Case Report: A converging pathology: Chediak–Higashi syndrome and IEI-associated lymphoproliferative disease

Introduction

Chediak–Higashi syndrome is an infrequent disease characterized by lysosomal malfunction. This autosomal recessive disorder is caused by a mutation in the LYST gene. Common clinical presentation includes partial ocular and cutaneous albinism, neurological dysfunction, and lymphoproliferative dysregulation. This disorder has a classical early stage and delayed atypical presentation (1, 2). According to the International Union of Immunological Societies (IUIS) classification, Chediak–Higashi syndrome is an inborn error of immunity and is part of the category “Diseases of immune dysregulation” (1). Inborn errors of immunity present clinically as increased susceptibility to recurrent infections, autoimmune manifestations, lymphoproliferation, and an increased risk of lymphoma and gastric carcinoma (3, 4) and predispose to lymphomas through impaired T-cell immunosurveillance and Epstein–Barr virus (EBV) control.

Lymphomas arising in the context of inborn errors of immunity (IEIs) (3) exhibit a bimodal age distribution, peaking during the first and third decades of life. Approximately two-thirds present at advanced stages (III or IV), with a male predominance (M:F ratio of 1.5:1), particularly evident in X-linked disorders. Predominantly, antibody deficiencies account for the most frequent underlying IEIs associated with lymphoma, with higher reported prevalence across Australia, eastern Asia, Egypt, Europe, Latin America, and North America (5, 6). In contrast, the epidemiological data on Chediak–Higashi syndrome (CHS) remain scarce, primarily due to its extreme rarity. Estimating the incidence and prevalence of CHS is particularly challenging, as fewer than 500 cases have been documented in the medical literature to date (7). The coexistence or overlap of these two conditions further complicates diagnosis, treatment, and prognosis, given that their combined clinical presentations may obscure distinguishing features, delay targeted therapeutic interventions, and ultimately impact patient outcomes.

Understanding the pathophysiology and clinical interplay between these disorders is crucial for improving diagnostic accuracy and optimizing management strategies. Contextually speaking, the diagnosis and treatment of complex pathologies are more challenging in developing countries due to different socioeconomic and technological gaps compared to vanguard high-tech medical centers in first-world countries, or even metropolitan cities in the third world (8). As of the date of writing this article, a serious armed conflict is occurring within the region of the medical center involved in this case report. Indirect consequences due to warfare disrupt the healthcare system, patient influx, and medication supplies, among other detrimental consequences to patient wellbeing (9). Nevertheless, this healthcare center successfully attended to and diagnosed this patient presented here despite its geopolitical context. The purpose of this article is to present a case of a young patient with the double diagnosis of Chediak–Higashi and T-cell IEI-LPD, its medical findings, and its prognosis to contribute to the medical scientific literature.

Materials and methods

A retrospective, monocentric case report was conducted, involving a patient who presented with Chediak–Higashi and peripheral T-cell lymphoma. Data from this patient were collected retrospectively in the year 2023 from “Unidad Hemato-Oncológica Especializada” in Cúcuta, Norte de Santander, Colombia, where the diagnosis and treatment were conducted. The medical approach was tailored to the case based on clinical and paraclinical findings. Ethical approval was waived due to the retrospective nature of the study, which relied on clinical record data. The patient’s relatives provided signed consent for the use of the data. This study falls under the category of “research with no risk” as outlined by Resolution 8430 of 1993 in Colombian legislation. According to Article 11 of this regulation, such research involves the retrospective review of clinical records without intervention or modification of the participants’ biological, physiological, psychological, or social variables and does not involve sensitive aspects of behavior. When contextualized within global IRB standards, this study would be classified as involving minimal risk.

Case report

We present a 25-year-old male patient referred from another medical service due to incapacitating lower back pain experienced in the prior week and quantifiable weight loss of 5 kg in the last 2–3 months, accompanied by asthenia, adynamia, fatigue, and skin pallor. His medical history describes left ocular surgery due to suspected cataract, with endophthalmitis as a surgical complication and finally left ocular sight loss. On physical examination, the patient demonstrated skin pallor, left ocular hypopigmentation in the lower nasal quadrant, translucent left iris, generalized hypotrophy in the extremities, walking abnormalities, and generalized skin lesions described as multiple hypochromic maculae along with hair hypopigmentation (Figure 1). The initial laboratory evaluation revealed leukopenia (3,830 cells/µL), neutropenia (1,370 cells/µL), and moderate normocytic normochromic anemia with a hemoglobin level of 8.6 g/dL. Peripheral blood smear showed hyperpigmentation and large cytoplasmic inclusions with atypical morphology and staining in lymphocytes and neutrophils (Figure 2). Serum LDH was 342 IU/L (within normal range), total protein was decreased at 4.7 g/dL with hypoalbuminemia of 2.6 g/dL, and β2-microglobulin was elevated at 5.29 mg/L. Serum creatinine (1.1 mg/dL) and calcium (7.81 mg/dL) were within normal limits. Serum ferritin was elevated at 302 ng/mL. Protein electrophoresis demonstrated hypogammaglobulinemia, with IgG 567 mg/dL, IgA 19.4 mg/dL, and IgM 11.6 mg/dL. Peripheral blood flow cytometry showed increased CD3+ T lymphocytes (3,347.8 cells/µL), normal CD4+ T cells (553.7 cells/µL), increased CD8+ T cells (2,436.4 cells/µL), a reduced CD4/CD8 ratio (0.2), and decreased NK cells (73.2 cells/µL).

Initial imaging was a lumbosacral spine MRI, which revealed compression fractures at T12 and L1, associated with a paravertebral retroaortic left mass adjacent to the T10–T12 vertebral bodies measuring 91 mm × 53 mm × 30 mm, as well as splenomegaly (Figure 3). Bone gammagraphy reported lesions in T12 and L1 with blastic hyperactivity. CT-guided Tru-cut biopsy of the left paravertebral mass revealed, on microscopic examination, a proliferation of small lymphoid-appearing cells with irregular nuclear condensed chromatin, occasional visible nucleoli, and up to 2 mitotic figures per 10 high-power fields. These cells were arranged in sheets and loosely formed nodules within a fibrous stromal background. The morphological and immunophenotypic findings were consistent with a T-cell lymphoproliferative disorder/lymphoma associated with primary immunodeficiency (CD2+, CD3+, CD4+/−, CD5+, CD7+, CD8+, PD1+/−, CD20−, PAX5−, CD79a−, CD30−, CD56−, GRANZYME−, ALK−, CD10−, BCL6−, BCL2−, CD21−, CYCLIN D1−, MUM1IRF4−, TdT−, CD34−, CD15−, S100−, SOX11−, Ki-67 <10%). Bone marrow aspiration described dense, stained granules with atypical morphology in the lymphoid and granulocytes series with medullary lymphocytosis (Figure 4). Bone marrow aspiration revealed dense, intensely stained granules with atypical morphology in both lymphoid and granulocytic series, associated with medullary lymphocytosis. Bone marrow flow cytometry demonstrated a predominance of T lymphocytes, mainly CD8+, with a cytotoxic/activated phenotype, along with polytypic B lymphocytes. Conventional karyotyping showed a normal male karyotype (46,XY [20]). Genomic DNA was extracted from a peripheral blood sample using the High Pure Template Preparation Kit (Roche) and sequenced on an Illumina MiSeq platform with a mean depth of 500×. Bioinformatic analysis identified a homozygous c.9464G>A (p.Arg3155Gln) variant in the LYST gene, corresponding to a non-synonymous single-nucleotide polymorphism, which is highly relevant to the diagnosis of Chediak–Higashi syndrome (Table 1).

Table 1. Biallelic exonic variant Lyst gene identified in this patient with Chediak–Higashi syndrome.

The clinical presentation, imaging studies, and lab reports concluded a diagnosis of classical presentation Chediak–Higashi syndrome and T-cell lymphoproliferative disorder/lymphoma associated with primary immunodeficiency stage IVBX, PIT high intermediate, adjusted PIT high, diminished IgA and IgM, and low natural killer cells.

The patient received six EPOCH protocol chemotherapy cycles complemented with pegfilgrastim to prevent febrile neutropenia as primary prevention. Further evaluation reported an intermediate complete response (mass and splenomegaly 100% clearance). A PET scan was ordered after the sixth cycle but was unavailable due to healthcare system constraints. One month later, the patient’s neurological condition worsened, with the onset of neurogenic bladder, leading to urinary tract infection, urosepsis, and ultimately, death.

Discussion

CHS is a rare autosomal recessive disorder caused by LYST gene mutations, leading to lysosomal dysfunction, partial albinism, neurological impairment, and immune dysregulation (1, 2). The LYST or CHS1 mutation affects the storage and secretory functions of lysosomal granules of leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes. The defects result in enlarged vesicles and non-functional lysosomes (10). The Leiden Open Variation Database reports 377 variants in this gene. Mutations in Lyst are distributed throughout the length of the protein, suggesting that the position of mutations may be irrelevant for the final functional outcome, and are a combination of point/missense mutations, insertion/deletion, or frameshift variants (1, 11). IEIs compromise T-cell immunosurveillance, increasing oncogenic risk through chromosomal instability and defective DNA repair, which may culminate in T-cell malignancies. Approximately 35% of these cases are classified as common variable immunodeficiency (3, 4). This case describes a 25-year-old male patient with CHS and T-cell IEI-LPD, initially admitted for severe lower back pain, weight loss, and constitutional symptoms. His history included left ocular surgery with sight loss, cutaneous and hair hypopigmentation, and neuromuscular abnormalities. Laboratory findings revealed leukopenia, normocytic anemia, diminished IgA and IgM, low natural killer cells, and T-cell predominance. Imaging detected vertebral fractures, a retroaortic mass, and splenomegaly, with biopsy confirming T-cell lymphoproliferative disorder/lymphoma associated with primary immunodeficiency. Epstein–Barr and type 8 herpes virus tests were not performed due to unavailability inside the institution. The patient underwent six cycles of EPOCH chemotherapy with a complete response, yet healthcare limitations prevented PET scan follow-up. Despite initial stabilization, he developed neurological decline, neurogenic bladder, and urosepsis and ultimately succumbed to disease progression. This case underscores the diagnostic and therapeutic challenges posed by rare hematologic malignancies, especially in locations affected by geopolitical instability.

The patient initially presented with typical clinical and hematologic findings, and over time developed neurological manifestations consistent with CHS. Due to the underlying immunodeficiency associated with CHS, a T-cell lymphoma risk was augmented, which aligns with reports in scientific literature documenting the increased risk of malignancy, particularly lymphoproliferative disorders, in these patients (7). Immunologically, the authors’ patient presented diminished G, A, and M immunoglobulins. Hypogammaglobulinemia is typically defined as immunoglobulin (Ig) levels at least two standard deviations below the age-specific mean (<5 g/L). Although the authors’ patient did not strictly meet the criterion for profound IgG deficiency, he had a marked decrease in the other immunoglobulin levels (12).

Also, their immunological profile revealed a diminished NK-cell population, highlighting the functional immune dysregulation due to CHS pathology. The Literature emphasizes that even without severe reductions in immunoglobulins, individuals diagnosed with CHS remain significantly immunocompromised due to impaired NK-cell cytotoxicity and defective T-cell-mediated responses, leading to heightened susceptibility to infections and malignancies (13). This increased outcome is attributed to impaired NK-cell function and chronic antigenic stimulation, potentially exacerbated by underlying defects in DNA repair and apoptosis pathways intrinsic to the CHS genetic mutation (14). The causes of hypogammaglobulinemia can be primary or secondary; primary causes occur associated with various inborn errors of immunity such as combined immunodeficiencies (with or without syndromic findings); however, according to the classification of the International Union of Immunological Societies (1), Chediak–Higashi syndrome is a “disease of immune dysregulation,” where its main immune functional defect is in NK and T cells. The hypogammaglobulinemia observed in the patient could be secondary to the patient’s cellular immune dysregulation or a secondary cause associated with lymphoma, mainly B cells (2). More extensive genomic studies would be necessary to exclude genetic defects of immunoglobulins; functional studies and the study of EBV should also be a necessary test in evaluating lymphomas associated with inborn errors of immunity. Rare cases of T lymphomas have been associated in the context of immune deficiency/dysregulation, such as peripheral T-cell lymphomas, anaplastic large cell lymphomas, angioimmunoblastic follicular T-cell lymphomas, hepatosplenic T-cell lymphomas, mycosis fungoides, and extranodal NK/T-cell lymphomas, with most of the described T-cell IEI-LPD EBV being negative (3).

Therapeutically, early aggressive chemotherapy regimens are often employed, reflecting the aggressive biology of these lymphomas and the necessity of timely intervention. The patient received six cycles of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) chemotherapy, complemented with pegfilgrastim as primary prophylaxis against febrile neutropenia. This regimen, consistent with established treatment protocols for aggressive lymphoid malignancies, is designed to optimize cytotoxic efficacy while minimizing treatment-related toxicity through dose adjustment based on hematologic tolerance. EPOCH combines agents targeting different phases of the cell cycle, achieving synergistic antitumor activity. Etoposide and doxorubicin inhibit topoisomerase II-mediated DNA repair, vincristine disrupts microtubule assembly, cyclophosphamide alkylates DNA to induce apoptosis, and prednisone exerts cytotoxic and anti-inflammatory effects on lymphoid cells. The addition of pegfilgrastim, a long-acting granulocyte colony-stimulating factor, aligns with current international guidelines recommending prophylactic use of granulocyte colony-stimulating factors in regimens associated with a significant risk of myelosuppression and febrile neutropenia. It is also important to consider that vincristine, a key component of the EPOCH regimen, is associated with cumulative neurotoxicity due to its interference with axonal microtubule dynamics. This mechanism could plausibly have contributed to the progressive neurodegenerative manifestations observed in our patient, underscoring the ongoing challenge of balancing disease control with the neurological adverse effects of cytotoxic therapy. Intermediate evaluations following treatment reported a complete response, demonstrating resolution of the lymphoma-related mass and associated splenomegaly, underscoring the efficacy of intensive chemotherapy in achieving clinical remission in these high-risk patients. Nevertheless, the literature repeatedly underscores that despite achieving temporary remission with chemotherapy alone, definitive management ideally involves hematopoietic stem cell transplantation (HSCT) (15). While HSCT is considered the only curative therapy for the immunologic and hematologic manifestations of CHS, it was not regarded as a curative option in this case due to the coexistence of advanced neurodegenerative involvement and its associated lymphoproliferative process. In such contexts, HSCT may prevent further immune dysregulation but does not reverse established neurological injury or control ongoing lymphoproliferation, limiting its overall curative potential. A particular study revealed that the 5-year probability of overall survival is 62% (16). The literature also reports consistent epidemiological patterns, with most diagnoses occurring in the third decade of life and at advanced stages, typically stage IV (5). In conclusion, the clinical trajectory of the authors’ patient closely mirrors established knowledge in scientific literature regarding CHS-related immunodeficiency, lymphoma development, appropriate therapeutic approaches, and high risk of infection due to immunocompromise, which unfortunately leads to its lethal outcome.

Estimating the combined incidence of this case is nearly impossible due to the extreme rarity of both conditions. Our search identified three reported cases of T-cell lymphoma associated with Chediak–Higashi syndrome, one case of CHS with B-cell lymphoma, and one case of CHS with lymphoma, documented in China, Japan, Turkey, Brazil, and the United States, respectively (17–21). However, none of these cases specifically reported T-cell IEI-LPD, underscoring the scarcity, extrapolating as a one-of-a-kind presentation. T-cell lymphoma predominantly affects older individuals; however, immune disorders and dysregulation can lead to earlier onset (13). Given that Chediak–Higashi syndrome disrupts immune function (1, 2), it provides a plausible explanation for its premature presentation in this case.

The Lys gene, located on the long arm of chromosome 1 [1q42.3] (22), contains 53 exons with an open reading frame of 11,406 bp and encodes for a 3801 amino acid protein, also known as CHS1 (23). This study utilized only the sequencing strategy of the Lyst gene to determine its mutational status. The variant c.9464G>A (p.R3155Q) located in exon 40 of the Lyst gene has been detected in a homozygous state, and the mutation was detected with a VAF of 100% (in two siblings with a diagnosis of Chediak–Higashi). This variant has not been previously reported by any study in this pathology. This variant corresponds to a change of the reference sequence G (guanine) by an altered sequence A (adenine) at position 9464. This change produces, at the protein level, a substitution of arginine by glutamine at position 3155, specifically in the BEACH domain. This variant is documented in public databases RefSeq (dbSNP: rs1266965849) and is classified as a variant of uncertain significance (VUS) (24). Patients with mutations in the BEACH domain have been reported to have more numerous granules, of normal size or slightly enlarged, but less numerous, as presented in this patient described in the present study (1).

The variant identified in this study, initially classified as a VUS, was found to be biallelic in two siblings with Chediak–Higashi from the Colombian population, and this consistent familial presentation strongly suggests that the variant may be pathogenic and is likely contributing to the observed disease. The autosomal recessive inheritance pattern further supports the hypothesis that this variant is deleterious, as both siblings inherited one allele from each parent. Based on these findings, the authors propose that c.9464 G>A (p. R3155Q), identified with rs1266965849, could be a mutation with probable deleterious functions. This variant is reconsidered for reclassification from VUS to pathogenic.

Diagnosing rare diseases remains a major challenge, as demonstrated by a 2004 survey of nearly 6,000 European patients and caregivers across eight different conditions, where 41% reported receiving a prior misdiagnosis. Additionally, respondents experienced a diagnostic delay of 5 years or more, highlighting the complexity and prolonged uncertainty these patients often face (25). The diagnosis of Chediak–Higashi itself is even more challenging due to its rarity, phenotypic variability, and clinical overlap with various immune, hematological, neurological, and pigmentary disorders, including Griscelli syndrome and Hermansky–Pudlak syndrome (26). The patient’s medical history includes a prior misdiagnosis that resulted in an ocular surgical intervention, ultimately leading to left eye vision loss. The diagnosis in the authors’ institution was realized due to morphological findings in the bone marrow and peripheral blood smear and not semiological or symptomatological findings. Also, a case report has the limitation of a low epidemiological impact (27–30). Next-generation sequencing (NGS) has transformed genetic diagnosis by allowing massive and parallel reading of DNA sequences. The complete analysis of the Lyst gene at the exome level allows the identification of both known mutations and new sequence variants that could be playing an important role in the pathology. Thus, the implementation of next-generation sequencing in the diagnosis of this disease may help elucidate the genetic background of the authors’ population, contributing to more accurate diagnoses and a better understanding of the genetics of this disorder (31, 32).

Conclusion

This report underscores the complex diagnostic, therapeutic, and prognostic challenges presented by T-cell IEI-LPD in a patient with CHS. Our patient demonstrated classical CHS manifestations, including hypopigmentation, neurological decline, ocular impairment, and marked immunological dysfunction characterized by diminished immunoglobulin levels and impaired natural killer cell activity. Despite prompt chemotherapy and supportive therapy with pegfilgrastim, achieving initial complete remission, the severe underlying immunodeficiency inherent to CHS eventually resulted in neurological complications, severe infections, and a fatal outcome. The rarity of this clinical association complicates timely diagnosis and underscores the importance of comprehensive morphological assessments. Identifying the variant in the LYST gene offers valuable insight into possible genotype–phenotype correlations, although current data are insufficient to definitively classify this mutation as pathogenic. The standardization of diagnostic criteria, unification of terminology, and enhancement of genetic characterization through next-generation sequencing can significantly improve management, survival outcomes, and quality of life in rare disorders. Further research, particularly population-focused genetic studies, is essential to define molecular targets and establish effective, personalized therapeutic interventions, ultimately improving the prognosis for individuals diagnosed with CHS and associated aggressive malignancies such as T-cell IEI-LPD.

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Footnotes

Edited by: Maria Cecilia Poli, Universidad del Desarrollo, Chile

Reviewed by: Blachy Javier Dávila Saldaña, Cincinnati Children’s Hospital Medical Center, United States

Matilde Scaldaferri, AOU Città della Salute e della Scienza di Torino, Italy