Pierre Mauran

Metabolic control in children with diabetes mellitus who are younger than 6 years at diagnosis: continuous subcutaneous insulin infusion as a first line treatment?

OBJECTIVE To assess long-term metabolic outcomes in children with diabetes mellitus that was diagnosed when they were <6 years old. STUDY DESIGN A cohort of 66 children with diabetes mellitus that had a duration of at least 5 years and was diagnosed before they were 6 years old. Thirty-four children were treated at diagnosis with multiple daily subcutaneous insulin injections (MDI), and all these children, except 3, were switched to continuous subcutaneous insulin infusion (CSII; group A). Thirty-two children received CSII as initial treatment (group B). RESULTS Hemoglobin A1c values were significantly lower in patients receiving CSII than MDI during all the 8 years of follow-up except one (year 1: 6.9%+/-0.9% versus 7.6%+/-1%, P=.011 ; year 4: 7.4%+/-0.8% versus 8.1%+/-0.9%, P=.006; year 7: 7.6%+/-0.5% versus 8.3%+/-0.8%, P=.001). The incidence of severe hypoglycemia was greatly decreased for the CSII group (9.8 versus 22.3 episodes/100 patient-years, P=.016). In group A, hemoglobin A1c values increased during the study period, and in group B, they increased only during the first 2 years and remained constant thereafter. Only 9.1% of patients did not use or abandoned CSII. CONCLUSION CSII in children<6 years of age enables better long-term metabolic control and lowers the risk of severe hypoglycemia better than MDI, especially when initiated at diagnosis.

Pure direct duplication (12)(q24.1 q24.2) in a child with Marcus Gunn phenomenon and multiple congenital anomalies

Partial trisomy of the region 12q24.1 → q24.2 is rare and usually associated with other rearrangements. We report on the clinical and cytogenetic findings in a girl with a pure de novo direct duplication dup(12)(q24.1 → q24.2). She had developmental and growth retardation, facial dysmorphism with upslanting palpebral fissures, wide downturned mouth, short neck, and Marcus Gunn phenomenon. She also had single transverse creases, hypoplasia of the corpus callosum, and cardiac malformations consisting of a bicuspid aortic valve, multiple ventricular septal defects, and kinking of the aorta. The size of the duplication was characterized by molecular cytogenetics and comparative genomic hybridization (CGH) to be 11.5 Mb in size and extended from the BAC probe RP11‐256L11 loci (108.2 Mb) ± 1 Mb to the BAC probe RP11‐665J20 loci (119.7 Mb) ± 1 Mb. No such pure 12q24 duplication was detected out of the 23 patients reported in the literature with duplications in 12q region. Comparison with these reported 12q trisomies suggests the duplication dup(12)(q24.1 → q24.2) is associated with a recognizable phenotype consisting of characteristic facial dysmorphism, growth retardation, and cardiac malformation.

Novel mutational mechanism in the thyroglobulin gene: Imperfect DNA inversion as a cause for hereditary hypothyroidism

The objective of this study was to perform genetic analysis in three brothers of Turkish origin born from consanguineus parents and affected by congenital hypothyroidism, goiter and low levels of serum TG. The combination of sequencing of DNA, PCR mapping, quantitative real-time PCR, inverse-PCR (I-PCR), multiplex PCR and bioinformatics analysis were used in order to detect TG mutations. We demonstrated that the three affected siblings are homozygous for a DNA inversion of 16,962bp in the TG gene associated with two deleted regions at both sides of the inversion limits. The inversion region includes the first 9bp of exon 48, 1015bp of intron 47, 191bp of exon 47, 1523bp of intron 46, 135bp of exon 46 and the last 14,089bp of intron 45. The proximal deletion corresponds to 27bp of TG intron 45, while the distal deletion spans the last 230bp of TG exon 48 and the first 588bp of intergenic region downstream TG end. The parents were heterozygous carriers of the complex rearrangement. In conclusion, a novel large imperfect DNA inversion within the TG gene was identified by the strategy of I-PCR. This aberration was not detectable by normal sequencing of the exons and exon/intron boundaries. Remarkably, the finding represents the first description of a TG deficiency disease caused by a DNA inversion.

Effects of a three-day head-down tilt on renal and hormonal responses to acute volume expansion

To clarify whether exposure to 6° head-down tilt (HDT) leads to alterations in body fluid volumes and responses to a saline load similar to those observed during space flight we investigated eight healthy subjects during a 4-day, 6° HDT and during a time-control ambulatory period with cross-over. Compared with the ambulatory period, HDT was associated with greater urinary excretion of water and sodium (UV, UNaV) from 0 to 12 h (cumulated UV 1,781 ± 154 vs. 1,383 ± 170 ml, P < 0.05; cumulated UNaV 156 ± 14 vs. 117 ± 9 mmol, P < 0.05), and with higher plasma atrial natriuretic factor (ANF) at 4 h. Hemoglobin and hematocrit increased over the first 24 h, and blood and plasma volumes were decreased after 48 h of HDT ( P< 0.05). Plasma renin activity (PRA) and aldosterone did not differ between the two groups. With prolongation of HDT, UV and UNaV returned close to baseline values. On the fourth HDT day, a 30-min infusion of 20 ml/kg isotonic saline was performed, while a large oral water load maintained a high urine output. The ambulatory period experiment was done with the subjects in the acute supine posture. Sodium excreted within 4 h of loading was 123 ± 8 mmol during HDT vs. 168 ± 16 mmol during the ambulatory period ( P < 0.05). The increase in plasma ANF and decrease in PRA were greater during HDT than during the ambulatory period (ANF 30 ± 5 vs. 13 ± 4 pg/ml, P < 0.05; PRA -1.4 ± 0.4 vs. -0.5 ± 0.2 ng ⋅ ml-1 ⋅ h-1, P < 0.05). Our data suggest that after a 3-day HDT period, thoracic volume receptor loading returns to the level seen in the upright position, leading to blunted responses to volume expansion, compared with acute supine control.To clarify whether exposure to 6 degrees head-down tilt (HDT) leads to alterations in body fluid volumes and responses to a saline load similar to those observed during space flight we investigated eight healthy subjects during a 4-day, 6 degrees HDT and during a time-control ambulatory period with cross-over. Compared with the ambulatory period, HDT was associated with greater urinary excretion of water and sodium (UV, U(Na)V) from 0 to 12 h (cumulated UV 1,781 +/- 154 vs. 1,383 +/- 170 ml, P < 0.05; cumulated U(Na)V 156 +/- 14 vs. 117 +/- 9 mmol, P < 0.05), and with higher plasma atrial natriuretic factor (ANF) at 4 h. Hemoglobin and hematocrit increased over the first 24 h, and blood and plasma volumes were decreased after 48 h of HDT (P < 0.05). Plasma renin activity (PRA) and aldosterone did not differ between the two groups. With prolongation of HDT, UV and U(Na)V returned close to baseline values. On the fourth HDT day, a 30-min infusion of 20 ml/kg isotonic saline was performed, while a large oral water load maintained a high urine output. The ambulatory period experiment was done with the subjects in the acute supine posture. Sodium excreted within 4 h of loading was 123 +/- 8 mmol during HDT vs. 168 +/- 16 mmol during the ambulatory period (P < 0.05). The increase in plasma ANF and decrease in PRA were greater during HDT than during the ambulatory period (ANF 30 +/- 5 vs. 13 +/- 4 pg/ml, P < 0.05; PRA -1.4 +/- 0.4 vs. -0.5 +/- 0.2 ng. ml(-1). h(-1), P < 0.05). Our data suggest that after a 3-day HDT period, thoracic volume receptor loading returns to the level seen in the upright position, leading to blunted responses to volume expansion, compared with acute supine control.

Transient remission of childhood acute lymphoblastic and myeloid leukemia without any cytostatic treatment: 2 case reports and a review of literature.

Transient remissions (TRs) of acute leukemia without any antileukemic treatment are extremely rare events. We report 2 TRs of acute lymphoblastic leukemia and acute myeloid leukemia in a 2-year-old boy and a 12-year-old girl, respectively, both associated with red blood cells and platelets transfusions and infection. These 2 factors are frequently present in previously reported cases and could induce a stimulation of the immune system although the underlying mechanisms of TRs are still unknown.

Early Onset of Sleep-Disordered Breathing in Two Children With SEPN1-Related Myopathies

ABSTRACT Selenoprotein-related myopathy (SEPN1-RM) is a rare disease with a variable clinical presentation. The selenoprotein N1 gene (SEPN1) mutation causing this congenital muscular dystrophy was identified in 2001. Sleep-disordered breathing (SDB) may occur in young patients with SEPN1-RM who are still able to walk. We report the cases of two children with SEPN1-RM who presented with SDB at the ages of 7 and 12 years and for whom long-term nocturnal noninvasive ventilation yielded significant improvement. Based on literature review and our current cases, it seems that there is no obvious relationship between the time since SDB onset and outcome of pulmonary function tests or limb muscle weakness. We therefore suggest that SDB should be systematically screened for in patients with SEPN1-RM, at regular intervals using nocturnal polysomnography.