Coexisting Conditions Modifying Phenotypes of Patients with 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder with an extremely broad phenotypic spectrum. The aim of our study was to investigate how often the additional variants in the genome can affect clinical variation among patients with the recurrent deletion. To examine the presence of additional variants affecting the phenotype, we performed microarray in 82 prenatal and 77 postnatal cases and performed exome sequencing in 86 postnatal patients with 22q11.2DS. Within those 159 patients where array was performed, 5 pathogenic and 5 likely pathogenic CNVs were identified outside of the 22q11.2 region. This indicates that in 6.3% cases, additional CNVs most likely contribute to the clinical presentation. Additionally, exome sequencing in 86 patients revealed 3 pathogenic (3.49%) and 5 likely pathogenic (5.81%) SNVs and small CNV. These results show that the extension of diagnostics with genome-wide methods can reveal other clinically relevant changes in patients with 22q11 deletion syndrome.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Effects of prenatal and/or postnatal supplementation with iron, PUFA or folic acid on neurodevelopment: update.

Neurodevelopment has been linked, among other factors, to maternal and early infant diets. The objective of this review, which is part of the NUTRIMENTHE research project 'The effect of diet on the mental performance of children' (www.nutrimenthe.com), was to update current evidence on the effects of nutritional interventions such as iron, folic acid or n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy and/or in early life on the mental performance and psychomotor development of children. In May 2014, we searched MEDLINE and The Cochrane Database of Systematic Reviews for relevant studies published since 2009. The limited updated evidence suggests that iron supplementation of infants may positively influence the psychomotor development of children, although it does not seem to alter their mental development or behaviour. The use of multivitamin-containing folic acid supplements during pregnancy did not benefit the mental performance of the offspring. Evidence from randomised controlled trials (RCT) did not show a clear and consistent benefit of n-3 LCPUFA supplementation during pregnancy and/or lactation on childhood cognitive and visual development. Caution is needed when interpreting current evidence, as many of the included trials had methodological limitations such as small sample sizes, high attrition rates, and no intention-to-treat analyses. Taken together, the evidence is still inconclusive. Large, high-quality RCT to assess the effects of supplementation with iron, LCPUFA or folic acid are still needed to further clarify the effects of these, and other nutrients, on neurodevelopment. Recent recommendations from scientific societies are briefly presented.

Association between early life (prenatal and postnatal) antibiotic administration and coeliac disease: a systematic review.

OBJECTIVE: Whether prenatal or postnatal exposure to antibiotics is associated with an increased risk of coeliac disease (CD) is unclear. We systematically reviewed studies on the association between early life antibiotic exposure and the risk of CD or CD autoimmunity. DESIGN: Systematic review of observational studies. DATA SOURCES: The PubMed and Embase databases were searched up to December 2018, with no language restrictions. Additional references were obtained from reviewed articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Cohort, cross-sectional and case-control studies that assessed the association between prenatal and/or postnatal antibiotic exposure and the odds of developing CD (as defined by authors of the original studies) or CD autoimmunity were eligible for inclusion. RESULTS: Six studies were included. In two large cohort studies that focused on prenatal antibiotic exposure, no association with the risk of CD was found (adjusted OR=1.16; 95% CI 0.94 to 1.43 and adjusted HR=1.33; 95% CI 0.69 to 2.56) in the Norwegian and Swedish cohorts, respectively. In three studies that evaluated the association of postnatal antibiotic exposure with the risk of CD, the results were contradictory, with only the Italian cohort study reporting a significant positive association (adjusted incidence rate ratio=1.24; 95% CI 1.07 to 1.43). A large, multicentre cohort study that evaluated the association between postnatal antibiotic exposure and CD autoimmunity in human leukocyte antigen (HLA)-positive subjects found no association. CONCLUSIONS: We found no evidence of an association between prenatal or postnatal antibiotic exposure and CD.

Systematic review with meta-analysis: Lactobacillus rhamnosus GG for treating acute gastroenteritis in children - a 2019 update.

BACKGROUND: Recently, evidence from a large randomised controlled trial (RCT) negated efficacy of Lactobacillus rhamnosus GG for treating acute gastroenteritis in children. AIM: To review RCTs in which L rhamnosus GG was used to treat acute gastroenteritis in children. METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched from May 2013 (end of last search) to January 2019. The primary outcomes were stool volume and duration of diarrhoea. RESULTS: Eighteen RCTs (n = 4208) were included. Compared with placebo or no treatment, L rhamnosus GG use had no effect on stool volume but was associated with a reduced duration of diarrhoea (15 RCTs, n = 3820, mean difference, MD -0.85 day, 95% CI -1.15 to -0.56). L rhamnosus GG was effective when used at a daily dose of ≥1010 CFU or <1010 CFU; however, the latter produced results of borderline significance. L rhamnosus GG was more effective when used in European countries compared with non-European countries, particularly when considered by region. L rhamnosus GG use was associated with a reduced duration of hospitalisation. One RCT found that L rhamnosus GG had no effect on the total clinical severity score at 14 days after enrolment. CONCLUSIONS: Despite a recent large RCT demonstrating no effect of L rhamnosus GG, current evidence shows that, overall, L rhamnosus GG reduced both the duration of diarrhoea (with a higher impact in European countries) and hospitalisation in inpatients. These findings should be viewed in the context of the high heterogeneity and methodological limitations of the included trials.

Comprehensive genomic analysis of patients with disorders of cerebral cortical development.

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

Effectiveness of Lactobacillus reuteri DSM 17938 for the Prevention of Nosocomial Diarrhea in Children: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Multiple studies of probiotics used to prevent nosocomial diarrhea have provided conflicting results. The effects likely depend on the probiotic strain and/or dosage. The aim of this study was to assess the effectiveness of Lactobacillus reuteri DSM 17938 (L. reuteri; daily dose of 1 × 10 colony forming units) for preventing nosocomial diarrhea in children. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial in 184 children, 1-48 months of age, admitted to the hospital for reasons other than diarrhea. A computer-generated randomization scheme was used to allocate participants to receive either L. reuteri (n = 91) at a daily dose of 1 × 10 colony forming units, for the duration of hospitalization, or an identical appearing placebo (n = 93). Patients, study personnel and data analysts were blinded to assignment. The primary outcome was the occurrence of nosocomial diarrhea (≥3 loose or watery stools in 24 hours that occurred >72 hours after admission). Analysis was by intention-to-treat. RESULTS: Baseline characteristics were similar in the 2 groups. Nosocomial diarrhea occurred in 13 (7.1%) children. No difference was found between the L. reuteri and the placebo groups (7/91 vs 6/93, respectively; relative risk: 1.19; 95% confidence interval: 0.43-3.27). There was also no difference between the L. reuteri and placebo groups for any of the secondary outcomes, including adverse effects. Rotavirus vaccination status had no effect on the results. CONCLUSION: L. reuteri in the dosage regimen used was not effective in preventing nosocomial diarrhea in children.

Oculocutaneous albinism in a patient with 17p13.2-pter duplication - a review on the molecular syndromology of 17p13 duplication.

BACKGROUND: Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. AIMS: We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. METHODS: A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. CONCLUSION: The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance.

No effect of proton pump inhibitors on crying and irritability in infants: systematic review of randomized controlled trials.

Proton pump inhibitors are increasingly being used to treat infants with crying and/or irritability based on the assumption that these symptoms are attributable to gastroesophageal reflux. However, the data from a systematic review of randomized controlled trials do not support the use of proton pump inhibitors to decrease infant crying and irritability.

Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF1 gene.

Cardio-facio-cutaneous (CFC) syndrome is characterized by a variable degree of developmental delay and congenital anomalies, including characteristic facial, cardiac, and ectodermal abnormalities. It is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. In, however, approximately 10%-30% of individuals with a clinical diagnosis of CFCS, no mutation of the causative gene is found. Therefore, clinical studies in patients with the CFCS spectrum are valuable. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting genes encoding serine/threonine kinases, a group of 15 children and young adults with a diagnosis of CFCS was screened. We documented three novel mutations in the BRAF gene and correlated clinical findings with causative mutations in the BRAF or MEK1/MEK2 genes.

Effects of prenatal and/or postnatal (maternal and/or child) folic acid supplementation on the mental performance of children.

It has been suggested that a deficiency in folic acid during early, critical central nervous system development may result in persistent cognitive and behavioral effects. The purpose of this systematic review was to evaluate evidence regarding whether folic acid supplementation during pregnancy and early life influences mental performance outcomes in children. The following electronic databases were searched through December 2009 for studies relevant to mental performance and folic acid: MEDLINE, EMBASE and The Cochrane Library; additional references were obtained from reviewed articles. Only randomized controlled trials (RCTs) were included. Of 8 RCTs identified, only 2 met the inclusion criteria. Both studies involved periconceptional, multivitamin-containing, folic acid supplementation. Evidence from these 2 RCTs suggests that such supplementation does not affect the postnatal mental development of infants at a mean age of 11 mo, the developmental quotient (DQ) at 2 y of age, or the intelligence quotient (IQ) and Goodenough man drawing test quotient (DrQ) at 6 y of age. We conclude that the use of multivitamin-containing folic acid supplementation during pregnancy is associated with no benefit to the mental performance of children. These findings should be interpreted with caution due to the very limited number of studies included in this systemic review.

Diagnostic difficulties in Krabbe disease: a report of two cases and review of literature.

Globoid cell leukodystrophy (GLD, also known as Krabbe disease), whose pathophysiology is still not completely elucidated, is an inherited, metabolic, and neurodegenerative disease, caused by the deficiency of ß-galactocerebrosidase (GALC) or in very rare cases by lack of active saposin A. We describe two patients, in whom first MRI changes were not suggestive of GLD. Additionally, in Patient 1, the residual ß-galactocerebrosidase activity was rather high leading to difficulties in the diagnosing process. Molecular analysis of the GALC and PSAP genes in Patient 1, and of the GALC gene in Patient 2 confirmed the diagnosis of Krabbe disease. We have detected a novel mutation in the GALC gene in Patient 2, a deletion in exon 16, leading to the STOP codon (c.1851delT, p.Y617X). This deletion interrupts the reading frame prematurely: codon 617 is replaced by a STOP codon. A careful clinical description of presented patients is followed by a discussion of radiological, biochemical, genetic, and neuropathological studies. It concludes with a discussion of the potential difficulties encountered when diagnosing patients with rare diseases. In Patient 1 the postmortem examination of CNS revealed the presence of globoid cells grouped in multiple clusters seen in the white matter near the vessels. We would like to emphasize that proper clinical-radiological-biochemical co-operation and exchange of information between parents and specialists is a key issue in the diagnosis of rare and difficult neurological diseases, in particular, if the clinical picture is inconclusive.