Pudlak Syndrome based on a multidisciplinary approach to the diagnosis of albinism.

Hermansky-Pudlak Syndrome (HPS) is a rare (1-9 per 1 million people) hereditary disorder characterized by oculocutaneous albinism, impaired platelet aggregation, and potential systemic complications such as pulmonary fibrosis, granulomatous colitis, and cardiomyopathy. To date, 11 types of HPS have been described, associated with mutations in various genes encoding components of the AP3 and BLOC protein complexes, which play a key role in the formation of intracellular organelles. As part of a scientific and diagnostic program for the study of albinism conducted at the Research Centre for Medical Genetics (RCMG) since 2018, one of the largest Russian cohorts of patients with Hermansky-Pudlak syndrome has been established. The study included 21 patients from 15 families, who underwent comprehensive clinical and instrumental examinations, molecular genetic testing, and medical genetic counseling. Ophthalmologic examinations revealed that all patients had macular hypoplasia of at least grade 2, which explains the significant reduction in visual acuity, as well as hypermetropia of varying severity. Progressive cataracts with childhood-onset were diagnosed in 19% of cases. An important ophthalmologic distinction between HPS and oculocutaneous albinism type 1A was the retention of   partial pigmentation in the iris and retinal pigment epithelium, which correlated with a moderate degree of iris transillumination. The characteristic appearance of the optic nerve head (grayish-pink coloration in 86% of cases) may lead to diagnostic errors and misinterpretation of lesions as optic nerve atrophy. Analysis of clinical data showed that 100% of HPS patients had a history of hemorrhagic conditions, which was confirmed by abnormalities in coagulation tests. All patients with HPS1 and HPS4 reported abdominal pain, highlighting the need to include gastroenterological examination in the diagnostic protocol. Molecular genetic analysis, performed using high-throughput sequencing (targeted panels, whole-exome, and whole-genome sequencing) followed by Sanger sequencing verification, identified causative genes. Mutations in the HPS1 gene were the most frequently detected (48% of cases). These findings emphasize highlight the need for further research of Hermansky-Pudlak syndrome using a comprehensive approach to diagnosis, including extended molecular genetic testing and multidisciplinary examination.

1. https://www.orpha.net/

2. Grønskov K., Ek J., Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007;2:43. DOI: 10.1186/1750-1172-2-43.

3. El-Chemaly S., Young L.R. Hermansky-Pudlak Syndrome. Clin Chest Med. 2016;37(3):505–511. DOI: 10.1016/j.ccm.2016.04.012.

4. Garrido G., Fernández A., Montoliu L. HPS11 and OCA8: Two new types of albinism associated with mutations in BLOC1S5 and DCT genes. Pigment Cell Melanoma Res. 2021;34(1):10-12. doi: 10.1111/pcmr.12929.

5. Pennamen P., Le L., Tingaud-Sequeira A. et al. BLOC1S5 pathogenic variants cause a new type of Hermansky-Pudlak syndrome. Genet Med. 2020;22(10):1613–1622. DOI: 10.1038/s41436-020-0867-5.

6. Bobreshova A.M., Ionova S.A., Sukhanova N.V., et al. Masks of Albinism: Clinical Spectrum of Hermansky-Pudlak Syndrome. Int. J. Mol. Sci. 2024; 25(20): 11260. https://doi.org/10.3390/ijms252011260

7. Han C.G., O’Brien K.J., Coon L.M. et al. Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant. Am J Med Genet A. 2018;176(12):2819–2823. DOI: 10.1002/ajmg.a.40514.

8. Ammann S., Schulz A., Krägeloh-Mann I. et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016;127(8):997–1006. DOI: 10.1182/blood-2015-09-671636.

9. Mohammed M., Al-Hashmi N., Al-Rashdi S. et al. Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder. Eur J Med Genet. 2019;62(11):103583. DOI: 10.1016/j.ejmg.2018.11.017.