ADA2 deficiency complicated by EBV-driven lymphoproliferative disease.

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.

Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency.

: The objective was to examine the genotypic and phenotypic characteristics of individuals with hereditary factor X deficiency (FXD), a rare autosomal recessive bleeding disorder caused by mutations in the F10 gene located on chromosome 13q34-ter. To date, 149 F10 mutations have been identified as contributory to FXD. Three open-label phase 3 trials enrolled individuals with mild, moderate, or severe FXD. Individuals received plasma-derived factor X concentrate as routine prophylaxis, to treat bleeds, and/or during or after surgery. F10 genotyping was performed (studies 1 and 2) or genotype data was collected at screening (study 3), and identified F10 mutations were compared against the Human Gene Mutation Database to assess novelty. Genotype data were combined to evaluate the number, type, and novelty of the F10 mutations identified. Genotype data were available for 24 of 27 individuals with mild (n = 2), moderate (n = 2), or severe (n = 20) FXD. Analyses identified 22 separate mutations, including 15 missense mutations, 2 deletions, 4 splice site mutations, and 1 nonsense mutation. Sixteen individuals had homozygous mutations; 8 had compound heterozygous mutations. Eleven unique novel mutations (all compound heterozygous) were identified in seven individuals: six missense mutations, three splice site mutations, one exon deletion, and one nonsense mutation. In silico analyses strongly supported the pathogenicity of all novel mutations. The identification of 11 novel F10 mutations provides a substantial contribution to the mutations known to cause FXD.

Non-irradiated female survivors of childhood acute lymphoblastic leukaemia are at risk of long-term increases in weight and body mass index.

We report long-term, including final height, auxological data from our retrospective study of non-irradiated survivors of childhood acute lymphoblastic leukaemia (ALL). Body mass index (BMI) standard deviation score (SDS) increases in females, due to increased weight-SDS, persisted to final height, with probable adverse long-term health outcomes. In contrast, males demonstrated increased BMI-SDS in follow-up, due to reduced height-SDS, not increased weight-SDS, but such changes had resolved by final height. Childhood ALL survivors, particularly females, are therefore at potential increased risk of developing the metabolic syndrome during follow-up. We recommend that strategies to minimize weight gain should be implemented during ALL treatment.