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.

Cancer Risk in Patients with Gaucher Disease Using Real-World Data.

The association between GD and cancer has been uncertain due to ascertainment bias in previously published studies. We analyzed cancer incidence using the Maccabi Healthcare Service (MHS) electronic health records among 264 patients with GD compared to 3440 matched controls. We ascertained cancers diagnosed before and after the index date (i.e., the first documentation of GD in cases and the corresponding date for controls). Before the index date, cancers were diagnosed in 18 individuals, with 11 (4.2%) in the GD group and 7 (0.2%) in the control group. After the index date, cancers were diagnosed in 57 individuals, with 20 (7.9%) in the GD group and 37 (1.1%) in the control group, with a median follow-up of almost 13 years in both groups. The most common cancers diagnosed in GD were non-melanoma skin cancer (NMSC) and hematological malignancies, with a clustering of diagnoses around the time of GD diagnosis. The incidence of cancers (excluding MNSC) was 4.1 (95% CI 2.2-7.1) and 0.7 (95% CI 0.4-0.9) per 1000 patient-years in the GD and control groups, respectively, with an incidence rate ratio of 6.37 (95% CI 3-12.7). Patients with GD underwent more cancer screening tests than their counterparts in the control group. While our study revealed an increased occurrence of cancers in patients with GD, this finding might be partly attributed to the more rigorous surveillance procedures employed in this patient population.

Simultaneous Bilateral Femoral Osteonecrosis in Gaucher Disease.

Gaucher disease (GD) is one of the most common lysosomal storage disorders. Bone complications are the most critical irreversible consequence of GD. Osteonecrosis (ON) of the femoral head inevitably leads to osteoarthritis and may be managed by hip arthroplasty. The introduction and worldwide use of therapeutic agents (specifically enzyme replacement therapies (ERT)) lowered the prevalence of osteonecrosis events per patient. We present the cases of two female patients who sustained simultaneous bilateral femoral head osteonecrosis after receiving ERT for long periods while exposed to concomitant risk factors related to femoral head ON. Both patients suffered severe pain and deterioration of their daily activity capabilities, and thus, were offered bilateral hip arthroplasty. Surgery was performed in both hip joints during the same procedure. The current report highlights several key aspects of femoral head ON in young patients with GD.

[PERIOPERATIVE MANAGEMENT OF AN ADOLESCENT GIRL WITH SEVERE FACTOR XI DEFICIENCY AND INHIBITORS].

INTRODUCTION: Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by injury-related hemorrhage, mostly associated with surgical procedures at sites noted for high fibrinolytic activity. Severe FXI deficiency is defined when the FXI level is lower than 15-20 IU/dL. Perioperative prophylactic treatment for high-bleeding-risk surgery in patients with severe FXI deficiency is based on fresh frozen plasma (FFP) transfusions or FXI concentrate (where available). Exposure to FFP and to FXI concentrate may lead to the development of inhibitory antibodies against FXI. This phenomenon occurs mostly in patients with very severe FXI deficiency (baseline FXI <1IU/dL) and is associated with an increased risk of substantial perioperative bleeding, unresponsive to FXI replacement. Thus, in individuals with severe FXI deficiency, routine testing for the presence of inhibitory antibodies against FXI is recommended. We present a 17-year-old adolescent patient with very severe FXI deficiency, who developed an inhibitor to FXI following FFP exposure associated with neurosurgery for medulloblastoma. Prophylactic treatment for subsequent invasive procedures consisted of single low dose (10 mcg/kg) recombinant activated factor VII (rFVIIa) and tranexamic acid (Hexakapron). The procedures were performed uneventfully, with no hemorrhagic or thrombotic complications. In patients with very severe FXI deficiency, the development of inhibitory antibodies following plasma replacement therapy comprises a rare and challenging occurrence. The formulation of a safe and effective evidence-based protocol for hemostatic support in these patients requires multi-center collaboration.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry.

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

Enzyme replacement therapy leading to improvement in myeloma indices in a patient with concomitant Gaucher disease.

Patients with Gaucher disease (GD) have been shown previously to carry an increased risk for cancer, most commonly multiple myeloma (MM). It is currently unknown whether treatment for GD has an effect on the prevention or amelioration of MM. We present the case of a 41-year-old patient simultaneously diagnosed with GD and smouldering MM. Enzyme replacement therapy with Velaglucerase-alfa significantly improved myeloma indices.

Gaucher Disease Diagnosis Using Lyso-Gb1 on Dry Blood Spot Samples: Time to Change the Paradigm?

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced ß-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1-78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9-1340) ng/mL and 5.4 (1.5-16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9-1050), compared to GD1 and severe GBA1 variants, 447 (38-1340) ng/mL, and neuronopathic GD, 325 (116-1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5-15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5-16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7-10.7) in heterozygous GBA1 carriers with Parkinson's disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

Pediatric severe factor XI deficiency: A multicenter study.

BACKGROUND: Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder. Only scarce publications address its clinical features in children. The increased prevalence of FXI deficiency in Israel enabled data collection for this large multicenter cohort study. OBJECTIVE: Some hemostatic challenges may be unique or more common in children, such as bleeding in the neonatal period or trauma-related injury. The current study was designed to explore the potential impact of these differences in children with severe FXI deficiency. METHODS: Medical files of all children with FXI level under 15% followed at five tertiary centers were evaluated. The retrieved data comprised demographic and clinical characteristics, including bleeding episodes, surgical interventions, treatment strategies, as well as laboratory features. RESULTS: Sixty children, whose median age at diagnosis was 4.2 years and their median FXI level was 4%, were included. Three children experienced triggered intracranial hemorrhage (ICH) and two children had major bleeds. No bleeding complications occurred in surgeries in which hemostatic treatment consisting mostly of tranexamic acid or fresh frozen plasma was applied (n = 45). In contrast, excessive bleeding was noted in 25% of surgical procedures performed without hemostatic preparation (p = .002). CONCLUSION: This study's findings confirm the generally favorable outcome of this rare bleeding disorder, with no spontaneous bleeds or cases of perinatal ICH. Nonetheless, proper diagnosis and adequate hemostasis in the surgical setting are imperative. Unlike previous studies in adults, our pediatric study suggests an association between the severity of FXI deficiency and bleeding tendency.

Hematological manifestations and complications of Gaucher disease.

Introduction: Gaucher disease (GD), although pan-ethnic and rare (common in Ashkenazi Jews), is of great importance to hematologists both for diagnosis and management. The need for increased awareness of GD is that delayed diagnosis may lead to preventable irreversible complications (mainly skeletal) or unnecessary invasive procedures (e.g. bone marrow biopsy), and the birth of another affected sibling due to lack of genetic consulting.Areas covered: The review outlines the common hematological manifestations of GD, including splenomegaly, thrombocytopenia, and anemia. Other hematological manifestations such as coagulation abnormalities, platelet dysfunction, gammopathy, and other hematological malignancies associated with GD are also discussed. Current and future treatment modalities are delineated, including enzyme replacement and substrate reduction therapy, pharmacological chaperon, and gene therapy. A literature search was conducted to identify original research articles relevant to hematology manifestations and GD published before November 2020.Expert opinion: Patients with GD should be ideally followed and treated in a center of excellence where the GD expert benefits from experienced consultants in relevant disciplines. Due to the availability of several very expensive treatment options, it is important to have an unbiased expert who can select the most suitable management for the individual patients (including withholding prescription in asymptomatic patients).

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

OBJECTIVES: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ±â€Š0.87) to week 24 (-1.76 ±â€Š0.75; P = 0.30, n = 21 with both scans). CONCLUSIONS: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.

A patient with Gaucher disease and plasma cell dyscrasia: bidirectional impact.

Patients with Gaucher disease (GD), a rare autosomal recessive glycosphingolipid storage disease, commonly present to hematologists with unexplained splenomegaly, thrombocytopenia, anemia, and bone symptoms. Patients with GD may develop other manifestations, such as autoimmune thrombocytopenia, monoclonal gammopathy, multiple myeloma, or, even more rarely, other hematological malignancies; sometimes they are first diagnosed during an assessment of those disorders. Although the diagnosis and management of patients with GD have significantly evolved over the last 30 years, some patients remain poor responders to GD-specific therapy, needing novel and investigational therapies. Ideally, patients with GD, like patients with other rare diseases, should be managed by a multidisciplinary team expert with the diverse clinical manifestations and potential GD-related or -unrelated comorbidities. The hematology community should be knowledgeable regarding the presentation and the variety of hematologic complications and comorbidities associated with Gaucher disease.

Nasopharyngeal carcinoma in children and young adults-Beyond 5-year survival.

Nasopharyngeal carcinoma (NPC) is a rare and locally aggressive form of childhood cancer. Treatment of NPC includes chemotherapy and radiotherapy. With current treatment protocols, survival rates for patients with nonmetastatic disease is over 80%. Data regarding very late events including long-term treatment-related morbidities and second malignancies are scarce. We present our data on 42 patients with NPC treated in Israel between 1989 and 2014, and followed until 2019. During follow up, five patients had disease recurrence, and four children developed secondary malignancy. Median time to diagnosis of secondary malignancy was 105 months. Eighty-eight percent of patients have long-term treatment-related morbidities.

Essential thrombocythemia A retrospective case series.

BACKGROUND: Essential thrombocythemia (ET) is rare in children, and pediatric guidelines are lacking. Therefore, we aimed to evaluate ET diagnosis and treatment in a pediatric cohort. PROCEDURE: Data of patients with ET from three hospitals were reviewed. Molecular diagnosis included JAK2V617F, CALR, and MPL mutations. Patients were evaluated for acquired von Willebrand syndrome (AVWS). Follow-up included clinical symptoms, adverse events, and treatment. RESULTS: Twelve children (median age: 8 years, range 1-14.5) were included. Mean lag period between the first documentation of thrombocytosis until ET diagnosis was 36 months. Six patients were positive for JAK2V617F and two for CALR mutations. In six of nine patients, AVWS was diagnosed. At diagnosis, only 33% of patients started therapy with aspirin (n = 4) and hydroxyurea (n = 2). In three of eight untreated patients, therapy was added during follow-up. The cohort was followed for a median of 32.5 months (range: 4-108 months). Clinical follow-up disclosed vascular complications in 4 of 12 patients (deep vein thrombosis, n = 1; transient ischemic attack, n = 3). Two females experienced excessive bleeding; both were diagnosed with AVWS. Neither leukemia nor myelofibrosis evolved in our cohort. CONCLUSION: Increased awareness to pediatric ET is warranted, as delayed diagnosis is common. Compared to adults, AVWS may be more prevalent among children with ET.

Epidemiology and outcomes of clinically unsuspected venous thromboembolism in children: A systematic review.

BACKGROUND: Clinically unsuspected venous thromboembolic events (uVTE) detected during routine imaging pose a management challenge due to limited knowledge about their clinical significance. Unsuspected VTE are often referred as "asymptomatic," "incidental," or "clinically silent/occult" VTE. OBJECTIVE: To understand the epidemiology, management, and outcomes of uVTE in children. METHODS: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search criteria included controlled vocabulary and keywords for VTE, incidental findings, and children (ages ≤ 21 years). RESULTS: Among 10 875 articles, 51 studies (8354 children with 758 uVTE) were selected. The studies were heterogeneous, I2 96%; P < .0001. Unsuspected VTE were diagnosed in two settings: first, asymptomatic VTE (aVTE) diagnosed through surveillance imaging for VTE (46 studies; n = 5894; aVTE: 715, pooled frequency: 19%, 95% confidence interval [CI]: 13%-24%); second, incidental VTE (iVTE) diagnosed during imaging performed for indications without primary suspicion for VTE (6 studies; n = 2460; iVTE: 43). The majority (94%) of aVTE were associated with central venous lines (CVL). Non-CVL settings included post-spinal surgery, post-splenectomy, trauma, nephrotic syndrome, and newborns. In general, aVTE were reported to have a benign clinical course, were mostly transient, and resolved without intervention and with few immediate or long-term functional complications. Incidental VTE were primarily detected in children with cancer and ranged from tumor-associated thrombi to pulmonary embolism (PE) with insufficient evidence to draw meaningful conclusions about their management. CONCLUSION: Clinically uVTE were predominantly diagnosed with CVL and their outcomes were generally favorable implying limited benefit of routine surveillance and thromboprophylaxis. Prospective research is needed to clarify the optimal management of iVTE.

Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population.

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

Improvement in bone marrow infiltration in patients with type I Gaucher disease treated with taliglucerase alfa.

Preliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-naïve patients (median age 48 [range 24-68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 ('bone at risk'). All significantly improved from a median baseline FF of 0.24 (0.15-0.32) to 1st year FF of 0.37 (0.25-0.54) and 2nd year FF of 0.42 (0.27-0.59) (p = 0.01). Among the 11 'switch-over' patients (median age 42 [range 33-69] years; median imiglucerase exposure 8 [range 1-17] years), eight had baseline FF ≤ 0.3, five of those with FF < 0.23. All, but one, significantly improved from a median baseline FF of 0.17 (0.08-0.28) to 1st year FF of 0.3 (0.05-0.34) and 2nd year FF of 0.34 (0.08-0.44) (p = 0.03). Two elderly female patients (age 43 and 58 years, with 17 years imiglucerase exposure) who remained at the same enzyme replacement therapy dose, increased from baseline FF of 0.13 and 0.19 to 0.26 at 1 year. Although the number of observations is small, we hypothesize that switching to taliglucerase may result in an improved bone marrow response. A larger study is needed to assess the early benefit of taliglucerase alfa in adult patients with type 1 Gaucher disease on the bone marrow compartment.

Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding.

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbß3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency.

Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis.