Background
Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the ...treatment modalities for patients with SCD in Germany.
Procedure
A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available.
Results
Most patients had homozygous SCD (HbSS 75.1%, HbS/β‐thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6‐4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/β thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years.
Conclusion
With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.
A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase ...(CML-BP)) received imatinib up-front (300, 400, 500 mg/m
, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion ...of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)– and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas α/β and γ/δ T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).
Introduction: Pearson syndrome (PS) was originally reported as a sideroblastic anemia in infancy with vacuolization of marrow precursors and exocrine pancreas dysfunction. It is now recognized as a ...fatal multisystem mitochondrial disorder caused by single mitochondrial DNA deletions (SLSMDs) presenting with anemia. PS, Kearns-Sayre Syndrome (KSS) and progressive external ophthalmoplegia (PEO) form a continuous spectrum of disease associated with SLSMDs. There have been only a few systematic studies on PS.
Methods: We retrospectively reviewed hematological features and clinical course of 25 children with PS diagnosed between 1987 and 2019.
Results: Patients presented with normo/macrocytic transfusion-dependent anemia (n=25), failure to thrive (n=3), diarrhea (n=1), acidosis (n=1) and/or omphalocele/esophageal atresia (n=1) at a median age of 5 (0-31) months. A median hemoglobin, platelet count and neutrophil count were 6.5 (1.9-9.8) g/dl, 104 (31-300) G/L, and 0.9 (0.1-2.4) G/L, respectively. Bone marrow (n=24) was normo- (n=15) or hypocellular (n=9). Vacuoles in erythroid and myeloid precursors were observed in all patients, but ring sideroblasts were present in only 16 of 23 patients examined. Morphology can resemble Diamond-Blackfan anemia (DBA) because of erythroid hypoplasia (15/21). Dysplastic features are often observed including micromegakaryocytes. Lactic acid was elevated in most patients examined (14/18). Exocrine pancreas insufficiency at diagnosis was documented in 5 patients only. The detection of SLSMDs confirmed the diagnosis of PS in all patients.
The median age at the time of the last follow-up was 47 (7 - 183) months. Among 11 patients with hematological follow-up for more than 3 years after diagnosis, 8 had spontaneous resolution of anemia at a median age of 28 (12-67) months, and 3 died at the age of 3, 6 or 8 years without hematological recovery. Clinical course was highly heterogeneous and various organ dysfunctions appeared. Renal tubulopathy/Fanconi syndrome (n=7) and cardiomyopathy/arrhythmia (n=5) were often fatal complications which developed at the median age of 32 and 45 months, respectively. Failure to thrive/short stature (n=13) and muscle hypotonia (n=9) were commonly observed. Other complications included pancreas insufficiency (n=7), liver dysfunction (n=4), endocrine dysfunctions (n=7), hearing loss (n=1), ophthalmoplegia (n=1), retinitis pigmentosa (n=1), cataract (n=1), ataxia (n=2) and encephalopathy (n=1). Thirteen patients died of acute metabolic acidosis with/without other complications (n=7), arrhythmia (n=2), respiratory failure (n=3) and liver/renal failure (n=1) at the median age of 50 (14-183) months. Two patients developed KSS and PEO-like phenotypes at the age 92 months and 19 months, respectively.
Summary: Anemia is generally the only presenting syndrome of PS. While the bone marrow morphology can resemble DBA or myelodysplastic syndrome, recognition of vacuolated myeloid/erythroid precursors lead to the correct diagnosis of PS in all cases. Other classical signs of PS, ring-sideroblasts and pancreas insufficiency, are often missing. Anemia spontaneously resolves in most patients surviving early childhood. However, PS is unexceptionally fatal (Figure), most patients succumb to metabolic acidosis and various forms of multi-organ failure. Since there is no effective therapy, the diagnosis of PS is one of the saddest news that pediatric hematologists have to break to parents of an anemic infant.
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Niemeyer:Celgene: Consultancy.
Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by ...hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.
We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.
All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.
Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.
Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, ...and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.
It is currently unknown whether immunosuppressive therapy or hematopoietic stem cell transplantation is the most appropriate treatment strategy for children with refractory cytopenia and normal ...karyotype or trisomy 8. We report on 31 children with hypoplastic refractory cytopenia treated with immunosuppressive therapy consisting of antithymocyte globulin and cyclosporine. At 6 months, 22 of 29 evaluable patients had a complete or partial response; a total of ten patients achieved a complete response at varying time points. Six patients subsequently received a transplant because of non-response, progression to advanced myelodysplastic syndrome or evolution of monosomy 7. Overall and failure-free survival rates at 3 years were 88% and 57%, respectively.
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