Uncomplicated autoimmune cytopenias in children can present emergently but usually respond to first- or second-line treatment (steroids, immunoglobulin replacement therapy, and +/- rituximab) without long-term sequelae. In contrast, refractory cytopenias of childhood requiring repeated cycles of multi-agent immunosuppressive therapy constitute severe and debilitating conditions with significant long-term morbidity and compromise in quality of life. Genetic immune diseases causing global immune dysregulation are often associated with refractory cytopenias (AIHA, ITP, Evans syndrome, less frequently AIN, and aplastic anemia) along with other autoimmune manifestations (colitis, lung disease, vitiligo, alopecia, etc.) and, collectively, heighten suspicion for a primary immune dysregulation syndrome and prompt a comprehensive immunological and genetic evaluation.
Here we report our experience with a cohort of pediatric and young adult patients with presumed autoimmune cytopenia, referred to our interdisciplinary hemato-immunology clinic after failing multiple lines of immunosuppressive therapy in which isolated recalcitrant cytopenias were the only presenting symptom. More than half of these patients had an underlying genetic diagnosis [18/32; 56%], of which 77% (14/18) predisposed them to autoimmunity or autoinflammation. In patients with genetic forms of immune dysregulation, only one hematopoietic lineage was affected in 23% (6/26 patients). Importantly, all patients in whom targeted treatments addressing the underlying immunopathology could be identified responded significantly more favorably to therapy compared with patients who received broad immunosuppression with a combination of steroids and second-line agents (steroids, MMF, 6MP, azathioprine, cyclosporine, and tacrolimus).
Our experience highlights that genetic causes of immune/inflammatory dysregulation should be considered even in patients with isolated therapy-refractory cytopenia affecting only one hematopoietic lineage. A comprehensive immune workup and genetic screening is of paramount importance in cases of refractory cytopenia, as findings carry prognostic significance and influence treatment choices; targeted therapies should be explored whenever available. Those with an identified monogenic disease experienced significant benefit from targeted therapies and tolerated them well. The successful management of these complex conditions is facilitated by establishing multidisciplinary teams, underscoring their pivotal role in comprehensive care.
Underlying genetic diseases in our cohort of pediatric and young adult patients with presumed autoimmune cytopenia.
Underlying genetic diseases in our cohort of pediatric and young adult patients with presumed autoimmune cytopenia.
Characteristics of patients with an underlying PIRD or PID assessed at our immunology-hematology clinic.
| Patients | Age at diagnosis | Gender | Clinical | Diagnosis | Hematology | Genetic variants | Treatment and response to therapy |
|---|---|---|---|---|---|---|---|
| Rheumatology | |||||||
| Pat #1 | 14 yo | Female | Arthralgia | SLE without any underlying PID/monogenic disease | ITP and Coombs positive AHAI | PID Invitae panel (PID): no pathogenic variant | Plaquenil, transfusions, steroids, rituximab (Reaction to Rituximab) then sirolimus. On sirolimus for 2 years, then slow taper. In remission on 1 mg/day of sirolimus |
| Pat #2 | 15 yo | Female | Fatigue | SLE without any underlying PID/monogenic disease | Warm AIHA plus ITP | Negative WES trio | History of steroid, s/p 4 doses of rituximab. In remission, on hydrochloroquine |
| Pat #3 | 5 yo | Male | Arthralgia, fatigue | SLE without any underlying PID/monogenic disease | Chronic refractory ITP | PID panel: VUS in TNFRSF6B c.364C>T (p.His122Tyr), reported to be associated with juvenile arthritis, autoimmune cytopenia and SLE | Multiple courses of steroids, transfusions, IVIG, on Promacta 75 mg/day |
| Bone marrow failure | |||||||
| Pat #4 | 2 yo | Female | Fatigue | Myelodysplastic syndrome | Combs positive warm AHAI and ITP | PID panel: no pathogenic variant | Multiple courses of steroids, transfusions, IVIG, rituximab, HSCT: Allogeneic 5/10 mismatched maternal haploidentical peripheral blood stem cells |
| Pat #5 | Birth | Male | Microcephaly, short stature, lower limb asymmetry, developmental delay | AR Schwachman-Diamond syndrome | Bone marrow failure, aplastic anemia | WES trio: homozygous c.544>T (p.R182) pathogenic variant in DNAJC21, each inherited from one parent | Transfusions for a Hgb < 7 and platelets <10k. HSCT: Paternal haploidentical peripheral blood stem cells |
| Pat #6 | 7 yo | Female | Polydactyly | Aplastic anemia | Coombs positive aplastic anemia | PID panel: PMM2 [c.703G>T (p.Glu235*)], likely pathogenic; PMM2 is associated with AR congenital disorder of glycosylation | Transfusions for a Hgb < 7 and platelets <10k; s/p ATG) and started on cyclosporine and Eltrombopag. She is stable on Cyclosporine, Elthrombopag, prednisone taper |
| Pat #7 | 3 yo | Male | Disseminated pseudomonal infection with ecthyma gangrenosum/Jeune syndrome/fat pancreas | AR Schwachman-Diamond syndrome | Pancytopenia | WES trio: Compound heterozygous with 2 pathogenic variants in the SBDS gene - SBDS (c.258+2T>C; GT / c.184A>T; p.Lys62*), inherited respectively from father and mother | Transfusions for a Hgb < 7 and platelets <10k. HSCT has been considered |
| Pat #8 | 29 yo | Male | Recurrent bacterial infections in the first few months of life. Short stature, gingivitis, multiple mouth ulcers | G6PC3 LOF | Congenital neutropenia and thrombocytopenia | PID panel: homozygous variant in the G6PC3 gene, Exon 1, c210del (p.Phel71Serfs*46), each inherited from one parent | Received prolonged therapy with steroids and G-CSF (neupogen). In remission on SGLT2 inhibitor (Jardiance 10 mg per day) |
| Pat #9 | 10 yo | Male | Recurrent epistaxis | Fanconi Anemia | Neutropenia, thrombocytopenia, and macrocytic anemia | PID panel: one pathogenic variant and one variant of uncertain significance identified in FANCA. FANCA: c.987_990del (p.His330Alafx*4) inherited from mother, and one VUS c.2222+8C>T(intronic) inherited from father | Stable on Promacta, currently been evaluated for HSCT |
| PID/PIRD | |||||||
| Pat #10 | 2 yo | Female | Fatigue | AD NFkb1 | ITP and neutropenia, immunodeficiency/humoral defect) | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | IVIG q4 wks. In remission on Sirolimus 0.5 mg/day and Promacta 25 mg/day) |
| Pat #11 | 7 yo | Female | No clinical symptom | AD NFkb1 | Severe neutropenia | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | Sirolimus (1 mg/day)- partial remission |
| Pat #12 | 11 yo | Female | No clinical symptom | AD NFkb1 | Neutropenia | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | - |
| Pat #13 | 1 yo | Male | Bloody discharge from eyes | X-linked MAGT1 | ITP and Coombs positive AHAI | PID panel: likely pathogenic variant in the MAGT1 gene: deletion exon 2-10 | Steroid taper, sirolimus has been considered |
| Auto-inflammatory | |||||||
| Pat #14 | 16 yo | Male | Fatigue, short stature | SPENCDI | AHAI, ITP | WES trio: biallelic compound heterozygous pathogenic variants in the ACP5 gene (c.325G>A, p.Gly109Arg/c.526C>T, p.Arg176*) inherited from mother and father respectively | Stable on ruxolitinib 5mg-0mg-5mg per day |
| Pat #15 | 4 yo | Female | Fatigue, short stature, speech delay | SPENCDI | AHAI, ITP | PID panel: biallelic compound heterozygous variants in the ACP5 gene (c.733C>T, p.Gln245*/c.611G>A, p.Gly204Asp), inherited respectively from mother and father | Unstable on ruxolitinib. Anifrolumab (Saphnelo) been considered |
| Pat #16 | 10 yo | Female | Fatigue, short stature, speech delay | SPENCDI | AHAI, ITP | PID panel: homogonous pathogenic variant in the ACP5 gene, c.643G>A (p.Gly215Arg). Parents not tested | Deceased due to non-adherence: s/p steroids, Rituximab, and ruxolitinib |
| Pat #17 | 2 yo | Female | Fatigue, short stature, developmental delay | C terminal CDC42 mutation | Severe thrombocytopenia and anemia | WES trio: De novo likely pathogenic in the CDC42 gene c.563G>A;p.C188Y | Received multiple transfusions, in remission on Anakinra 4mg/kg/day |
| Partial DiGeorge | |||||||
| Pat #18 | 2 months | Male | Cardiac defect | Partial DiGeorge | Pancytopenia; DAT+, cold agglutinin+ | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received multiple transfusions, steroids; On sirolimus 1.8 mg, he is doing well |
| Pat #19 | 16 yo | Male | Speech/language delay, cardiac defect | Partial DiGeorge | Pancytopenia, hx of epistaxis | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received steroids; On sirolimus 2 mg, stable Plat, WBC and Hb count, doing well |
| Pat #20 | 8 yo | Male | Developmental delay, cardiac defect | Partial DiGeorge | Chronic refractory ITP | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received steroids; IVIG and on sirolimus 0.5mg, he is doing well |
| Pat #21 | 6yo | Female | Developmental delay, chronic lung disease, oral food aversion, cardiac defect, intermittent fever, cytopenia, fatigue | Partial DiGeorge | Hx of neutropenia with positive DAT, chronic thrombocytopenia and anemia | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome; WES trio: VUS in JAK2 gene: c.1279T>C (pCys427Arg) inherited from father (asymptomatic)? | Received IVIG, considering adding ruxolitinib |
| Thymic aplasia | |||||||
| Pat #22 | 2 yo | Male | Dysmorphic faces, ear anomalies, hearing loss, branchial defects, and skeletal and vertebral anomalies | Thymic aplasia | Refractory AHAI 6 months after receiving post cultured thymus tissue transplant | PID panel: homozygous variant in the PAX1 gene: c.509C>A (p.Pro170His), each inherited from one parent | Received Rituximab (x4), plasmapheresis (x5), Abatacept (x4 weekly doses), IVIg q weekly |
| Others | |||||||
| Pat #23 | 18 yo | Male | No clinical symptom | CVID | Severe ITP | WES trio: negative | Steroids, rituximab, IVIG q 4 weeks/Plat ∼10,000 |
| Pat #24 | 17 yo | Female | Depression | Fontan | Evans syndrome with severe ITP | PID panel: negative | Steroids, sirolimus in remission |
| Patients | Age at diagnosis | Gender | Clinical | Diagnosis | Hematology | Genetic variants | Treatment and response to therapy |
|---|---|---|---|---|---|---|---|
| Rheumatology | |||||||
| Pat #1 | 14 yo | Female | Arthralgia | SLE without any underlying PID/monogenic disease | ITP and Coombs positive AHAI | PID Invitae panel (PID): no pathogenic variant | Plaquenil, transfusions, steroids, rituximab (Reaction to Rituximab) then sirolimus. On sirolimus for 2 years, then slow taper. In remission on 1 mg/day of sirolimus |
| Pat #2 | 15 yo | Female | Fatigue | SLE without any underlying PID/monogenic disease | Warm AIHA plus ITP | Negative WES trio | History of steroid, s/p 4 doses of rituximab. In remission, on hydrochloroquine |
| Pat #3 | 5 yo | Male | Arthralgia, fatigue | SLE without any underlying PID/monogenic disease | Chronic refractory ITP | PID panel: VUS in TNFRSF6B c.364C>T (p.His122Tyr), reported to be associated with juvenile arthritis, autoimmune cytopenia and SLE | Multiple courses of steroids, transfusions, IVIG, on Promacta 75 mg/day |
| Bone marrow failure | |||||||
| Pat #4 | 2 yo | Female | Fatigue | Myelodysplastic syndrome | Combs positive warm AHAI and ITP | PID panel: no pathogenic variant | Multiple courses of steroids, transfusions, IVIG, rituximab, HSCT: Allogeneic 5/10 mismatched maternal haploidentical peripheral blood stem cells |
| Pat #5 | Birth | Male | Microcephaly, short stature, lower limb asymmetry, developmental delay | AR Schwachman-Diamond syndrome | Bone marrow failure, aplastic anemia | WES trio: homozygous c.544>T (p.R182) pathogenic variant in DNAJC21, each inherited from one parent | Transfusions for a Hgb < 7 and platelets <10k. HSCT: Paternal haploidentical peripheral blood stem cells |
| Pat #6 | 7 yo | Female | Polydactyly | Aplastic anemia | Coombs positive aplastic anemia | PID panel: PMM2 [c.703G>T (p.Glu235*)], likely pathogenic; PMM2 is associated with AR congenital disorder of glycosylation | Transfusions for a Hgb < 7 and platelets <10k; s/p ATG) and started on cyclosporine and Eltrombopag. She is stable on Cyclosporine, Elthrombopag, prednisone taper |
| Pat #7 | 3 yo | Male | Disseminated pseudomonal infection with ecthyma gangrenosum/Jeune syndrome/fat pancreas | AR Schwachman-Diamond syndrome | Pancytopenia | WES trio: Compound heterozygous with 2 pathogenic variants in the SBDS gene - SBDS (c.258+2T>C; GT / c.184A>T; p.Lys62*), inherited respectively from father and mother | Transfusions for a Hgb < 7 and platelets <10k. HSCT has been considered |
| Pat #8 | 29 yo | Male | Recurrent bacterial infections in the first few months of life. Short stature, gingivitis, multiple mouth ulcers | G6PC3 LOF | Congenital neutropenia and thrombocytopenia | PID panel: homozygous variant in the G6PC3 gene, Exon 1, c210del (p.Phel71Serfs*46), each inherited from one parent | Received prolonged therapy with steroids and G-CSF (neupogen). In remission on SGLT2 inhibitor (Jardiance 10 mg per day) |
| Pat #9 | 10 yo | Male | Recurrent epistaxis | Fanconi Anemia | Neutropenia, thrombocytopenia, and macrocytic anemia | PID panel: one pathogenic variant and one variant of uncertain significance identified in FANCA. FANCA: c.987_990del (p.His330Alafx*4) inherited from mother, and one VUS c.2222+8C>T(intronic) inherited from father | Stable on Promacta, currently been evaluated for HSCT |
| PID/PIRD | |||||||
| Pat #10 | 2 yo | Female | Fatigue | AD NFkb1 | ITP and neutropenia, immunodeficiency/humoral defect) | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | IVIG q4 wks. In remission on Sirolimus 0.5 mg/day and Promacta 25 mg/day) |
| Pat #11 | 7 yo | Female | No clinical symptom | AD NFkb1 | Severe neutropenia | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | Sirolimus (1 mg/day)- partial remission |
| Pat #12 | 11 yo | Female | No clinical symptom | AD NFkb1 | Neutropenia | PID panel: AD NFkb1 [NFkB1 c.418-427del (pLeu.140Phefs*3)], inherited from father | - |
| Pat #13 | 1 yo | Male | Bloody discharge from eyes | X-linked MAGT1 | ITP and Coombs positive AHAI | PID panel: likely pathogenic variant in the MAGT1 gene: deletion exon 2-10 | Steroid taper, sirolimus has been considered |
| Auto-inflammatory | |||||||
| Pat #14 | 16 yo | Male | Fatigue, short stature | SPENCDI | AHAI, ITP | WES trio: biallelic compound heterozygous pathogenic variants in the ACP5 gene (c.325G>A, p.Gly109Arg/c.526C>T, p.Arg176*) inherited from mother and father respectively | Stable on ruxolitinib 5mg-0mg-5mg per day |
| Pat #15 | 4 yo | Female | Fatigue, short stature, speech delay | SPENCDI | AHAI, ITP | PID panel: biallelic compound heterozygous variants in the ACP5 gene (c.733C>T, p.Gln245*/c.611G>A, p.Gly204Asp), inherited respectively from mother and father | Unstable on ruxolitinib. Anifrolumab (Saphnelo) been considered |
| Pat #16 | 10 yo | Female | Fatigue, short stature, speech delay | SPENCDI | AHAI, ITP | PID panel: homogonous pathogenic variant in the ACP5 gene, c.643G>A (p.Gly215Arg). Parents not tested | Deceased due to non-adherence: s/p steroids, Rituximab, and ruxolitinib |
| Pat #17 | 2 yo | Female | Fatigue, short stature, developmental delay | C terminal CDC42 mutation | Severe thrombocytopenia and anemia | WES trio: De novo likely pathogenic in the CDC42 gene c.563G>A;p.C188Y | Received multiple transfusions, in remission on Anakinra 4mg/kg/day |
| Partial DiGeorge | |||||||
| Pat #18 | 2 months | Male | Cardiac defect | Partial DiGeorge | Pancytopenia; DAT+, cold agglutinin+ | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received multiple transfusions, steroids; On sirolimus 1.8 mg, he is doing well |
| Pat #19 | 16 yo | Male | Speech/language delay, cardiac defect | Partial DiGeorge | Pancytopenia, hx of epistaxis | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received steroids; On sirolimus 2 mg, stable Plat, WBC and Hb count, doing well |
| Pat #20 | 8 yo | Male | Developmental delay, cardiac defect | Partial DiGeorge | Chronic refractory ITP | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome | Received steroids; IVIG and on sirolimus 0.5mg, he is doing well |
| Pat #21 | 6yo | Female | Developmental delay, chronic lung disease, oral food aversion, cardiac defect, intermittent fever, cytopenia, fatigue | Partial DiGeorge | Hx of neutropenia with positive DAT, chronic thrombocytopenia and anemia | 22q11.2 deletion (FISH), TBX1 gene mutation, consistent with known DiGeorge syndrome; WES trio: VUS in JAK2 gene: c.1279T>C (pCys427Arg) inherited from father (asymptomatic)? | Received IVIG, considering adding ruxolitinib |
| Thymic aplasia | |||||||
| Pat #22 | 2 yo | Male | Dysmorphic faces, ear anomalies, hearing loss, branchial defects, and skeletal and vertebral anomalies | Thymic aplasia | Refractory AHAI 6 months after receiving post cultured thymus tissue transplant | PID panel: homozygous variant in the PAX1 gene: c.509C>A (p.Pro170His), each inherited from one parent | Received Rituximab (x4), plasmapheresis (x5), Abatacept (x4 weekly doses), IVIg q weekly |
| Others | |||||||
| Pat #23 | 18 yo | Male | No clinical symptom | CVID | Severe ITP | WES trio: negative | Steroids, rituximab, IVIG q 4 weeks/Plat ∼10,000 |
| Pat #24 | 17 yo | Female | Depression | Fontan | Evans syndrome with severe ITP | PID panel: negative | Steroids, sirolimus in remission |
AD: autosomal dominant; AIHA: Autoimmune hemolytic anemia; AR: Autosomal recessive; G6PC3: CVID: common variable immunodeficiency; Glucose 6 phosphatase catalytic subunit-3 deficiency; ITP: idiopathic thrombocytopenia; IVIG: immunoglobulin replacement therapy; HSCT: Hematopoietic stem cell transplant; MAGT1: Magnesium transporter 1; NFkb1: Nuclear factor NF-kappa-B p105 subunit 1; PID: Primary immunodeficiency; PMM2: Perpetual motion machine of the second kind; SGLT2: Sodium-glucose cotransporter-2 (SGLT2) inhibitors; SLE: Systemic lupus erythematosus; TBX1: T-box transcription factor 1; VUS: Variant of unknown significance; WES: Whole-exome sequencing.
