Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.

Symptomatic corpus luteum hemorrhage in adolescent females with ITP.

Patients with immune thrombocytopenia (ITP) usually present with minor mucocutaneous bleeding. Corpus luteum hemorrhage (CLH) is generally asymptomatic but may, rarely, lead to severe intraperitoneal bleeding, mostly in patients with coagulation disorders. CLH causing intraperitoneal bleeding has only been described in few individuals with ITP. The objective of this retrospective observational study was to assess the clinical course and incidence of symptomatic CLH in adolescent females with newly diagnosed or chronic ITP. Additionally, a comprehensive literature review was conducted to scrutinize cases of pediatric female patients with ITP, complicated by CLH. We identified three patients with ITP and hemoperitoneum secondary to CLH. They presented with acute abdominal pain, had severe thrombocytopenia (platelet counts below 20 × 109/L), and required blood transfusions as well as ITP-directed therapy. All the patients were hemodynamically stable and did not require emergency surgical intervention.  Conclusion: CLH could potentially pose a significant complication in the context of adolescent females with ITP, requiring a strong index of suspicion to direct expedient therapy. What is Known: • Immune thrombocytopenia is typically associated with minor bleeding tendency. • Corpus luteum hemorrhage is generally asymptomatic; however, in women with bleeding disorders, it has the potential to result in substantial intra-abdominal bleeding. What is New: • Corpus luteum hemorrhage leading to intra-abdominal bleeding is a potential severe complication of immune thrombocytopenia in adolescent females.

Excellent response to treatment with hydroxychloroquine in pediatric patients with SLE-related immune thrombocytopenia.

BACKGROUND: Pediatric immune thrombocytopenia (ITP) may precede systemic autoimmune disorders. In adolescent patients with ITP, routine screening for systemic lupus erythematosus (SLE) may be performed by testing for antinuclear antibody (ANA) titer. Hydroxychloroquine (HCQ) is a safe and effective immunomodulatory drug in patients with SLE but rarely used in ITP. We analyzed the platelet count response and safety of HCQ in treating pediatric patients with SLE-related ITP. METHODS: A retrospective study including pediatric patients with ITP and definite or incomplete SLE, who were treated with HCQ during 2010-2021. SLE was defined by ANA titer ≥ 1:160 as measured by immunofluorescence and ≥10 points according to the 2019 EULAR/ACR 2019 classification criteria, while patients with incomplete SLE achieved a score < 10. Complete response (CR) of the platelet count was defined as platelet count > 100 × 109/L; partial response (PR) as platelet count 30-100 × 109/L and exceeding ≥ twice baseline counts. RESULTS: Of the 17 patients included (median age 15.5 years; IQR 3.6), 15 (88.2%) were female, 13 had definite SLE, and four had incomplete SLE. HCQ was initiated at a median of 17 months after ITP diagnosis with a median platelet count of 38 × 109/L (IQR 28). At 8 weeks, 8 (47.1%) patients responded, including 6 (35.3%) achieving CR. After one year, the overall response was 82.4%, with the remaining patients having stable platelet counts requiring no additional ITP therapy. The response was maintained at a median follow-up of 42 months. No adverse effects to HCQ were noted. CONCLUSION: Pediatric patients with SLE-related ITP may benefit from treatment with HCQ.

Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2.

Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.

Early response markers predict survival after etoposide-based therapy of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is most commonly treated with etoposide and dexamethasone. This standard of care therapy has improved survival, but ∼15% of patients still die in the first months after diagnosis, and poor responses prompting salvage therapy are frequent. Thus, identifying patients at risk promptly is likely to improve outcomes. We conducted a multi-institutional, retrospective study of pediatric and young adults treated per HLH-94 or HLH-2004 from 2010 to 2019 to identify patients at risk for early mortality. Biweekly data during the first 100 days of treatment were analyzed using receiver operating curves to define optimal prognostic indicators and their thresholds. The primary end point was survival to bone marrow transplant (BMT) or ∼1 year if no BMT was pursued. Eighty-nine patients met the study inclusion criteria. Pre-BMT mortality was 13% (n = 12), and overall mortality was 27% (n = 24). Laboratory markers measured on day 7 of therapy more efficiently predicted outcomes than did either pretreatment or later assessments. The most potent day 7 unfavorable marker was improvement in soluble CD25 (sCD25) of less than 25% from pretherapy levels. Absolute sCD25 level, platelet count, absolute lymphocyte count, and blood urea nitrogen were also discriminatory markers (area under the curve ≥ 0.7). The presence of ≥3 of these unfavorable markers was strongly associated with pre-BMT mortality (accuracy, 0.93). Thus, serial monitoring of sCD25 and assessment of other early (day 7) response markers optimally predicts prognosis with etoposide-based therapy and may indicate the need for earlier use of alternative, response-adapted therapeutic strategies for HLH.

[DEMOGRAPHIC, CLINICAL AND LABORATORY CHARACTERISTICS OF CHILDREN DIAGNOSED WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) IN THE SCHNEIDER CHILDREN'S MEDICAL CENTER BETWEEN 2004-2020].

AIMS: To characterize the clinical, demographic, laboratory, and molecular biologic findings in children with HLH diagnosed and treated in our center. BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare immuno-hematologic disorder more common in children than adults. It is divided into two separate conditions which are not always easy to differentiate: familial/primary HLH (FHL) and acquired/secondary HLH associated with malignant, infectious, and other inflammatory conditions. FHL is a life-threatening disorder caused mainly by mutations in genes that code for proteins participating in perforin-dependent cell death. METHODS: We collected data from the records of all children who were diagnosed with HLH according to the accepted HLH criteria, and treated in the Schneider Children's Medical Center of Israel between the years 2004-2020. Demographic, clinical and laboratory data were summarized into a national database. RESULTS: A total of 36 children (18 boys,18 girls) who were diagnosed as having HLH according to the diagnostic criteria and received treatment according to the Histiocyte Society '94 or 2004 international protocols, entered the study. Eleven of the patients were Arab (30%), while 25 were Jewish (70%). The most frequent clinical signs were fever (89%) and hepatosplenomegaly (61%). Laboratory tests showed bipenia in 100% and increased levels of Interleukin-2 receptor (IL-2R) in 97%. Mutations in 3 out of the 4 common HLH genes were found in 15 (42%) children. The most common mutant gene was MUNC 13-4 comprising 40% of mutant genes. Mutations were quite common among Arab patients (81%) compared to the Jewish HLH population (20%) (p<0.001). Patients bi-allelic MUNC 13-4 mutations had a particularly poor prognosis with 66% succumbing to the disease. CONCLUSIONS: HLH is a severe, multisystem disorder. High clinical suspicion leading to timely diagnosis and treatment are crucial for preventing poor outcome and death. Genetic studies are of upmost importance in our population due to the high percentage of mutations, especially in the Arab population.

Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children.

AIM: This study assessed the validity of using established Japanese risk scoring methods to predict intravenous immunoglobulin (IVIG) resistance to Kawasaki disease in Israeli children. METHODS: We reviewed the medical records of 282 patients (70% male) with Kawasaki disease from six Israeli medical centres between 2004 and 2013. Their mean age was 2.5 years. The risk scores were calculated using the Kobayashi, Sano and Egami scoring methods and analysed to determine whether a higher risk score predicted IVIG resistance in this population. Factors that predicted a lack of response to the initial IVIG dose were identified. RESULTS: We found that 18% did not respond to the first IVIG dose. The three scoring methods were unable to reliably predict IVIG resistance, with sensitivities of 23%-32% and specificities of 67%-87%. Calculating a predictive score that was specific for this population was also unsuccessful. The factors that predicted a lacked of response to the first IVIG dose included low albumin, elevated total bilirubin and ethnicity. CONCLUSION: The established risk scoring methods created for Japanese populations with Kawasaki disease were not suitable for predicting IVIG resistance in Caucasian Israeli children, and we were unable to create a specific scoring method that was able to do this.

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.