Rare Albinism Syndrome Case Defies Genetic Expectations in Russian Girl

A ten-year-old girl in Russia has been diagnosed with Hermansky-Pudlak syndrome type 1, a rare genetic disorder, but her case is turning heads for what she does not show. Despite carrying two confirmed disease-causing variants in the HPS1 gene, she lacks one of the hallmark eye signs of the condition: iris transillumination, in which light passes through patches of missing pigment in the iris. Her complete absence of this feature, scored zero out of five on a standardized scale, contrasts sharply with another published patient who carries the exact same two variants and showed grades one to two transillumination. The case, reported by physicians at Sechenov University in Moscow and the Research Centre for Medical Genetics, was published in Frontiers in Pediatrics on 28 October 2026.

Hermansky-Pudlak syndrome is a rare autosomal recessive disorder caused by defects in the biogenesis of lysosome-related organelles, specialized cellular compartments that include melanosomes in the skin and eyes and dense granules in platelets. The classic triad consists of oculocutaneous albinism, a bleeding tendency driven by platelet dysfunction, and visceral complications such as pulmonary fibrosis and granulomatous colitis. Eleven subtypes are currently recognized, each tied to pathogenic variants in genes encoding subunits of the adaptor protein-3 complex or the BLOC-1, BLOC-2 and BLOC-3 biogenesis complexes. Type 1, caused by biallelic variants in the HPS1 gene at locus 10q24.2, is the most common form and carries a high risk of progressive pulmonary fibrosis. Global prevalence is estimated at one to nine cases per million people, although in Puerto Rico a well-documented founder effect raises it to roughly one in 1,800.

The girl, identified as Patient D., was ten years and one month old at evaluation. She was born at 39 weeks by elective cesarean section after a pregnancy complicated by acute pyelonephritis in the second trimester, weighing 3,200 grams with Apgar scores of 8 and 9. Divergent strabismus was noted from birth, and horizontal nystagmus appeared at one month of age, prompting ophthalmological referral. By three months she was diagnosed with oculocutaneous albinism. From her first year she developed signs of a bleeding diathesis: frequent ecchymoses that took up to three weeks to resolve, periodic nosebleeds, and prolonged bleeding after dental procedures. A retrospective assessment with the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool yielded a score of 6, indicating a clinically significant bleeding tendency. From age three she had recurrent upper respiratory infections, up to seven episodes annually, sometimes with fever, vomiting and diarrhea.

When a hematology consultation at age seven found no abnormalities on routine laboratory tests, the overall clinical picture still pointed toward Hermansky-Pudlak syndrome, and genetic testing was recommended. At age ten she presented with three weeks of lower abdominal pain. Ultrasound of the abdomen and pelvis revealed a gallbladder fold, bilateral renal pelvic dilation, and an infantile uterus suggestive of uterine hypoplasia. On physical examination her growth was proportionate and age-appropriate, with a height of 139 centimeters, weight of 37.2 kilograms and body mass index of 19.2 kilograms per square meter. She was hemodynamically stable, breathing room air with an oxygen saturation of 99 percent. Her skin was dry, depigmented and photosensitive, with silvery-yellow hair and eyebrows, keratosis pilaris, multiple resolving bruises on the lower extremities and buttocks, a small chest hemangioma and scattered nevi. Cardiopulmonary examination was normal, with clear breath sounds and no hepatosplenomegaly.

The ophthalmological findings were the most striking deviation from the expected phenotype. Her uncorrected visual acuity was 0.1 in the right eye and 0.15 in the left, with a horizontal fine-beating nystagmus. Slit-lamp biomicroscopy showed a complete absence of iris transillumination, grade zero on a standardized five-point scale. Yet the posterior segment told a different story: fundus examination revealed an albinotic appearance with prominent peripheral choroidal vessels, and optical coherence tomography confirmed foveal hypoplasia, later graded as stage 3 according to the Thomas et al. classification. This dissociation between the anterior and posterior segments of the eye matters clinically. The authors argue that absent iris transillumination should not be treated as an exclusionary criterion for HPS-1 when it appears alongside congenital nystagmus, foveal hypoplasia, albinotic fundus changes and systemic bleeding signs. In such presentations, comprehensive ophthalmological evaluation and molecular genetic verification remain essential.

Laboratory workup reinforced the classic HPS-1 pattern of qualitative platelet dysfunction rather than a coagulation defect. Her platelet count was normal at 216 × 10⁹ per liter, confirmed by peripheral smear after adjusting for citrate dilution, but mean platelet volume was mildly elevated at 11.6 femtoliters against a reference range of 6.5 to 10. Coagulation studies and thromboelastography on a TEG 5000 were entirely within normal limits: reaction time 6.2 minutes, clot formation time 1.7 minutes, maximum amplitude 61.9 millimeters and lysis at 30 minutes 0.2 percent. This profile is consistent with the HPS-1 mechanism, in which a deficiency of platelet δ-granules impairs primary hemostasis while leaving platelet number and coagulation pathways intact. Platelet transmission electron microscopy is in limited supply in the Russian Federation, which shaped the diagnostic strategy.

That strategy followed the ISTH diagnostic algorithm for inherited platelet function disorders. The first step excluded thrombocytopenia and von Willebrand disease, along with immune thrombocytopenia, based on the normal platelet count, normal routine coagulation tests, normal factor VIII and von Willebrand factor antigen levels, and absence of autoimmune markers. Differential diagnosis then weighed isolated forms of oculocutaneous albinism such as OCA1, OCA2 and OCA4, which lack platelet storage pool deficiency, against other HPS subtypes that require molecular testing to distinguish, and against Chédiak-Higashi syndrome and Griscelli syndrome, both excluded by the patient’s age-appropriate immunologic and neurologic findings and by the genetic result. Targeted next-generation sequencing using an inherited eye disease panel ultimately identified two heterozygous variants in HPS1: c.397G>T, p.(Glu133Ter) in exon 5, and c.972dup, p.(Met325HisfsTer128) in exon 11. Both were classified as pathogenic under ACMG/AMP guidelines, and segregation analysis confirmed the alleles were in trans, inherited from both parents, consistent with autosomal recessive inheritance. The variants match entries in the ClinVar and HGMD databases.

The genotype-phenotype comparison is the heart of the report. Bobreshova and colleagues described in 2024 another patient harboring the identical compound heterozygous HPS1 variants who exhibited grades one to two of iris transillumination. The Russian girl, by contrast, shows none at all while still displaying marked posterior ocular albinism. The authors conclude that the severity of ophthalmological manifestations is not strictly determined by the HPS1 genotype alone and point to additional genetic, epigenetic or developmental modifying factors. The case also adds unusual gynecological and renal observations. Pelvic ultrasound showed a cylindrical uterus measuring 21.3 by 4.8 by 4.5 millimeters, well below the age-appropriate reference length of 28.0 to 43.0 millimeters for a ten-year-old and comparable to measurements in a one- to three-year-old child. Both ovaries were afollicular with volumes up to 1.0 cubic centimeter, below the norm of 1.0 to 2.5 cubic centimeters. The patient is prepubertal at Tanner stage I. Renal ultrasound additionally noted bilateral pyelectasis up to 8 millimeters without ureteral dilation, a finding considered likely transient. The authors interpret the uterine and ovarian findings as constitutional delay of puberty rather than a direct consequence of BLOC-3 deficiency, while acknowledging that reporting such coincident findings is needed to determine whether genitourinary developmental delay might represent an unrecognized part of the HPS-1 spectrum or merely independent incidental findings.

Management after confirmation was multidisciplinary and largely anticipatory. The family received structured education on strict avoidance of NSAIDs and platelet-inhibiting drugs and of trauma-prone contact activities, and standby hemostatic prophylaxis with oral tranexamic acid at 20 milligrams per kilogram was prescribed for acute bleeding episodes. Ophthalmological care centered on individualized refractive correction for the nystagmus and foveal hypoplasia, which was well tolerated, with no surgical intervention required. On follow-up, best-corrected visual acuity improved in the right eye from 0.10 to 0.15 and remained stable at 0.15 in the left; repeat slit-lamp examination confirmed persistent absence of iris transillumination, validating the reproducibility of the finding, and the nystagmus remained unchanged. Because pulmonary fibrosis and granulomatous colitis are not typically expected at this young age, the patient was referred for baseline pulmonary and gastrointestinal assessment as part of anticipatory surveillance. For future menstrual health, the authors note that her phenotype cannot yet be predicted; prophylactic strategies for heavy menstrual bleeding, including tranexamic acid at 25 to 50 milligrams per kilogram per day or hormonal suppression, will be evaluated only upon menarche, in line with ISTH-SSC and ACOG guidance.

The broader lesson the authors draw is about diagnostic practice and rare-disease data collection. Absent iris transillumination does not exclude HPS, and where platelet electron microscopy is unavailable, immunofluorescence analysis of peripheral blood smears for platelet granule proteins such as LAMP-1/CD107a or CD63, as validated by Zaninetti and Greinacher, offers a practical alternative requiring only a small blood sample that can be shipped to specialized laboratories; in the absence of such methods, molecular genetic confirmation by next-generation sequencing remains the definitive standard. The authors emphasize that reporting atypical presentations expands the recognized clinical spectrum of rare disorders and that centralized national registries are a valuable tool for aggregating such nuances and standardizing multidisciplinary diagnostic algorithms. As a single case report, the observation cannot establish how commonly this dissociation occurs, but it documents a reproducible phenotypic feature in a molecularly confirmed patient and adds a concrete data point to the growing map of HPS-1 variability.

Subject of Research: A case report of Hermansky-Pudlak syndrome type 1 in a Russian girl with atypical ophthalmological and gynecological findings

Article Title: Case Report: Hermansky-Pudlak syndrome type 1 in the Russian Federation presenting with genotype-phenotype discordance

Article References: Khachatryan, L. G., Chincharauli, N. V., Golosnaya, G. S., Kazakova, K. A., Trifonova, N. S., Kaptilnyy, V. A., Poznyak, M. V., Zinchenko, R. A., Kulagin, A. S., Ionova, S. A., Zhukova, E. V., Minashkina, E. V., Lukyanchuk, O. S., & Chilova, R. A. (2026). Case Report: Hermansky-Pudlak syndrome type 1 in the Russian Federation presenting with genotype-phenotype discordance. Frontiers in Pediatrics, 14, Article 1946494. https://doi.org/10.3389/fped.2026.1946494

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1946494

Keywords: Hermansky-Pudlak syndrome, HPS1 gene, oculocutaneous albinism, iris transillumination, platelet storage pool deficiency, next-generation sequencing, foveal hypoplasia, bleeding diathesis, case report, rare disease, genotype-phenotype discordance, pulmonary fibrosis risk