Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

Clinical and Genetic Features of Patients With Fanconi Anemia in Lebanon and Report on Novel Mutations in the FANCA and FANCG Genes.

Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and presents with cytopenias, characteristic physical features, increased chromosomal breaks, and a higher risk of malignancy. Genetic features of this disease vary among different ethnic groups. We aimed to identify the incidence, outcome, overall condition, and genetic features of patients affected with FA in Lebanon to optimize management, identify the most common genes, describe new mutations, and offer prenatal diagnosis and counseling to the affected families. Over a period of 17 years, 40 patients with FA were identified in 2 major diagnostic laboratories in Lebanon. Information was obtained on their clinical course and outcome from their primary physician. DNA was available in 20 patients and was studied for underlying mutations. FANCA seemed to be the most frequent genetic alteration and 2 novel mutations, one each in FANCA and FANCG, were identified. Nine patients developed various malignancies and died. This is the first study looking at clinical and genetic features of FA in Lebanon, and points to the need for establishing a national and regional registry for this condition.

A Novel Deletion in the RPL5 Gene in a Lebanese Child With Diamond Blackfan Anemia Unresponsive to Steroid Treatment.

Diamond-Blackfan Anemia (DBA) is a rare inherited form of pure red cell aplasia that usually manifests in infancy or early childhood, and is characterized by normochromic macrocytic anemia and bone marrow erythroblastopenia. The majority of DBA cases are associated with mutations in ribosomal protein genes. Here, we describe a Lebanese girl with RPL5-mutated DBA unresponsive to steroid treatment who died from complications following late hematopoietic stem cell transplantation performed at the age of 15 years.

Ongoing issues with the management of children with Constitutional Mismatch Repair Deficiency syndrome.

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare cancer predisposition syndrome, presenting in childhood, in which affected patients develop various malignancies such as hematological, gastrointestinal and central nervous system tumors. Although guidelines are being increasingly developed for surveillance and early detection of cancers in affected families, there are no clear recommendations regarding choice of therapy and very scarce information about tolerance to chemotherapy and radiation in these patients. We report the pedigree of a consanguineous family with four affected children. Although clinical and molecular tests confirm CMMRD, genetic testing revealed heterogeneous mutations. The index case developed severe toxicity from therapy for glioblastoma and T-cell leukemia and died from an infection while in complete remission. His sister developed a malignant brain tumor while undergoing surveillance for a low grade brain lesion and is still undergoing follow-up. This family illustrates the difficulties and opportunities with challenging diagnosis, surveillance and choice of therapy for children with CMMRD and the need for increased awareness and more information about this rare but important syndrome.

A Multicenter Experience from Lebanon in Childhood and Adolescent Acute Myeloid Leukemia: High rate of Early Death in Childhood Acute Promyelocytic Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a disease with marked heterogeneity. Despite major improvement in outcome, it remains a life-threatening malignancy. Demographic and clinical data on pediatric AML is lacking among the Lebanese population. PURPOSE: We aimed to identify clinical, molecular and outcome data in children with AML in Lebanon. METHODS: A retrospective chart review of children with AML diagnosed in three Lebanese hospitals during the past 8 years was conducted. RESULTS: From May 2002 through March 2010, we identified 24 children with AML in Saint George Hospital University Medical Center, University Medical Center Rizk Hospital, and Abou-Jaoude Hospital. Males and females were equally represented; median age at diagnosis was 9 years (range 1-24) and median WBC at diagnosis was 31 × 10(9)/L (range: 2.1-376 × 10(9)/L). Twenty five percent of patients (6 out of 24) had acute promyelocytic leukemia (APL). Karyotype was normal in 33% of patients; t(8;21), inv (16), t(8;9), t(7;11), t(9;11), complex chromosomal abnormality, monosomy 7 and trisomy 8 were the most common cytogenetic abnormalities encountered. Patients were treated on different European and North American protocols. Twelve patients (50%) achieved morphologic CR after cycle 1, 6 of them (50%) had bone marrow relapse within 11 months from diagnosis. Nine patients underwent allogeneic stem cell transplant, and 3 of them are alive at 5 years post-transplant. Early death rate was 16.6% of patients, mainly those with APL and a presenting WBC > 10 × 10(9)/L. Fifty per cent of APL patients had an early death due to DIC despite starting ATRA therapy. Overall, median survival for AML patients who died from disease progression was 25.8 months (range: 1-60 months). Overall disease-free survival was 30.4%. Patients < 10 years of age had a 50% survival rate compared to 0% in patients > 10 years. CONCLUSIONS: Our report highlights the needs in Lebanon for better supportive care of children with APL, including faster ATRA administration and, aggressive transfusions, easy access to stem cell transplant for high-risk AML patients and the need for a national homogenous treatment strategy for children with AML.

Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma.

Neuroblastoma (NB) is a rare pediatric disease in Lebanon for which poor prognosis remains a major challenge. Genetic polymorphism of genes coding for drug­metabolizing enzymes may influence the response of a patient to chemotherapy. This study investigates a possible association between CYP3A4/5 polymorphism and expression levels and survival in NB patients. All patients with stage III and IV NB diagnosed between 1993 and 2012 in three major hospitals in Beirut were included (n=27). Demographic information and survival time were obtained from medical records. CYP3A4 and CYP3A5 genotypes and expression levels were determined in archival tumors by polymerase chain reaction (PCR) and restriction fragment length polymorphism and quantitative PCR, respectively. Additionally, MYCN amplification was assessed. A Cox proportional hazards model was used to evaluate potential associations, adjusting for MYCN amplification. A statistically significant increase in the risk of mortality was observed in patients with MYCN amplification [hazard ratio (HR) 4.11, 95% confidence interval (CI) 1.14­14.80]. Patients with CYP3A5 expression levels above the median had a lower risk of mortality (HR 0.61, 95% CI 0.21­1.74) and patients with CYP3A4 expression levels above the median had a higher risk of mortality (HR 2.00, 95% CI 0.67­5.90). CYP3A5*3/*3 homozygote mutants had a 4.3­fold increase in the risk of mortality compared with that of homozygote wild­type or heterozygote mutants (HR 4.30, 95% CI 0.56­33.30). Carriers of the CYP3A4*1B mutant allele had a 52% lower risk of mortality compared with that of non­carriers (HR 0.48, 95% CI 0.06­3.76). Although the results of the present study did not achieve statistical significance, associations were observed, which indicates that CYP3A4 and CYP3A5 may modulate the clinical outcome of NB. Further studies with larger sample sizes are required to characterize the effects of the polymorphism and expression levels of CYP3A4/5 on the survival of patients with NB.

Spontaneous epidural hematoma in a child with inherited factor XIII deficiency.

We report the case of a 2-year-old Lebanese male child, known to have congenital factor XIII (FXIII) deficiency, who presented to the emergency department with somnolence and projectile vomiting without any head trauma. He has been on a prophylactic dose of 10 IU/kg of FXIII concentrate every 4 weeks since birth, but he missed his last 2 doses due to shortage of supply. Imaging studies showed an epidural hematoma with a midline shift. The child was started on 20 IU/kg of FXIII replacement, and a left parietal craniotomy was performed immediately. He tolerated the surgery well with an uneventful postoperative course. Previous DNA analysis carried out for the family members detected a small deletion (c.1475-1476delGA) in exon 12 in this child and his eldest brother. This mutation has been previously reported once in another Lebanese child with FXIII deficiency who presented with spontaneous splenic rupture. To the best of our knowledge, this is the first case of acute nontraumatic spontaneous epidural hematoma in a child with congenital FXIII deficiency. Furthermore, patients on FXIII replacement therapy have less bleeding events, thus lifelong adherence to the prophylaxis is essential to decrease the morbidities and the mortalities associated with FXIII deficiency, most notably intracranial hemorrhages.

Acquired protein C deficiency in a child with acute myelogenous leukemia, splenic, renal, and intestinal infarction.

We report the case of a 6-year-old boy diagnosed with acute promyelocytic leukemia (AML-M3V) when he presented with pallor, abdominal pain, anorexia, and fatigue. Induction chemotherapy was started according to the AML-BFM 98 protocol along with Vesanoid (ATRA, All-trans retinoic acid). On the sixth day of induction, he developed splenic and gallbladder infarcts. Splenectomy and cholecystectomy were performed while chemotherapy induction continued as scheduled. Four days later, he developed ischemic areas in the kidneys and ischemic colitis in the sigmoid colon. Hypercoagulation studies showed severe deficiency of protein C. Tests showed protein C 16% (reference range 70-140%), protein S 87% (reference range 70-140%), antithrombin III 122% (reference range 80-120%), prothrombin time 13.6 s (reference = 11.3), INR (international normalized ratio) 1.21, partial thromboplastin time 33 s (reference = 33), fibrinogen 214 mg/dl, D-dimer 970 µg/ml, factor II 98%, and that antinuclear antibody, antiphospholipid antibodies, mutation for factor II gene (G20210A), and mutation for Arg506 Gln of factor V were all negative (factor V Leiden). There was no evidence of clinical disseminated intravascular coagulation (DIC). He was treated with low molecular weight heparin and did well. He continues to be in complete remission 7 years later with normal protein C levels. Acquired protein C deficiency can occur in a variety of settings and has been reported in acute myelocytic leukemia. However, clinically significant thrombosis in the absence of clinical DIC, such as our case, remains extremely rare.

Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients.

Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.