Hermansky–Pudlak Syndrome Type 6 Accompanied with Bowel Vascular Malformation: Clinical Case

Background. Hermansky–Pudlak syndrome type 6 is rare hereditary disease caused by pathogenic variants in base sequence, deletions, and insertions in the HPS6 gene encoding the transmembrane protein of the same name. This disease occurs with hemorrhagic syndrome, oculocutaneous albinism, and inflammatory bowel diseases (in some cases). The clinical picture of the disease, including the gastrointestinal tract pathology, has not been studied completely due to the syndrome rarity.

Clinical case description. We would like to present the description of clinical case of the patient with Hermansky–Pudlak syndrome type 6 accompanied with bowel vascular malformation. The patient diagnosed with “oculocutaneous albinism” at the age of 4.5 has shown recurrent intestinal bleedings, blood hemoglobin concentration decrease to 45 g/l; platelet count, mean platelet volume and platelet distribution width remained within the reference values. Slight decrease of Quick’s value to 68% (normal range 70–120%) was revealed. The study of platelet morphology has revealed a decrease in the number of dense granules: < 3 in 25% platelets, < 6 — in 64%. Ultrasound investigation has revealed signs of vascular malformation in ascending colon: significant changes of diameter (widening) and shape of intestinal wall vessels. Molecular genetic analysis (NGS) has revealed the nucleotide variant c.1133T>G (p.Leu378Arg) in homozygous state in the HPS6 gene. The same variant in homozygous state was revealed in the younger proband sister who also had vascular changes in the ascending colon wall.

Conclusion. Differential diagnosis of Germanic–Pudlak syndrome type 6 should be performed with other types of this syndrome as well as with syndrome and non-syndrome forms of oculocutaneous albinism. Molecular genetic confirmation of the diagnosis is suggested via massive parallel sequencing (NGS) methods (exome sequencing included) due to the rarity of Hermansky–Pudlak syndrome.

1. Huizing M, Pederson B, Hess RA, et al. Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6. J Med Genet. 2009;46(12):803–810. doi: 10.1136/jmg.2008.065961

2. Zhang Q, Zhao B, Li W, et al. Ru 2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet. 2003;33(2):145–153. doi: 10.1038/ng1087

3. Huizing M, Malicdan MCV, Gochuico BR, et al. Hermansky-Pudlak Syndrome. In: GeneReviews ® [Internet]. Adam MP, Ardinger HH, Pagon RA, et al., eds. Seattle (WA): University of Washington, Seattle; 1993–2021. Available online: https://www.ncbi.nlm.nih.gov/books/NBK1287. Accessed on December 07, 2021.

4. OMIM: Hermansky-Pudlak syndrome — PS203300. Available online: https://www.omim.org/phenotypicSeries/PS203300. Accessed on December 07, 2021.

5. Huizing M, Malicdan MCV, Wang JA, et al. Hermansky-Pudlak syndrome: Mutation update. Hum Mutat. 2020;41(3):543–580. doi: 10.1002/humu.23968

6. Di Franza LT, Chen D, Marboe CC, Rai AJ. Absence of dense platelet granules and ceroid-laden macrophages: Investigating the diversity of clinical presentations in Hermansky-Pudlak syndrome. Human Pathology: Case Reports. 2021;25:2214–3300. doi: 10.1016/j.ehpc.2021.200535

7. O’Brien KJ, Parisi X, Shelman NR, et al. Inflammatory bowel disease in Hermansky-Pudlak syndrome: a retrospective single-centre cohort study. J Intern Med. 2021;290(1):129–140. doi: 10.1111/joim.13224

8. Ishihara J, Mizuochi T, Uchida T, et al. Infantile-onset inflammatory bowel disease in a patient with Hermansky-Pudlak syndrome: a case report. BMC Gastroenterol. 2019;19(1):9. doi: 10.1186/s12876-019-0929-9

9. Hull S, Arno G, Holder GE, et al. The ophthalmic presentation of Hermansky–Pudlak syndrome 6. Br J Ophthalmol. 2016;100(11):1521–1524. doi: 10.1136/bjophthalmol-2015-308067

10. Chan HW, Schiff ER, Tailor VK, et al. Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism. Genes. 2021;12(4):508. doi: 10.3390/genes12040508

11. Velázquez-Díaz P, Nakajima E, Sorkhdini P, et al. Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics. Front Pharmacol. 2021;12:644–671. doi: 10.3389/fphar.2021.644671

12. Ryzhkova OP, Kardymon OL, Prohorchuk EB, et al. Guidelines for the interpretation of massive parallel sequencing variants (update 2018, v 2). Medical genetics. 2019;18(2):3–24. (In Russ). doi: 10.25557/2073-7998.2019.02.3-23

13. Han CG, O’Brien KJ, Coon LM, et al. Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant. Am J Med Genet A. 2018;76(12):2819–2823. doi: 10.1002/ajmg.a.40514

14. O’Brien KJ, Lozier J, Cullinane AR, et al. Identification of a novel mutation in HPS6 in a patient with hemophilia B and oculocutaneous albinism. Mol Genet Metab. 2016;119(3):284–287. doi: 10.1016/j.ymgme.2016.08.009