BACKGROUND: Rauch-Steindl syndrome (RAUST) is a very rare genetic syndrome caused by a pathogenic variant in NSD2 on chromosome 4p16.3. Although NSD2 was previously thought to be the major gene in Wolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome of chromosome 4p16.3 deletion, RAUST has been found to present different facial and clinical features from WHS. In this study, we report the details of two newly diagnosed individuals with RAUST in order to better understand the molecular and clinical features of RAUST.
METHODS: Whole-genome sequencing was performed on two individuals with psychomotor delay and growth failure. Detailed clinical evaluation of growth parameters, craniofacial features, electroencephalogram (EEG), magnetic resonance imaging of the brain, and developmental assessment were performed.
RESULTS: Both individuals had de novo truncating variants in NSD2. One had a novel variant (c.2470C>T, p.Arg824*), and the other had a recurrent variant (c.4028del, p.Pro1343Glnfs*49). Both exhibited characteristic RAUST facial features, growth failure, and mild psychomotor delay. A novel finding of RAUST was seen in individual 2, a Chiari malformation type 1, and both showed delayed bone age. They lacked common WHS features such as congenital heart defects, cleft lip/palate, and seizures (EEG with abnormal findings).
CONCLUSIONS: We present a novel variant and clinical presentations of RAUST, expand the molecular and clinical diversity of RAUST, and improve our understanding of this rare syndrome, which is distinct from WHS. Further researches are needed on more RAUST cases and on functional analysis of NSD2.

Methemoglobinemia is due to oxidization of divalent ferro-iron of hemoglobin to ferri-iron of methemoglobin (MetHb) which is incapable of transferring oxygen to tissues. This disease may be acquired by intoxication with oxidizing agents or inherited with a mutation of CYB5R3, the gene coding for the methemoglobin reductase or cytochrome B5 reductase 3 responsible for the reduction of MetHb to hemoglobin. We report the case of 2 sisters aged respectively of 15 and 8 months. They were born to a second-degree consanguineous marriage with a history of precocious and unexplained deaths in 3 relatives. Both sisters presented neurological features including psychomotor retardation, microcephaly, and axial hypotonia. Cerebral magnetic resonance imaging revealed cerebral atrophy in both cases associated with hypoplasia of the corpus callosum in the younger child. The association of neurological disability, cyanosis, and hypoxemia prompted a search for methemoglobinemia, with MetHB levels respectively of 26% and 15.8%in the 2 sisters. Initial treatment was based on methylene blue, then ascorbic acid. The genetic study revealed a c.463+8G>C mutation of CYB5R3 confirming the diagnosis of methemoglobinemia type II. The diagnosis of methemoglobinemia, although rare, should be considered in the presence of psychomotor retardation with cyanosis and subacute onset hypoxemia, especially in the presence of a family history.

Classic phenylketonuria (PKU) is caused by defective activity of phenylalanine hydroxylase (PAH), the enzyme that coverts phenylalanine (Phe) to tyrosine. Toxic accumulation of phenylalanine and its metabolites, left untreated, affects brain development and function depending on the timing of exposure to elevated levels. The specific mechanisms of Phe-induced brain damage are not completely understood, but they correlate to phenylalanine levels and on the stage of brain growth. During fetal life, high levels of phenylalanine such as those seen in maternal PKU can result in microcephaly, neuronal loss and corpus callosum hypoplasia. Elevated phenylalanine levels during the first few years of life can cause acquired microcephaly, severe cognitive impairment and epilepsy, likely due to the impairment of synaptogenesis. During late childhood, elevated phenylalanine can cause alterations in neurological functioning, leading to ADHD, speech delay and mild IQ reduction. In adolescents and adults, executive function and mood are affected, with some of the abnormalities reversed by better control of phenylalanine levels. Altered brain myelination can be present at this stage. In this article, we review the current knowledge about the consequences of high phenylalanine levels in PKU patients and animal models through different stages of brain development and its effect on cognitive, behavioural and neuropsychological function.

The aim of this study was to compare the incidence of mild psychomotor delay in infants whose mothers were treated for thyroid dysfunction regardless of the cause during first trimester of pregnancy with those whose mothers did not use medications prenatally. The sample included 200 infants up to 4 months of age. Half of the infants were examined by a pediatric physiatrist, while the other half were chosen randomly from the primary pediatric clinic. Binary logistic regression was performed to assess the impact of factors on psychomotor delay. The model contained seven independent variables derived from bivariate analyses and clinical relevance. Results showed that the infant\'s chance of having psychomotor delay was 5.53 times higher if the mother had drug-compensated thyroid dysfunction. Younger gestational age increased the likelihood of delay 2.12 times per each gestational week. The likelihood of psychomotor delay also rose by 1% per 1 g of birth weight reduction. We found strong positive linear correlation between maternal drug-compensated thyroid dysfunction during pregnancy and psychomotor delay in infants, which has not been reported elsewhere. This differentiates an important and common prenatal risk factor and lays the foundation for faster initiation of habilitation of infants at risk. These insights provide a basis for planning the National Screening Program for Neurorisk Infants.

Background: Psychomotor delay, epilepsy and dysmorphic features are clinical signs which are described in multiple syndromes due to chromosomal imbalances or mutations involving key genes implicated in the stages of Early Embryonic Development. In this context, we report a 10 years old Tunisian patient with these three signs. Our objective is to determine the cause of developmental, behavioral and facial abnormalities in this patient. Methods: We used banding cytogenetics (karyotype) and Array Comparative Genomic Hybridization (Array CGH) to this purpose. Results: The karyotype was in favor of a derivative of chromosome 7 in the patient and Array CGH analysis revealed a loss of genetic material in 7p22.3-p22.1 (4,56 Mb) with a gain at 8q24.23-q24 (9.20 Mb) resulting from maternal 7/8 reciprocal translocation. An in silico analysis of the unbalanced region was carried out and showed that the 7p22.3-p22.1 deletion contains eight genes. Among them, BRAT1 gene, previously described in several neurodevelopmental diseases, may be a candidate gene which absence could be correlated to the patient\'s phenotype. However, the 8q24.23-q24 duplication could be involved in the phenotype of this patient. Conclusion: In this study, we report for the first time a 7p deletion/8q duplication in a patient with psychomoteur delay, epilepsy and facial dysmorphism. Our study showed that Array CGH still useful for delivering a conclusive genetic diagnosis for patients having neurodevelopmental abnormalities in the era of next-generation sequencing.

Mevalonate kinase (MK) deficiency is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the MVK gene with a broad phenotypic spectrum including autoinflammation, developmental delay and ataxia. Typically, neurological symptoms are considered to be part of the severe end of the phenotypical spectrum and are reported to be in addition to the autoinflammatory symptoms. Here, we describe a patient with MK deficiency with severe neurological symptoms but without autoinflammation and we found several similar patients in the literature. Possibly, the non-inflammatory phenotype is related to a specific genotype: the MVK p.(His20Pro)/p.(Ala334Thr) variant. There is probably an underdetection of the neurological MK deficient phenotype without inflammatory symptoms as clinicians may not test for MK deficiency when patients present with only neurological symptoms. In conclusion, although rare, neurological symptoms without hyperinflammation might be more common than expected in MK deficiency. It seems relevant to consider MK deficiency in patients with psychomotor delay and ataxia, even if there are no inflammatory symptoms.

UNASSIGNED: children infected with HIV are at increased risk of impaired neurodevelopmental, due to several environmental factors.
UNASSIGNED: we conducted a cross-sectional analytical study on HIV-infected children aged 12 to 59 months, followed up in five hospitals in Yaounde, Cameroon. Sociodemographic, clinical, and biological variables as well as the antecedents were collected. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 25 software. The Denver test was used to assess the psychomotor development of these children. Global psychomotor delay, defined as a global development quotient of less than 70 with an alteration in at least two of the four domains of the test, was retained as the primary endpoint. The significance threshold was set at 5%.
UNASSIGNED: one hundred and eighty-one children were included in the study. The sex ratio was 0.6. The age range 48-59 months was the most represented. None of these children had a known chronic pathology other than HIV infection. The proportion of global psychomotor delay was 11.04%, with language (16%) and fine motor skills (16%) being the most affected domains of psychomotor development. The independent factors significantly associated with global psychomotor delay were birth weight below 2500 grams (OR= 17.61 [1.76-181.39], p= 0.022), growth retardation (OR= 17.64 [1.63-190.24], p= 0.018) and elevated viral load (OR= 22.75 [2.78-186.02], p= 0.004).
UNASSIGNED: psychomotor delay affects about one out of ten children living with HIV. Its occurrence is linked to various factors that must be taken into account in the development of public health policies in connection with the management of HIV infection in children.

Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete.
The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia.
These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

Achondroplasia (ACH) is a hereditary disorder of dwarfism that is caused by the aberrant proliferation and differentiation of chondrocyte growth plates. The common findings of macrocephaly and facial anomalies accompany dwarfism in these patients. Fibroblast growth factor receptor 3 ( FGFR3 ) gene mutations are common causes of achondroplasia. The current study presents a case of 2-year-old male child patient presenting with phenotypic characteristics of ACH. The interesting finding of the case is the presence of psychomotor delay that is not very common in these patients. Clinical exome sequencing analyzing 4.813 disease causing genes revealed a de novo c.1138G > A mutation within the FGFR3 gene. In conclusion, the mutation confirms the clinical diagnosis of ACH, and it seems to be causing the psychomotor delay in this patient.

BACKGROUND: In 2016, the U.S. Food and Drug Administration expressed concern that neurodevelopment may be negatively affected by anesthesia or sedation exposure in pregnancy or before three years of age. We examined the association between general anesthesia at the time of cesarean delivery and early childhood neurodevelopment.
METHODS: A secondary analysis of a multicenter randomized controlled trial assessing magnesium for prevention of cerebral palsy in infants at risk for preterm delivery. Exposure was general compared to neuraxial anesthesia. The primary outcome was motor or mental delay at two years of age, assessed by Bayley Scales of Infant Development II (BSIDII). Secondary outcomes included BSIDII subdomains and perinatal outcomes. Multivariable logistic regression models were performed to control for confounders.
RESULTS: Of 557 women undergoing cesarean delivery, 119 (21%) received general anesthesia. There were no differences in the primary composite outcome of developmental delay (aOR 0.93, 95% CI 0.61 to 1.43) or the BSIDII subdomains of mild, moderate, or severe mental delay, or mild or moderate motor delay. Severe motor delay was more common among infants exposed to general anesthesia (aOR 1.98, 95% CI 1.06 to 3.69). Infants exposed to general anesthesia had longer neonatal intensive care stays (51 vs 37 days, P=0.010).
CONCLUSIONS: General anesthesia for cesarean delivery was not associated with overall neurodevelopmental delay at two years of age, except for greater odds of severe motor delay. Future studies should evaluate this finding, as well as the impact on neurodevelopment of longer or multiple anesthetic exposures across all gestational ages.