Autoimmune lymphoproliferative syndrome identified through reverse phenotyping.

Autoimmune lymphoproliferative syndrome (ALPS) is a chronic non-malignant lymphoproliferative disorder caused by mutations in the genes involved in programmed cell death. It is inherited as an autosomal dominant pattern with variable penetrance. In this paper we present the first report of a Macedonian family with ALPS, caused by a novel heterozygous variant in the FAS gene. The next generation sequencing (NGS) analysis in a patient with splenomegaly, suspected for hereditary spherocytosis, showed presence of the FAS c.913dupA, p.Thr305AsnfsTer16 variant. The same variant was present in the patient's mother, but not in the mother's parents (proband's grandparents). Thus, the pathogenic FAS variant has arisen as a de novo event in the proband's mother. Later, analysis of the newborn affected sister showed presence of the same FAS variant. Additional clinical and laboratory investigations in the proband and her sister confirmed the presence of specific biomarkers for ALPS. A first-line NGS analysis allows identification of the genetic defect and initiation of appropriate clinical examinations to promptly establish the clinical diagnosis in patients with rare diseases. Reverse phenotyping in our case provided a prompt and accurate diagnosis and early initiation of specific therapy.

Clinical Characteristics and Treatment Results of Childhood Acute Lymphoblastic Leukemia in North Macedonia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. This study was designed to determine the clinical, biological features and outcomes among children with ALL treated at the only pediatric hematology-oncology center in North Macedonia. PATIENTS AND METHODS: Seventy four consecutive children age 1 to 14 years, diagnosed with ALL between January 1, 2010 and October 31, 2017 and treated according to ALL IC BFM 2002 protocol were retrospectively evaluated. RESULTS: The median age at diagnosis was 5 years and males were predominant (60.8%). Precursor B-cell ALL was diagnosed in 81.1% of patients, while 18.9% had T cell ALL. CNS involvement at the time of diagnoses was present in 6.8% of patients. Complete remission was achieved in 93.2% of patients. The induction death rate was 5.4%. The rate of death during first complete remission was 4.1%. Relapse occurred in 13.5% of patients. After a median observation time of 44 months, the 5-year overall survival (OS) and event-free survival (EFS) rates (± standard error) were 79.4% ± 5.2% and 74% ± 5.7%, respectively. The 5-year EFS rate for patients categorized as standard risk by NCI criteria was significantly higher than for high risk patients (83.3% versus 46.7%; P<0.001). Patients with precursor B-cell ALL and negative minimal residual disease (MRD) status at the end of induction had the best prognoses. CONCLUSION: Our study demonstrated that the treatment results of childhood ALL in North Macedonia are comparable to those obtained in the ALL IC BFM 2002 trial.

Clinical Significance of Minimal Residual Disease at the End of Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Detection of minimal residual disease (MRD) in the early phase of therapy is the most powerful predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL). AIM: We aimed to determine the significance of MRD at the end of remission induction therapy in the prediction of treatment outcome in children with ALL. METHODS: Sixty-four consecutive patients aged 1-14 years with newly diagnosed ALL were enrolled in this study from January 2010 to October 2017. All patients were treated according to the ALL IC BFM 2002 protocol. MRD was detected at the end of remission induction therapy (day 33) by multiparameter 6-colour flow cytometry performed on bone marrow specimens with a sensitivity of 0.01%. RESULTS: Overall, 42.2% of patients had detectable MRD on day 33 of therapy. MRD measurements were not significantly related to presenting characteristics but were associated with a poorer blast clearance on day 8 and 15 of remission induction therapy. Patients with negative MRD status on day 33 had a 5-year event-free survival of 94.6% compared with 76.1% for those with positive MRD status (P = 0.044). CONCLUSION: MRD levels at the end of remission induction therapy measured by multiparameter flow cytometry have clinical significance in childhood ALL. High levels of MRD are strongly related to poor treatment outcome.

HLA-DR-DQ haplotypes and type 1 diabetes in Macedonia.

The lowest incidence of childhood type 1 diabetes in Europe has been reported from the Republic of Macedonia. To assess the possible genetic contribution we analyzed the distribution of HLA-DR-DQ haplotypes among 163 diabetic children and 239 healthy controls. Similar disease associations were found as in other Caucasian populations. HLA-(DR3)-DQA1*05-DQB1*02 was the most common disease associated haplotype, but several DRB1*04-DQB1*0302 haplotypes were also found increased among patients. DRB1*0402 was the most common DR4 allele among them. The high frequency of protective (DR11/12)-DQA1*05-DQB1*0301 and (DR14)-DQB1*0503 haplotypes as well as of neutral (DR1/10)-DQB1*0501 and (DR16)-DQB1*0502 haplotypes were characteristic for the background population. Although a relatively low frequency of predisposing and a high frequency of protective haplotypes was detected, the haplotype frequency distribution did not markedly differ from that reported from other Eastern Mediterranean populations and these differences cannot be the sole explanation for the low disease incidence in Macedonia.