Genomic and phenotypic delineation of congenital microcephaly.

PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.

The cumulative risk assessment of phthalates exposure in preterm neonates.

Phthalates are widely used plasticizers in various consumer products and medical devices, with some reporting as having estrogenic and anti-androgenic endocrine-disrupting effects. Premature neonates may be exposed to high levels of specific phthalates during hospitalization in the neonatal intensive care unit (NICU) because of reliance on multiple medical procedures that pose a possible health risk. The present study utilized seven urinary phthalate metabolites of dibutyl phthalate isomers [(di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)], butylbenzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) that had been previously measured in 33 preterm neonates sampled at hospital admission (N = 23) and daily during their NICU stay (N = 260). We aimed to perform: (1) cumulative risk assessment (CRA) using the volume and creatinine-adjusted models; (2) examine the temporal variability of CRA from repeated measures and (3) estimate the risk of cumulative exposure to phthalates based on their anti-androgenic and/or estrogenic properties. We multiplied the relative activity of individual phthalates exhibiting estrogenic or anti-androgenic effects by daily intake. For each preterm neonate, CRA was assessed based on the hazard index (HI) metric [the sum of hazard quotients] based on three reference doses for anti-androgenicity: the tolerable daily intake (TDI) from the European Food Safety Authority, the reference dose (RfD-AA) published in 2010 and newly revised published in 2020 (NRfD-AA). The metabolites of BBzP and DEHP were 2-23 fold higher in preterm neonates during their NICU stay. Median HIs increased in the order of HINRfDAA > HIRfDAA > HITDI. In the creatinine-based model, 87% (92%), 87% (96%), and 100% (100%) of preterm neonates at admission (during NICU stay) showed HITDI, HIRfD-AA, and HINRfD-AA exceeding 1, respectively with DEHP the most prevalent. The temporal reproducibility of HI (based on three reference doses) during preterm neonate stay in the NICU was high, with intra-class correlation coefficients ranging between 0.77 and 0.97, suggesting persistent exposure to phthalates. The four phthalates that preterm neonates were exposed to in the NICU exhibited estrogenic binding and anti-androgenic effects with median values (creatinine-based) of 98.7 and 56.9 µg/kg body weight/day, respectively. This was especially true for DEHP. The results indicate that preterm neonates in this NICU setting are probably at high risk of cumulative phthalate exposure with anti-androgenic properties that may have long-term adverse reproductive and developmental effects.

Exposure of preterm neonates receiving total parenteral nutrition to phthalates and its impact on neurodevelopment at the age of 2 months.

This prospective study assessed the exposure to phthalates of preterm neonates who received total parenteral nutrition (TPN) during their stay in the neonatal intensive care unit (NICU) and the risk of neurodevelopment delays at the age of 2 months. Our study recruited 33 preterm neonates who required TPN upon NICU admission. Urine samples for analyzing phthalate metabolites were obtained at admission and then daily until the last day of receiving TPN. Phthalates in the daily TPN received by the preterm neonates were analyzed. The neurodevelopment of the neonates was assessed using the Ages and Stages Questionnaire Edition 3 (ASQ-3). Diethyl phthalate and butyl benzyl phthalate were found in all TPN samples, while 27% and 83% contained dibutyl phthalate and di-(2-ethylhexyl) phthalate (DEHP), respectively. Yet, the daily dose of each phthalate that our preterm neonates received from TPN was much lower than the recommended tolerable limit. Urinary levels of monobenzyl phthalate and four metabolites of DEHP [i.e., mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)] and the sum of four DEHP metabolites (∑4DEHP) increased significantly in preterm neonates before discharge. However, these levels were not correlated with their phthalate parent compounds in TPN, suggesting other sources of exposure in the NICU. At 2 months, we found that urinary levels of mono-iso-butyl phthalate (MiBP), MECPP, MEHP, and ∑4DEHP were inversely related to fine motor skills. After adjusting for head circumference, the inverse relationships remained significant, suggesting direct effects from phthalates. Given the extreme vulnerability of our population, it is critical to minimize exposure to phthalates during their NICU stay.

Exposure of preterm neonates to toxic metals during their stay in the Neonatal Intensive Care Unit and its impact on neurodevelopment at 2 months of age.

BACKGROUND: Premature neonates might be exposed to toxic metals during their stay in the neonatal intensive care unit (NICU), which could adversely affect neurodevelopment; however, limited evidence is available. The present study was therefore designed to assess the exposure to mercury, lead, cadmium, arsenic, and manganese of preterm neonates who received total parenteral nutrition (TPN) and/or red blood cell (RBC) transfusions during their NICU stay and the risk of neurodevelopment delay at the age of 2 months. METHODS: We recruited 33 preterm neonates who required TPN during their NICU admission. Blood samples were collected for metal analysis at two different time points (admission and before discharge). Metals in the daily TPN received by preterm neonates were analyzed. Neurodevelopment was assessed using the Ages and Stages Questionnaire Edition 3 (ASQ-3). RESULTS: All samples of TPN had metal contamination: 96% exceeded the critical arsenic limit (0.3 µg/kg body weight/day); daily manganese intake from TPN for preterm neonates exceeded the recommended dose (1 µg/kg body weight) as it was added intentionally to TPN solutions, raising potential safety concerns. All samples of RBC transfusions exceeded the estimated intravenous reference dose for lead (0.19 µg/kg body weight). Levels of mercury, lead and manganese in preterm neonates at discharge decreased 0.867 µg/L (95% CI, 0.76, 0.988), 0.831 (95%CI, 0.779, 0.886) and 0.847 µg/L (95% CI, 0.775, 0.926), respectively. A decrease in ASQ-3-problem solving scores was associated with higher levels of blood lead in preterm neonates taken at admission (ß = -0.405, 95%CI = -0.655, -0.014), and with plasma manganese (ß = -0.562, 95%CI = -0.995, -0.172). We also observed an association between decreased personal social domain scores with higher blood lead levels of preterm neonates before discharge (ß = -0.537, 95%CI = -0.905, -0.045). CONCLUSION: Our findings provide evidence to suggest negative impacts on the neurodevelopment at 2 months of preterm infants exposed to certain metals, possibly related to TPN intake and/or blood transfusions received during their NICU stay. Preterm neonates may be exposed to levels of metals in utero.

Maternal Vitamin D Levels and Its Correlation With Low Birth Weight in Neonates: A Tertiary Care Hospital Experience in Saudi Arabia.

Introduction A meta-analysis showed that 63.6% of the Saudi population have vitamin D deficiency, including many pregnant women. Studies showed that maternal vitamin D deficiency during pregnancy is a risk factor for low birth weight (LBW) in neonates. Neonatal LBW is a risk factor for multiple neonatal complications including respiratory distress syndrome, necrotizing enterocolitis, chronic renal disorders, seizures, and sepsis. Our objective in this study is to determine a correlation between low maternal vitamin D level and neonatal LBW in Saudi Arabia. Methods Neonates (n = 119) were divided based on their gestational age (GA) into full-term neonates (≥37 weeks) and preterm neonates (< 37 weeks) and based on birth weight into normal birth weight neonates (full-term = 2,500-3,500 g or preterm > 10th percentile) and LBW neonates (full-term < 2,500 g or preterm < 10th percentile). Vitamin D deficiency is defined as 25- hydroxyvitamin D level less than 50 nmol/L. Results Correlating neonatal birth weight with maternal vitamin D level during pregnancy was statistically insignificant for both full-term neonates and preterm neonates. In contrast, comparing the mean maternal vitamin D levels in each neonatal group showed that the mean were higher in mothers of neonates with normal birth weight. Conclusion Because 87.4% of mothers had low vitamin D levels during their pregnancy, correlation between maternal vitamin D level and LBW in neonates could not be found. However, mean maternal vitamin D levels were higher in mothers with normal birth weight neonates. Therefore, further detailed studies are required to establish local guidelines about the treatment of vitamin D deficiency during pregnancy.