Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.

BACKGROUND: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. RESULTS: By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. CONCLUSIONS: Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.

The effect of common origin of the carotid arteries in neurologic outcome after neonatal ECMO.

BACKGROUND: Common origin of the carotid arteries (COCA) is a normal anatomic variant reported to occur in approximately 11% of the general population. The objective of this study was to determine whether this variant places venoarterial extracorporeal membrane oxygenation (ECMO) patients at a higher risk for adverse neurologic sequelae owing to potential occlusion of both carotid arteries by the arterial cannula. METHODS: The authors reviewed clinical records and echocardiograms of the initial 220 ECMO patients at their institution. Aortic arch morphology was determined by a pediatric cardiologist blinded to all other data. After exclusion of predetermined patients, 131 patients were divided into 2 groups: those with separate origin of the carotid arteries (n = 111) and those with COCA (n = 20). The neurologic outcome variables studied included the results of magnetic resonance imaging (MRI); computed tomography (CT); electroencephalogram (EEG); brainstem auditory-evoked response (BAER), head ultrasound scan, and Bayley Scales of Infant Development reported as Psychomotor Developmental Index (PDI) and Mental Developmental Index (MDI). RESULTS: COCA had no predictive value in determining PDI and MDI outcomes and no significance in predicting an increased risk of adverse neurologic sequelae based on MRI, CT, EEG, BAER, or head ultrasound scan. CONCLUSIONS: This study confirms that COCA is a common aortic arch variant (15%, n = 20 of 131) and that this variant does not appear to increase the risk of neurologic injury in infants undergoing venoarterial ECMO.

Surveillance of ventilator-associated pneumonia in very-low-birth-weight infants.

BACKGROUND: Surveillance of ventilator-associated pneumonia (VAP) is an essential part of quality patient care. Very-low-birth-weight (VLBW) infants, many with tracheal microbial colonization and bronchopulmonary dysplasia (BPD), comprise a difficult group in whom to make a diagnosis of pneumonia with the Centers for Disease Control and Prevention (CDC) criteria for infants younger than 1 year. OBJECTIVE: Our objective was to retrospectively compare VAP surveillance diagnoses made by the hospital infection control practitioner (ICP) with those made by a panel of experts with the same clinical and laboratory evidence and supportive radiologic data. A secondary objective was to compare radiologic diagnosis of pneumonia made by the general hospital radiologists, by the panel of experts, and by a pediatric radiologist from another hospital. STUDY POPULATION: Thirty-seven VLBW infants identified as at risk for VAP by the ICP on the basis of a positive bacterial tracheal culture and the application of CDC criteria for the definition of pneumonia were studied. METHODS: Clinical and laboratory evidence and routine radiologic reports made by the general radiologist were reviewed independently by a panel of experts composed of 3 experienced neonatologists. Chest x-rays from the day before, day of, and day after the surveillance date were reviewed separately by the 3 neonatologists and also by a pediatric radiologist. RESULTS: After inter-reader reliability was found satisfactory (kappa's coefficient, 0.47-0.75; P <.05), the panel of neonatologists determined that the 37 VLBW infants represented 4 distinct clinical categories. Group 1 comprised 12 airway-colonized infants, aged 14 to 30 days, who on the surveillance date, albeit intubated, were asymptomatic, not treated with antibiotics, and survived. Group 2 comprised 11 airway-colonized infants, aged 7 to 42 days, who presented with equivocal clinical, laboratory, or radiologic signs of VAP and survived. Group 3 comprised 7 airway-colonized infants, aged 14 to 21 days, who were acutely ill (3 died) and had clinical and laboratory evidence of nosocomial bloodstream infection (BSI) but no radiologic signs of pneumonia. Group 4 comprised 7 infants, aged 14 to 28 days, who were acutely ill (4 died) and had clinical and laboratory evidence of infection and radiologic changes consistent with VAP. Radiologic Findings: General radiologists, neonatologists, and the pediatric radiologist agreed that none of the asymptomatic airway-colonized infants (Group 1) had VAP. General radiologists reported signs suggestive of pneumonia in 8 of 11 infants (Group 2), a finding not corroborated by the others. Everybody agreed on the absence of radiologic pneumonia in 6 of 7 patients with nosocomial BSI (Group 3) and on the presence of signs consistent with pneumonia in the remaining 7 infants (Group 4). CONCLUSION: Surveillance diagnosis of VAP in VLBW infants is difficult because current CDC definitions are not specific for this population. Isolated positive tracheal culture alone does not distinguish between bacterial colonization and respiratory infection. Clinical and laboratory signs of VAP, mostly nonspecific, can be found in other conditions such as bronchopulmonary dysplasia and nosocomial BSI. Routine radiologic reports suggestive of pneumonia in airway-colonized infants without definitive clinical and laboratory evidence of infection could be misleading. To improve accuracy, surveillance diagnosis of VAP in special populations such as VLBW infants should be reformulated; meanwhile, ICPs should seek consultation with experienced clinicians for interpretation of data.