Duplication of 10q24 locus: broadening the clinical and radiological spectrum.

Split-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM.

Prediction of bronchopulmonary dysplasia.

OBJECTIVE: To determine whether elevation of a biological marker of inflammation would be a better predictor of bronchopulmonary dysplasia (BPD) development than lung function measurement results. DESIGN: Prospective study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 78 prematurely born infants (median gestational age 29 (range 24-32) weeks) were studied; 39 developed BPD. INTERVENTIONS: BPD was diagnosed as oxygen dependence at 28 days. MAIN OUTCOME MEASURES: Levels of a biological marker of inflammation (carbon monoxide) were assessed by measurement of end-tidal carbon monoxide (ETCO) and lung function by measurement of functional residual capacity (FRC) and compliance (Crs) and resistance (Rrs) of the respiratory system on days 3 and 14 after birth. Possible predictive factors were modelled for BPD and for BPD severity. RESULTS: Gestational age, birth weight, ETCO, FRC and Crs results on days 3 and 14 differed significantly between infants who did and did not develop BPD. In multifactorial logistic regression, only birth weight and ETCO results (on day 14) remained significant predictors of BPD with an area under the curve of 0.97. The final multifactorial model for the severity of BPD included those two factors, plus septic episodes. CONCLUSION: These results emphasise the importance of ongoing inflammation in the development of BPD; ETCO levels, rather than lung function test results, were the more accurate predictor of BPD development.

Chorioamnionitis, lung function and bronchopulmonary dysplasia in prematurely born infants.

OBJECTIVE: To determine whether prematurely born infants exposed to chorioamnionitis compared to those not exposed have poorer lung function and are more likely to develop severe bronchopulmonary dysplasia (BPD). DESIGN: Results were analysed from consecutive infants born at <33 weeks gestation with placental histology results and lung function measurement results on days 2 and/or 7 after birth and/or at 36 weeks postmenstrual age (PMA). SETTING: Tertiary neonatal intensive care unit. PATIENTS: 120 infants with a median gestational age of 29 (range 23-32) weeks were studied, 76 (63%) developed BPD and 41 (34%) had been exposed to chorioamnionitis and/or funisitis. INTERVENTIONS: Chorioamnionitis was diagnosed histologically. MAIN OUTCOME MEASURES: Lung function was assessed by measurement of lung volume and compliance and resistance of the respiratory system. If the infants remained oxygen dependent beyond 28 days, they were diagnosed at 36 weeks PMA to have mild BPD (no longer oxygen dependent), moderate BPD (required less than 30% oxygen) or severe BPD (required more than 30% oxygen and/or positive pressure support). RESULTS: No significant differences were found in the lung function results between the chorioamnionitis and non-chorioamnionitis groups at any postnatal age. There was no significant relationship between chorioamnionitis and the occurrence or severity of BPD. Regression analysis demonstrated BPD was significantly related only to birth weight, gestational age and use of surfactant. CONCLUSION: In prematurely born infants, routinely exposed to antenatal steroids and postnatal surfactant, chorioamnionitis was not associated with worse lung function or more severe BPD.

Absence of the ductus venosus.

Absence of the ductus venosus is a rare vascular anomaly, but clinicians should be aware that it can be diagnosed antenatally and the prognosis is dependent on the type of associated malformation of the fetal vascular system. Antenatal detection of a single umbilical artery and unexplained cardiomegaly should prompt detailed examination of the umbilical and portal veins. Absent ductus venosus is associated with three main patterns of abnormal venous circulation, the worst prognosis being seen when the umbilical vein bypasses the liver and connects to the right atrium. Fetuses with absence of the ductus venosus are at risk of other congenital anomalies including facial clefts, hemivertebrae, cardiac, genitourinary, gastrointestinal anomalies; affected infants also have a poorer prognosis. In conclusion, fetuses with features suggestive of absence of ductus venosus require referral to a tertiary perinatal center.

Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes.

Maternal anemia and low birth weight (LBW) may complicate malaria in pregnancy, and placental monocyte infiltrates have been associated with LBW, and anecdotally with anemia. We examined placental pathology from 357 Malawian women. Intervillous monocyte infiltrates were frequent in placental malaria and were not seen in uninfected placentas. Histology was grouped according to a 5-point scale. Dense monocyte infiltrates and presence of intramonocytic malaria pigment were associated with anemia and LBW. Of factors associated with LBW and/or anemia in univariate analysis, gravidity (P = 0.002), number of antenatal clinic (ANC) visits (P < 0.001), malaria pigment in fibrin (P = 0.03), and monocyte malaria pigment (P = 0.0001) remained associated with lower birth weight by multivariate analysis. Associated with maternal anemia were HIV infection (P < 0.0001), intervillous monocyte numbers (P < 0.0001), number of ANC visits (P = 0.002), and recent febrile symptoms (P = 0.0001). Pigment-containing placental monocytes are associated with anemia and LBW due to malaria, and may have a causative role in their development.

Placental tumor necrosis factor alpha but not gamma interferon is associated with placental malaria and low birth weight in Malawian women.

Malaria in pregnancy predisposes to maternal anemia and low birth weight (LBW). We examined the possible roles of the cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) in these adverse outcomes. We measured cytokine concentrations in placental, peripheral, and cord blood plasma in relation to malaria parasitemia and placental monocyte accumulation in 276 Malawian women. Maternal hemoglobin concentration, human immunodeficiency virus status, and infant birth weight were determined. Concentrations of TNF-alpha in placental blood were correlated with densities of Plasmodium falciparum-infected erythrocytes (P < 0.0001) and of intervillous monocyte infiltrates (P < 0.0001) on placental histology. Peripheral blood TNF-alpha concentrations were relatively low and were weakly associated with malaria. TNF-alpha concentrations were higher in placental blood, where they were strongly associated with malaria. Placental plasma TNF-alpha levels were higher in women who had LBW babies (P = 0.0027), women with febrile symptoms (P < 0.0001), and teenage mothers (P = 0.04) than in other women. The presence of TNF-alpha in cord blood was not associated with malaria infection. IFN-gamma levels were infrequently elevated, and elevated IFN-gamma levels were not associated with poor pregnancy outcomes. Placental production of TNF-alpha, but not of IFN-gamma, may be implicated in impaired fetal growth in Malawian women.