Sea-blue histiocytosis and thrombocytopenia successfully treated with an mTORC1 inhibitor: a case report

Abstract

This report describes a pediatric patient with acquired sea-blue histiocytosis (SBH) and refractory immune thrombocytopenia (ITP) who harbors a heterozygous variant in TSC2 (p.Arg1713His). The child failed to respond to conventional first-line therapies for ITP but achieved rapid platelet normalization within 1 months of sirolimus initiation. Regression of SBH was observed at 3 months post-treatment. The identification of the TSC2 variant, along with the dramatic resolution of both SBH and thrombocytopenia upon sirolimus therapy, suggests a possible association between TSC2-related mTOR pathway dysregulation, sea-blue histiocytosis, and thrombocytopenia.

Introduction

Sea-blue histiocytosis (SBH) is a rare histiocytic disorder characterized by lipid-laden macrophages infiltrated in the spleen, liver, bone marrow, and lymph nodes [1]. These cells result from an excessive accumulation of lipids that exceeds the lysosomal capacity of macrophages, leading to incomplete lipid degradation and the accumulation of lipofuscin and ceroid in their cytoplasm that stain blue or blue-green with May-Grünwald Giemsa stain [2]. While SBH is classically associated with inherited lysosomal storage diseases (e.g., Niemann-Pick disease) [3], it has been sporadically reported in some acquired disorders including immune thrombocytopenia (ITP) and myelodysplastic syndromes (MDS), with increased bone marrow cell turnover and membrane degradation [4, 5].

The mechanistic target of rapamycin (mTOR) is a central signaling molecule that controls cellular metabolism by integrating signals from nutrients, growth factors, and other environmental signals. mTOR forms two protein complexes, mTORC1 and mTORC2. mTORC1 is the direct target of the clinically important drug rapamycin and its activation in lysosome is negatively regulated by the components of tuberous sclerosis complex (TSC, including TSC1 and TSC2),depending on class I phosphoinositide 3-kinase (PI3K) signaling [6, 7].

The association between SBH and mTORC1 is undefined. Herein, we present a novel pediatric case with prominent bone marrow SBH and profound thrombocytopenia. Genomic analysis revealed a heterozygous TSC2 variant. Remarkably, both sea-blue histiocyte infiltration and thrombocytopenia exhibited dramatic resolution following sirolimus therapy. This report suggests the first clinical evidence of a possible link between mTORC1 dysregulation and SBH pathogenesis, and raises the hypothesis that mTORC1 inhibition may represent a potential therapeutic strategy for selected acquired disorders presenting with SBH.

Case presentation

A 7-year-old male of Han Chinese ethnicity (East Asian race) was admitted for recurrent epistaxis and severe thrombocytopenia (> 1 month). Past medical and family histories were unremarkable, and physical examination showed no developmental anomalies, neurological deficits, lymphadenopathy, or hepatosplenomegaly.

Complete blood counts revealed platelets < 20 × 10⁹/L, hemoglobin 112–120 g/L, and white blood cells 5.4 × 10⁹/L (normal differential). Peripheral smear confirmed thrombocytopenia without morphologic abnormalities. Plasma thrombopoietin (TPO), liver enzymes, cholesterol, triglycerides, and infectious screening (including EBV, CMV, HIV, HBV, HCV, and parvovirus B19) were all normal. Abdominal ultrasound excluded hepatosplenomegaly.

Bone marrow aspiration and biopsy showed megakaryocytic hyperplasia, with preserved erythroid and myeloid maturation. There was a striking infiltrate of histiocytes exhibiting foamy, microvacuolated cytoplasm in the marrow interstitium on hematoxylin-eosin (HE) stain (Fig. 1a). Giemsa staining further demonstrated that these histiocytes had abundant cytoplasm densely packed with coarse, sea-blue to blue-green granules or lipid vacuoles, consistent with sea-blue histiocytes (Fig. 1b, c). Enzymatic assays for acid sphingomyelinase and glucocerebrosidase were within normal limits, and lipid metabolism screening was unremarkable, excluding primary lysosomal storage disorders.

Fig. 1.

Bone marrow morphological features. a Bone marrow biopsy showing megakaryocytic hyperplasia(black arrow) and clustered sea-blue histiocytes (boxed area) with foamy, microvacuolated cytoplasm in marrow interstitium (hematoxylin–eosin stain, original magnification 400×). b, c Bone marrow aspirate showing sea-blue histiocytes laden with blue staining pigment granules or lipid vacuoles (Wright’s stain, original magnification 1000×)

Flow cytometric immunophenotyping of peripheral blood lymphocytes was performed at admission. The results showed lymphopenia (1179 cells/µL, reference range 2260–3820 cells/µL) with increased CD19 + B cells (26.0%, reference 10.21–20.12%), and increased CD16 + CD56+ NK cells (24.1%, reference 9.00-22.24%). Serum immunoglobulin levels (IgG, IgA, IgM) were all within age-appropriate normal ranges. All tested autoantibodies, including antinuclear antibodies (ANA), anti-double-stranded DNA antibodies, extractable nuclear antigen (ENA), direct Coombs test, and anti-platelet antibodies, were negative.

The patient was diagnosed with ITP (thrombocytopenia with megakaryocytic hyperplasia, normal TPO, ineffective platelet transfusion, no secondary causes) but was refractory to first-line therapies, including high-dose dexamethasone, intravenous immunoglobulin (IVIG), and TPO receptor agonists (eltrombopag and avatrombopag). Whole-exome sequencing of peripheral blood identified a heterozygous pathogenic TSC2 variant [c.5138G > A (p.Arg1713His)] inherited from his asymptomatic mother (Fig. 2). This variant has been previously reported as pathogenic in patients with atypical TSC presentations [8, 9]. Neither the patient nor his mother exhibited clinical phenotypes related to TSC, and the patient’s brain magnetic resonance imaging (MRI) scan was normal.

Fig. 2.

Sanger sequencing showing TSC2 mutation in the patient and his mother

Given that TSC2 mutations are known to cause overactivation of mTORC1 in TSC, as previously reported [10], oral sirolimus (an mTORC1 inhibitor, target trough concentration 4–12 ng/mL) was initiated after 8 months of persistent thrombocytopenia. Platelets increased from 15 × 10⁹/L to > 100 × 10⁹/L within 1 month. During the total follow-up period of 18 months, platelet counts remained stable at 150–200 × 10⁹/L on sirolimus monotherapy alone. The detailed treatment course and platelet count trends are shown in Fig. 3. Bone marrow biopsy at 3 months showed a marked reduction in sea-blue histiocytes (Fig. 4).

Fig. 3.

Platelet count trends during sequential treatment regimens. Colored bands represent treatment phases: untreated (grey), high-dose dexamethasone (HD-DEX, 0.6 mg/kg/d × 4 d, pulsed every 28 days, 2 courses; pink), eltrombopag (50 mg/d; blue), avatrombopag (20 mg/d; yellow), sirolimus plus avatrombopag (green), and sirolimus monotherapy (purple). Sirolimus was administered at 1–2 mg/m²/d with a target trough concentration of 4–12 ng/mL (patient weight, 27 kg). Avatrombopag was initiated at month 6, tapered from month 10 (green-to-transparent gradient), and discontinued at month 15. A sustained platelet response was achieved after the addition of sirolimus, with counts remaining stable at 150–200 × 10⁹/L on sirolimus monotherapy alone

Fig. 4.

Post-treatment bone marrow biopsy(hematoxylin–eosin stain, original magnification 400×). Bone marrow biopsy after 3 months of sirolimus therapy demonstrated a marked reduction in the burden of sea-blue histiocytes compared with the pretreatment specimen

Discussion

SBH was historically recognized as a hallmark of inherited lysosomal storage diseases (LSDs), such as Niemann-Pick disease or Gaucher disease, where defective lysosomal enzymes impair lipid degradation and trigger lipofuscin/ceroid accumulation in macrophages [3, 11]. Recently, emerging reports have linked SBH to acquired conditions, including myeloproliferative disorders, ITP, and rarely, immune-related cytopenia [4, 5, 12]. In these acquired settings, SBH is thought to arise from accelerated bone marrow cell turnover—with increased membrane degradation and lipid release—exceeding the catabolic capacity of macrophages, even in the absence of primary lysosomal enzyme defects. However, this cannot explain the rarity of SBH in such bone marrow proliferative disorders, and few reports have described whether SBH regresses following treatment.

This case report describes a pediatric patient with acquired SBH and refractory ITP. The identification of a heterozygous TSC2 variant [c.5138G > A (p.Arg1713His)], which was previously reported to be pathogenic in patients with TSC, was critical to unraveling the possible pathogenesis of this patient’s disease. TSC2, together with TSC1, forms a TSC complex that negatively regulates mTORC1. Loss-of-function TSC2 mutations abrogate the inhibitory activity of the TSC complex, leading to constitutive mTORC1 activation [10]. The presence of a pathogenic TSC2 variant and the dramatic resolution of both SBH and thrombocytopenia following sirolimus therapy in this case suggest a possible association between TSC2-related mTOR pathway dysregulation, sea-blue histiocytosis, and thrombocytopenia.

A potential mechanistic link between mTORC1 dysregulation and both SBH and thrombocytopenia may be explained as follows. For SBH, mTORC1 overactivity is well-documented to dysregulate lipid metabolism: it promotes de novo lipid synthesis via activation of sterol regulatory element-binding proteins (SREBPs) and inhibits lysosomal autophagy—a key pathway for clearing damaged organelles and excess lipids [13, 14]. In macrophages, this dual effect could lead to intracellular lipid accumulation, exceeding lysosomal degradation capacity and triggering lipofuscin/ceroid deposition—the hallmark of SBH.

For thrombocytopenia, mTORC1 dysregulation has been implicated in B-cell hyperfunction and promotes the imbalance of T-cell differentiation in ITP patients [15, 16]. The megakaryocytic hyperplasia with normal TPO level and ineffective platelet transfusion suggest immunological factors in this case. In addition, mTORC1 hyperactivation could impair megakaryocyte maturation and platelet production through abnormal autophagy, as previous studies have shown [17, 18]. This may partly explain why the patient failed to respond to traditional first-line treatments of ITP.

Notably, this patient and his mother did not exhibit clinical features of TSC (e.g., cutaneous angiofibromas, renal angiomyolipomas, seizures). The TSC2 c.5138G > A variant was detected in peripheral blood DNA with a variant allele frequency of approximately 50%, consistent with a heterozygous germline variant, and the same variant was confirmed in the asymptomatic mother by Sanger sequencing (Fig. 2). The absence of TSC stigmata in both carriers therefore likely reflects incomplete penetrance and variable expressivity of this TSC2 variant [19]. This case underscores the phenotypic heterogeneity of TSC2 mutations: classic TSC results from heterozygous germline loss-of-function variants with high penetrance, whereas low-penetrance variants may manifest as isolated hematologic or metabolic phenotypes. The present findings suggest that in patients with unexplained SBH or refractory thrombocytopenia, sequencing of TSC1/2 and other mTORC1 pathway genes should be considered even in the absence of classical TSC features.

In conclusion, this case suggests a possible association between mTORC1 dysregulation, acquired SBH, and refractory thrombocytopenia. It emphasizes the value of genomic testing in patients with unexplained SBH or refractory hematologic disorders and identifies mTORC1 inhibition as a potential targeted therapy for acquired SBH in hematologic disorders. However, direct evidence of mTORC1 activation in bone marrow histiocytes (e.g., immunohistochemical staining for p-S6 or p-4EBP1) was not obtained in this study, representing a limitation of this report.

Author contributions

Hongmin Li collected, analyzed, and interpreted the data, and drafted the manuscript. Jie Ma, Yu Hu, Jingyao Ma, Guoqing Liu, and Yunyun Wei participated in the patient’s diagnosis, treatment, and follow-up. Chao Yang provided pathological data. Runhui Wu primarily managed the patient and critically reviewed the manuscript for intellectual content.

Funding

This research was supported by the National Key Research and Development Program of China (Grant No. 2023UFC2706100).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.