Caplacizumab for relapsing thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is an ultra-rare disorder in childhood and belongs to the microangiopathic hemolytic anemias (MAHA) and the thrombotic microangiopathies (TMA). In the acquired form, autoantibodies against ADAMTS13 inhibit cleaving of von Willebrand factor (vWF) multimers, thereby promoting their interaction with thrombocytes, causing TMA and MAHA. A recently introduced nanobody, caplacizumab, inhibits the binding of platelets to vWF. CASE-DIAGNOSIS/TREATMENT: During a first episode, a 10-year-old girl was admitted for TTP. Plasma exchange (PE) and immunosuppressive therapy with corticosteroids and mycophenolate mofetil were initiated. The course was complicated by catheter-associated septicemia and a very slow hematological and clinical recovery. Platelet count became normal at day 40 after admission and treatment initiation. Three years later, the child presented again with TTP. During this second episode, caplacizumab was introduced together with PE and immunosuppressive therapy within 4 days after admission. With this regimen, platelet count normalized within 3 days of treatment, and PE treatment could be stopped after a total of 14 days. The child could be discharged and caplacizumab was continued on an outpatient basis until day 30 after initiation. Adverse events during the use of caplacizumab were not encountered. CONCLUSIONS: Caplacizumab treatment was safe and effective in a child with relapsing, autoantibody-mediated TTP. With respect to this potentially life-threatening condition, the add-on use of caplacizumab represents a novel option to reduce morbidity and mortality and improve quality of life in children and adolescents with TTP.

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development.

OBJECTIVE: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD. DESIGN: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. METHODS: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected. RESULTS: Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Müllerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism. CONCLUSION: We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5-15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.