Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations.

Aims/Hypothesis: Caused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. Methods: Clinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. Results: All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/Interpretation: Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.

Factors influencing neurological outcome of children with bacterial meningitis at the emergency department.

We performed a cohort study of children who survived bacterial meningitis after the neonatal period at a single pediatric center in France over a 10-year period (1995-2004) to identify predictors of death and long-term neurological deficits in children with bacterial meningitis. We performed multivariate regression to determine independent predictors of death and neurologic deficits. We identified 101 children with bacterial meningitis of which 19 died during initial hospitalization. Need for mechanical ventilation [hazard ratio (HR) 11.5, 95 % confidence interval (CI) 2.4-55.5)] and thrombocytopenia defined as a platelet count <150 × 10(9) per liter (HR 0.6, 95 % CI 0.4-0.9) at presentation were associated with death during initial hospitalization. At final assessment, 42 of the 70 survivors had no neurologic deficits identified; 20 had a single deficit, and eight had multiple deficits. A delay in initiation of antibiotics (HR 1.3, 95 % CI 1.1-1.7) and hydrocephalus on computed tomographic scan (HR 2.6, 95 % CI 1.1-6.0) were associated with having one or more long-term neurologic deficits. Identification of children at risk of death or long-term neurologic sequelae may allow therapeutic interventions to be directed to children at the highest risk.

Clinical, biological and genetic analysis of anorchia in 26 boys.

BACKGROUND: Anorchia is defined as the absence of testes in a 46,XY individual with a male phenotype. The cause is unknown. METHODS: We evaluated the clinical and biological presentation, and family histories of 26 boys with anorchia, and sequenced their SRY, NR5A1, INSL3, MAMLD1 genes and the T222P variant for LGR8. RESULTS: No patient had any associated congenital anomaly. At birth, testes were palpable bilaterally or unilaterally in 13 cases and not in 7; one patient presented with bilateral testicular torsion immediately after birth. The basal plasma concentrations of anti-Müllerian hormone (AMH, n = 15), inhibin B (n = 7) and testosterone (n = 19) were very low or undetectable in all the patients evaluated, as were the increases in testosterone after human chorionic gonadotropin (hCG, n = 12). The basal plasma concentrations of follicle stimulating hormone (FSH) were increased in 20/25, as was that of luteinising hormone in 10/22 cases. Family members of 7/26 cases had histories of primary ovarian failure in the mother (n = 2), or sister 46,XX, together with fetal malformations of the only boy with microphallus and secondary foot edema (n = 1), secondary infertility in the father (n = 2), or cryptorchidism in first cousins (n = 2). The sequences of all the genes studied were normal. CONCLUSION: Undetectable plasma concentrations of AMH and inhibin B and an elevated plasma FSH, together with 46,XY complement are sufficient for diagnosis of anorchia. The hCG test is unnecessary. NR5A1 and other genes implicated in gonadal development and testicle descent were not mutated, which suggests that other genes involved in these developments contribute to the phenotypes.