Hematopoietic stem cell transplantation in serine/threonine kinase 4 (STK4) deficiency: Report of two cases and literature review

Uygun, Vedat; Keleş, Sevgi; Daloğlu, Hayriye; Öztürkmen, Seda; Yalçın, Koray; Karasu, Gülsün; Yeşilipek, Akif

doi:10.1111/petr.14439

Cited by 7 publications

(5 citation statements)

References 10 publications

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“…Moreover, a high number of clinical studies have been published using sirolimus as bioactive molecules in the treatment of patients who underwent transplantation of the lung [ 47 ], heart [ 48 ], pancreas [ 49 ], liver [ 50 ], intestine [ 51 ], cornea [ 52 ], and bone marrow [ 53 ]. Consequently, sirolimus (rapamycin) is of great interest for several pathologies in which transplantation is a clinical option, including (but not restricted to) solid cancers (for instance liver transplantation in hepatocellular carcinoma, or kidney transplantation in renal cancers) [ 54 , 55 ], leukemia, lymphoma and other blood cancers (for instance bone marrow transplantation in leukemia) [ 56 ], cystic fibrosis (lung transplantation) [ 57 ], serine/threonine kinase 4 (STK4) deficiency, characterized by recurrent bacterial, viral, and fungal infections (allogeneic hematopoietic stem cell transplantation, HSCT) [ 58 ], and hematological diseases (bone marrow transplantation) [ 59 ]. In clinical allotransplantation, the long-term efficacy of rapamycin and other mTOR inhibitors has been firmly established, despite the fact that adverse events have been reported, such as the inhibition of wound healing, buccal ulceration, anemia, hyperglycemia, dyslipidemia, and thrombocytopenia [ 43 , 60 ].…”

Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients.

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Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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“…His GVHD controlled with immunosuppressive therapies. 24 None of DOCK8 and STAT3 de cient patients diagnosed as malignancy in our cohort. Important ndings in history and at clinical side supporting to each HIES phenotype summarized in supplementary Table 2.…”

Section: Clinical Ndingsmentioning

confidence: 82%

Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

Kapaklı¹,

HAZAR²,

Celik³

et al. 2023

Preprint

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Background: Serine/threonine kinase 4 (STK4) deficiency is a combined immunodeficiency with overlapping features with the autosomal dominant (AD)– and recessive (AR) forms of the Hyper IgE syndrome (HIES), including recurrent infections, eczema, eosinophilia and elevated serum IgE levels. The precise distinguishing features of STK4 deficiency versus the different forms of HIES remain unclear. Objective: We examined the comparative clinical and immunological features of STK4 deficiency versus AD- and AR forms of HIES, including signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8) respectively, with a focus on those attributes that distinguish STK4 deficiency from those disorders. Methods: Six STK4, 4 STAT3 and 14 DOCK8 deficient patients and 16 healthy controls enrolled in this study. Clinical and immunological features of the patients including detailed analysis of naïve and memory T and B cell subsets including T helper (TH), T follicular helper (TFH) and T regulatory (Treg) cells were evaluated and compared with age matched control subjects. Results: Recurrent infections and eczema were the most frequent clinical findings in AR- and eczema in AD-HIES. All STK4 deficient patients had recurrent herpetic facial lesions. Serum IgM level was significantly low in DOCK8 deficient patients compared to STAT3 and STK4 deficiency. Both CD4+T cell numbers and ratio were significantly lower in STK4 and DOCK8 deficient patients compared to control subjects. On the other hand, recent thymic emigrant (RTE) cell ratio was significantly lower, and T helper type 1 (TH1) cell frequencies were significantly higher in STK4 deficiency. While regulatory T (Treg) cell frequencies were significantly lower in DOCK8 deficiency, T helper type 17 (TH17) cell frequencies were significantly lower in both STAT3 and DOCK8 deficient patients. Conclusion: While STK4 deficiency presents with overlapping clinical and immunological features with DOCK8 deficiency, including recurrent herpetic lesion and CD4+ T cell lymphopenia, it is distinguished by the absence of severe allergic diseases and by a number of immunological findings including decreased RTE and increased TH1 cell frequencies. STK4 deficiency should be considered in patients with AR-HIES with a clinical phenotype of DOCK8 deficiency but with otherwise normal DOCK8 protein expression.

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“…A review of the literature reveals that 10 out of 26 reported patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) ( 16 , 21 ), with a post-transplant survival rate of 50%. Of these 10 patients, at least 7 were referred for transplant primarily due to EBV viremia/lymphoma.…”

Section: Discussionmentioning

confidence: 99%

A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report

Al-Saud,

Alajlan,

Alruwaili

et al. 2024

Front. Immunol.

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Mutations in STK4 (MST1) are implicated in a form of autosomal recessive combined immunodeficiency, resulting in recurrent infections (especially Epstein-Barr virus viremia), autoimmunity, and cardiac malformations. Here we report a patient with an atypically mild presentation of this disease, initially presenting with severe T cell lymphopenia (< 500 per mm3) and intermittent neutropenia, but now surviving well on immunoglobulins and prophylactic antibacterial treatment. She harbors a unique STK4 mutation that lies further downstream than all others reported to date. Unlike other published cases, her mRNA transcript is not vulnerable to nonsense mediated decay (NMD) and yields a truncated protein that is expected to lose only the C-terminal SARAH domain. This domain is critical for autodimerization and autophosphorylation. While exhibiting significant differences from controls, this patient’s T cell proliferation defects and susceptibility to apoptosis are not as severe as reported elsewhere. Expression of PD-1 is in line with healthy controls. Similarly, the dysregulation seen in immunophenotyping is not as pronounced as in other published cases. The nature of this mutation, enabling its evasion from NMD, provides a rare glimpse into the clinical and cellular features associated with the absence of a “null” phenotype of this protein.

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Hematopoietic stem cell transplantation in serine/threonine kinase 4 (STK4) deficiency: Report of two cases and literature review

Cited by 7 publications

References 10 publications

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Distinguishing Clinical and Immunological Features of Combined Immune Deficiency due to Serine/Threonine Kinase 4 deficiency

A unique STK4 mutation truncating only the C-terminal SARAH domain results in a mild clinical phenotype despite severe T cell lymphopenia: Case report

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