Brain Growth Retardation Research Articles

Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.

Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.

Microglia-Derived Insulin-like Growth Factor 1 Is Critical for Neurodevelopment.

Insulin-like growth factor 1 (IGF-1) is a peptide hormone essential for the proper development and growth of the organism, as a complete knockout of Igf1 in mice is lethal, causing microcephaly, growth retardation and the defective development of organs. In the central nervous system, neurons and glia have been reported to express Igf1, but their relative importance for postnatal development has not yet been fully defined. In order to address this, here, we obtained mice with a microglia-specific inducible conditional knockout of Igf1. We show that the deficiency in microglial Igf1, starting in the first postnatal week, leads to body and brain growth retardation, severely impaired myelination, changes in microglia numbers, and behavioral abnormalities. These results emphasize the importance of microglial-derived Igf1 for brain development and function and open new perspectives for the investigation of the role of microglial-Igf1 in neurological diseases.

A Case Report of Solitary Median Maxillary Central Incisor Reported in Tehsil Headquarter Hospital, Gujjar Khan, Pakistan

Solitary median maxillary central incisor is a rare dental anomaly and a complex disorder consisting of multiple mainly midline defects of development. In SMMCI, only one central incisor is present, and it develops exactly at the midline. It results from unknown factors(s) operating in utero. Early diagnosis and recognition of SMMCI are important for all practicing dentists, as it may be a sign of other severe congenital or developmental abnormalities. This case report discusses important aspects of SMMCI and presents a clinical case of a 2-year-old female patient of single median maxillary central incisor with missing maxillary and mandibular frena, along with brain growth retardation in Tehsil Headquarter Hospital, Gujjar Khan, Pakistan. Aligned with the literature early diagnosis and correction of SMMCI is of prime importance as the condition is associated with developmental problems. Moreover, the case should be managed by a multidisciplinary team of health professionals to ensure optimum health-related outcomes. Keywords: Solitary, median, maxillary, central incisor, case report

Salt Iodization and Urinary Iodine Concentration Levels among Primary School Children in Mt. Elgon Sub-County, Kenya

Aims: Iodine plays a key role in thyroid hormone production and functioning. Inadequate iodine intake results in iodine deficiency (ID) which impairs the normal functioning of the thyroid. The deficiency is responsible for damage to brain development, growth retardation, cretinism, and thyroid dysfunction. Millions of people have been condemned to a life of few prospects and continued underdevelopment due to ID. The study was conducted to assess iodine status among primary school children in the Mt. Elgon region and the impact of salt iodization on this status.
 Study Design: A school-based cross-sectional descriptive study to assess iodine status among primary school children was employed in the study.
 Study Area and Duration: The study was carried out in Kenya, Bungoma County, Mount Elgon Sub-County. The study period was between 27th November 2018 and 26th November 2019.
 Methodology: Healthy primary school children aged 6 to 12 years who met the inclusion criteria were included in the study. Spot urine samples were collected in schools, while water samples were collected from different water sources. Salt was collected from households (HH) and at distribution outlets. The Sandell Kolthoff reaction was used to analyse urine and water samples while salt was analysed using iodometric titration.
 Results: The median urinary iodine concentration (UIC) was 200.7 µg/l. Out of which 0.55% were severely deficient, 5.25% moderately deficient, 18.23% with a mild deficiency, 25.69% had adequate iodine levels, 22.38% had more than adequate, and 27.90% had excess iodine levels. Household and salt samples from different distribution outlets that conformed to set standards of iodization were 49.4% and 63.64%, respectively. Iodine was not detected in all the water samples collected.
 Conclusion: The study population was found to have adequate iodine based on the median UIC of 200.7 µg/l. However, there was a coexistence of both deficiency and excessive UIC and salt iodization within the population. No iodine was detected in the water samples in the region.

Ionizing radiation reduces larval brain size by inducing premature differentiation of Drosophila neural stem cells

DNA damaging agents, such as ionizing radiation (IR), induce cell cycle arrest, senescence, differentiation, or cell death of stem cells, which may affect tissue homeostasis. The specific response of stem cells upon irradiation seems to vary depending on the cell type and their developmental stages. Drosophila larval brain contains neural stem cells called neuroblasts (NBs) and maintaining an appropriate number of NBs is critical to maintain brain size. Irradiation of larvae at early larval stage results in microcephaly, whereas the DNA damage response of NBs that could explain this small brain size is not clearly understood. We observed that the irradiation of larvae in the second instar retarded brain growth, accompanied by fewer NBs. The IR-induced microcephaly does not seem to result from apoptosis since the irradiated larval brain was not stained with activated Caspase nor was the microcephaly affected by the ectopic expression of the apoptosis inhibitor. When analyzed for the percentage of mitotic cells, irradiated NBs recovered their proliferative potential within 6 h post-irradiation after transient cell cycle arrest. However, IR eventually reduced the proliferation of NBs at later time points and induced the premature differentiation of NBs. In summary, IR-induced microcephaly occurs by NB loss due to premature differentiation, rather than apoptotic cell death.

PREDIKTOR DETERMINAN BERAT BADAN LAHIR BAYI DI WILAYAH KERJA PUSKESMAS LINGKAR TIMUR KOTA BENGKULU TAHUN 2011

Nutrition for pregnant women is very influential on the fetus. Poor maternal nutritional status before conception and during pregnancy will lead to low birth weight infants (LBW), fetal brain growth retardation, anemia on fetus, susceptible to infectious diseases and abortion. The aim is to determine determinant predictor of infant birth weight in Puskesmas Lingkar Timur Area Bengkulu City 2011. This study used cross sectional by analytic approach. The sample were 88 people. Data obtained in Puskesmas Lingkar Timur Area Bengkulu City from January to February 2011. Data research used secondary data which consisted of weight gain of pregnant women TM2, TM3, MUAC, Hb, iron (Fe), infant birth weight that obtained from the register book KIA BPS in Puskesmas Lingkar Timur Area Bengkulu City. Significant value of MUAC 0.0005 (p <0.05) and significant value of Hb 0.0005 (p <0.05). This study shows that MUAC and Hb are determinant predictor of weight infants. Therefore it is necessary for the promotion of research results that can be followed by monitoring nutrient intake and nutritional status in pregnant women.

Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.

Psychiatric disorders are associated with aberrant brain development and/or aggressive behavior and are influenced by genetic factors; however, genes that affect brain aggression circuits remain elusive. Here, we show that neuronal Src-homology-2 (SH2)B adaptor protein-1 ( Sh2b1) is indispensable for both brain growth and protection against aggression. Global and brain-specific deletion of Sh2b1 decreased brain weight and increased aggressive behavior. Global and brain-specific Sh2b1 knockout (KO) mice exhibited fatal, intermale aggression. In a resident-intruder paradigm, latency to attack was markedly reduced, whereas the number and the duration of attacks was significantly increased in global and brain-specific Sh2b1 KO mice compared with wild-type littermates. Consistently, core aggression circuits were activated to a higher level in global and brain-specific Sh2b1 KO males, based on c-fos immunoreactivity in the amygdala and periaqueductal gray. Brain-specific restoration of Sh2b1 normalized brain size and reversed pathologic aggression and aberrant activation of core aggression circuits in Sh2b1 KO males. SH2B1 mutations in humans were linked to aberrant brain development and behavior. At the molecular level, Sh2b1 enhanced neurotrophin-stimulated neuronal differentiation and protected against oxidative stress-induced neuronal death. Our data suggest that neuronal Sh2b1 promotes brain development and the integrity of core aggression circuits, likely through enhancing neurotrophin signaling.-Jiang, L., Su, H., Keogh, J. M., Chen, Z., Henning, E., Wilkinson, P., Goodyer, I., Farooqi, I. S., Rui, L. Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression.

Disruption of YWHAE gene at 17p13.3 causes learning disabilities and brain abnormalities.

There is a broad phenotypic spectrum of patients with 17p13.3 deletions. One of the most prominent feature is lissencephaly caused by haploinsufficiency of the gene PAFAH1B1. The deletion of this gene and those distal to it, results in Miller-Dieker syndrome, however there have been many reports of patients with haploinsufficiency of the distal genes alone. The deletions of these genes including YWHAE CRK and TUSC5 have been studied extensively and YWHAE has been postulated to be the cause of neurological abnormalities. The patients with deletions of the Miller-Dieker syndrome distal region present with variable clinical features including brain abnormalities, growth retardation, developmental delay, facial dysmorphisms and seizures. While there have been many patients reported to have deletions involving the YWHAE gene along with other genes, here we present the first detailed clinical description of a patient with deletion of YWHAE alone, allowing a more accurate characterization of the pathogenicity of YWHAE haploinsufficiency. The patient reported here demonstrated brain abnormalities, learning disabilities, and seizures supporting the role of YWHAE in these features. We review the literature and use this case report to better characterize and further confirm the genotype-phenotype relationship of the genes within the critical region of Miller-Dieker Syndrome.

Signalling through the Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Interacts with Canonical Wnt Signalling to Promote Neural Proliferation in Developing Brain

Signalling through the IGF1R [type 1 IGF (insulin-like growth factor) receptor] and canonical Wnt signalling are two signalling pathways that play critical roles in regulating neural cell generation and growth. To determine whether the signalling through the IGF1R can interact with the canonical Wnt signalling pathway in neural cells in vivo, we studied mutant mice with altered IGF signalling. We found that in mice with blunted IGF1R expression specifically in nestin-expressing neural cells (IGF1RNestin−KO mice) the abundance of neural β-catenin was significantly reduced. Blunting IGF1R expression also markedly decreased: (i) the activity of a LacZ (β-galactosidase) reporter transgene that responds to Wnt nuclear signalling (LacZTCF reporter transgene) and (ii) the number of proliferating neural precursors. In contrast, overexpressing IGF-I (insulin-like growth factor I) in brain markedly increased the activity of the LacZTCF reporter transgene. Consistently, IGF-I treatment also markedly increased the activity of the LacZTCF reporter transgene in embryonic neuron cultures that are derived from LacZTCF Tg (transgenic) mice. Importantly, increasing the abundance of β-catenin in IGF1RNestin−KO embryonic brains by suppressing the activity of GSK3β (glycogen synthase kinase-3β) significantly alleviated the phenotypic changes induced by IGF1R deficiency. These phenotypic changes includes: (i) retarded brain growth, (ii) reduced precursor proliferation and (iii) decreased neuronal number. Our current data, consistent with our previous study of cultured oligodendrocytes, strongly support the concept that IGF signalling interacts with canonical Wnt signalling in the developing brain to promote neural proliferation. The interaction of IGF and canonical Wnt signalling plays an important role in normal brain development by promoting neural precursor proliferation.

Neurodevelopmental features in 2q23.1 microdeletion syndrome: Report of a new patient with intractable seizures and review of literature

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5-year-old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1 Mb at 2q23.1-q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200 kb to 5.5 Mb, comprising 1-15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently-delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR).

No effect of sustained systemic growth retardation on the distribution of Reelin-expressing interneurons in the neuron-producing hippocampal dentate gyrus in rats

Reelin signaling plays a role in neuronal migration and positioning during brain development. To clarify the effect of systemic growth retardation on the distribution of Reelin-expressing interneurons in the hilus of the hippocampal dentate gyrus, pregnant rats were fed a synthetic diet with either a normal (20% casein) or low (10% casein) protein concentration from gestational day 10 to postnatal day (PND) 21 at weaning. Male offspring were immunohistochemically examined at PND 21 and on PND 77. Protein-restricted offspring displayed systemic growth retardation through PND 77 and had decreased absolute brain weights and an increased number of external granular cells in the cerebellar cortex, suggestive of retarded brain growth at weaning. However, maternal protein restriction did not change the cellular distribution of immunoreactivity for Reelin, Calbindin-D-28K, or glutamic acid decarboxylase 67 or of NeuN-positive postmitotic neurons in the dentate hilus either at PND 21 or PND 77, which suggests that the population of γ-aminobutyric acid-ergic interneurons involving synthesis of Reelin was not affected. Furthermore, as well as the distribution of hilar neurons expressing neurogenesis-related FoxG1, cell proliferation and apoptosis in the subgranular zone were unaffected through PND 77. These results suggest that systemic growth retardation caused by maternal protein restriction does not affect neuronal migration and postnatal neurogenesis of the dentate gyrus resulting in unaltered distribution of Reelin-synthesizing interneurons.

Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury*

To investigate whether inhibition of cyclooxygenase-2, a critical component of the inflammatory pathway, is neuroprotective in a neonatal rat model of cerebral hypoxia-ischemia. The development of brain inflammation largely contributes to neonatal brain injury that may lead to a lifetime of neurologic deficits. Laboratory investigation. University research laboratory. Postnatal day ten Sprague-Dawley rats. Neonatal hypoxia-ischemia was induced by ligation of the right common carotid artery followed by 2 hrs of hypoxia (8% oxygen). The pups in treatment groups were administered 10 mg/kg (low dose) or 30 mg/kg (high dose) of a known selective cyclooxygenase-2 inhibitor (NS398). Animals were euthanized at three time points: 72 hrs, 2 wks, or 6 wks. Inflammation outcomes were assessed at 72 hrs; brain damage was assessed at 2 wks and 6 wks along with other organs (heart, spleen). Detailed neurobehavioral examination was performed at 6 wks. Pharmacologic inhibition of cyclooxygenase-2 markedly increased survivability within the first 72 hrs compared with untreated rats (100% vs. 72%). Low- and high-dose NS398 significantly attenuated the loss of brain and body weights observed after hypoxia-ischemia. Neurobehavioral outcomes were significantly improved in some parameters with low-dose treatment, whereas high-dose treatment consistently improved all neurologic deficits. Immunohistochemical results showed a marked decrease in macrophage, microglial, and neutrophil abundance in ipsilateral hemisphere of the NS398-treated group along with a reduction in interleukin-6 expression. Selective cyclooxygenase-2 inhibition protected neonatal rats against death, progression of brain injury, growth retardation, and neurobehavioral deficits after a hypoxic-ischemic insult.

Type 1 insulin‐like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus

Type 1 insulin-like growth factor receptor (IGF1R) signaling in neuronal development was studied in mutant mice with blunted igf1r gene expression in nestin-expressing neuronal precursors. At birth [postnatal (P) day 0] brain weights were reduced to 37% and 56% of controls in mice homozygous (nes-igf1r(-/-)) and heterozygous (nes-igf1r(-/Wt)) for the null mutation, respectively, and this brain growth retardation persisted postnatally. Stereological analysis demonstrated that the volumes of the hippocampal formation, CA fields 1-3, dentate gyrus (DG), and DG granule cell layer (GCL) were decreased by 44-54% at P0 and further by 65-69% at P90 in nes-igf1r(-/Wt) mice. In nes-igf1r(-/-) mice, volumes were 29-31% of controls at P0 and, in the two mice that survived to P90, 6-19% of controls, although the hilus could not be identified. Neuron density did not differ among the mice at any age studied; therefore, decreased volumes were due to reduced cell number. In postnatal nes-igf1r(-/Wt) mice, the percentage of apoptotic cells, as judged by activated caspase-3 immunostaining, was increased by 3.5-5.3-fold. The total number of proliferating DG progenitors (labeled by BrdU incorporation and Ki67 staining) was reduced by approximately 50%, but the percentage of these cells was similar to the percentages in littermate controls. These findings suggest that 1) the postnatal reduction in DG size is due predominantly to cell death, pointing to the importance of the IGF1R in regulating postnatal apoptosis, 2) surviving DG progenitors remain capable of proliferation despite reduced IGF1R expression, and 3) IGF1R signaling is necessary for normal embryonic brain development.

Expanding the Mind: Insulin-Like Growth Factor I and Brain Development

Signaling through the type 1 IGF receptor (IGF1R) after interaction with IGF-I is crucial to the normal brain development. Manipulations of the mouse genome leading to changes in the expression of IGF-I or IGF1R significantly alters brain growth, such that IGF-I overexpression leads to brain overgrowth, whereas null mutations in either IGF-I or the IGF1R result in brain growth retardation. IGF-I signaling stimulates the proliferation, survival, and differentiation of each of the major neural lineages, neurons, oligodendrocytes, and astrocytes, as well as possibly influencing neural stem cells. During embryonic life, IGF-I stimulates neuron progenitor proliferation, whereas later it promotes neuron survival, neuritic outgrowth, and synaptogenesis. IGF-I also stimulates oligodendrocyte progenitor proliferation although inhibiting apoptosis in oligodendrocyte lineage cells and stimulating myelin production. These pleiotropic IGF-I activities indicate that other factors provide instructive signals for specific cellular events and that IGF-I acts to facilitate them. Studies of the few humans with IGF-I and/or IGF1R gene mutations indicate that IGF-I serves a similar role in man.

Peptidergic Agonists of Activity‐Dependent Neurotrophic Factor Protect Against Prenatal Alcohol‐Induced Neural Tube Defects and Serotonin Neuron Loss

Prenatal alcohol exposure via maternal liquid diet consumption by C57BL/6 (B6) mice causes conspicuous midline neural tube deficit (dysraphia) and disruption of genesis and development of serotonin (5-HT) neurons in the raphe nuclei, together with brain growth retardation. The current study tested the hypothesis that concurrent treatment with either an activity-dependent neurotrophic factor (ADNF) agonist peptide [SALLRSIPA, (SAL)] or an activity-dependent neurotrophic protein (ADNP) agonist peptide [NAPVSIPQ, (NAP)] would protect against these alcohol-induced deficits in brain development. Timed-pregnant B6 dams consumed alcohol from embryonic day 7 (E7, before the onset of neurulation) until E15. Fetuses were obtained on E15 and brain sections processed for 5-HT immunocytochemistry, for evaluation of morphologic development of the brainstem raphe and its 5-HT neurons. Additional groups were treated either with SAL or NAP daily from E7 to E15 to assess the potential protective effects of these peptides. Measures of incomplete occlusion of the ventral canal and the frequency and extent of the openings in the rhombencephalon were obtained to assess fetal dysraphia. Counts of 5-HT-immunostained neurons were also obtained in the rostral and caudal raphe. Prenatal alcohol exposure resulted in abnormal openings along the midline and delayed closure of ventral canal in the brainstem. This dysraphia was associated with reductions in the number of 5-HT neurons both in the rostral raphe nuclei (that gives rise to ascending 5-HT projections) and in the caudal raphe (that gives rise to the descending 5-HT projections). Concurrent treatment of the alcohol-consuming dams with SAL prevented dysraphia and protected against the alcohol-induced reductions in 5-HT neurons in both the rostral and caudal raphe. NAP was less effective in protecting against dysraphia and did not protect against 5-HT loss in the rostral raphe, but did protect against loss in the caudal raphe. These findings further support the potential usefulness of these peptides for therapeutic interventions in pregnancies at risk for alcohol-induced developmental deficits. Notably, the ascending 5-HT projections of the rostral raphe have profound effects in regulating forebrain development and function, and the descending 5-HT projections of the caudal raphe are critical for regulating respiration. Protection of the rostral 5-HT-system may help prevent structural and functional deficits linked to abnormal forebrain development, and protection of the caudal systems may also reduce the increased risk for sudden infant death syndrome associated with prenatal alcohol exposure.

Light and Electron Microscope Studies of Effects of 50 Hz Electromagnetic Fields on Preincubated Chick Embryo

We investigated the effects of an electromagnetic field (EMF) of 50 Hz, 1.33–7.32 mT on sections of preincubated white leghorn chicken embryos using light, SEM and TEM microscopes. Five hundred healthy, fresh, and fertilized eggs (55–65 g) were divided into three groups of experimental (n = 18–20), control (n = 60), and sham (n = 50). Experimental eggs (inside the coil) were exposed to 15 different intensities (1.33–7.32 mT) for morphological surveys and to the known most effective intensities for light, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) studies. Sham groups were located inside the same coil with no exposure for 24 h before incubation. Control, sham, and experimental groups were then incubated in an incubator (38 ± 0.5°C, 60% humidity) for 4 days. At the end of this period, embryos were removed from their shells, prepared for morphometric, light, and SEM/TEM studies. Results of light microscopic studies (serial sections, 6μ) and morphometric data showed significant differences between different groups (P < 0.005). Larger and abnormal brain cavities, spina bifida, monophthalmia, microphthalmia, anophthalmia, and growth retardation were shown on SEM. TEM sections demonstrated that the nucleus was condensed, the nuclear envelope disappeared, and mitochondria degenerated. Golgi apparatus and endoplasmic reticulum were the least affected organelles. The Telencephlon was the most affected region, and the retina was altered more than the lens. We conclude that EMFs affect the brain, especially the Telencephalon and eye of preincubated-exposed chick embryo at the morphological and cellular level, nuclei are the most affected part, and our data agrees with “Ubeda's windows effects” of EMFs on preincubated chick embryos.

Distribution and prevalence of leukocyte phenotypes in brains of lupus-prone mice

Autoantibody-mediated compromise of central neurotransmission is a pathogenic mechanism proposed in etiology of neuropsychiatric lupus (NP-SLE). Recent experimental data support the hypothesis that intrathecally-synthesized antibodies play a key role in brain damage and behavioral dysfunction. However, autoantibody-producing plasma cells have not yet been detected in brain tissue. We presently use contemporary immunohistochemical markers and flow cytometry to assess distribution and prevalence of plasma cells and other phenotypes, which infiltrate brains of lupus-prone MRL-lpr mice. The functional status of infiltrates was confirmed by in situ hybridization for TNF-alpha mRNA. Consistent with the notion of breached blood–CSF and blood–brain barriers, CD3+ T-cells (∼ 20% of the mononuclear cell infiltrate) were plentiful in choroid plexuses and commonly seen around blood vessels. The CD138+ plasma cells were restricted to the choroid plexus and stria medullaris of diseased MRL-lpr mice. Although accounting for less than 1% of the total cell infiltrate, CD19+IgM+ B-cells increased with age in brains of MRL-lpr mice. Severe mononuclear cell infiltration was accompanied by splenomegaly and retarded brain growth. The results obtained support the hypothesis of progressive neurodegeneration as a consequence of leukocyte infiltration and intrathecal autoantibody synthesis. Further characterization of neuroactive antibodies and their targets may contribute to a better understanding of brain atrophy and behavioral dysfunction in the MRL model, and potentially in NP-SLE.

A rare cause of benign ventriculomegaly with associated syringomyelia: BRESEK/BRESHECK syndrome

We report our experience in the management of an 18-month-old boy, who presented to our institution with failure to thrive and seizures. The infant had a history of congenital ichthyosis, Hirschsprung disease, coarctation of the aorta, and an atrial septal defect. He had alopecia of the scalp, eyebrows, and eyelashes, bilateral microphthalmia, micrognathia, and large low-set ears (Fig. 1). His vision and hearing were grossly normal as were muscle tone and strength throughout the extremities, although his deep tendon reflexes were diminished. His left upper extremity was shortened with a well-formed thumb and only two digits. Height, weight and head circumference measurements were significantly below the 5th percentile. Cytogenetic testing revealed a normal karyotype, 46, XY; fluorescence in situ hybridization revealed no chromosomal abnormality. Magnetic resonance (MR) imaging of the brain showed a prominent ventricular system without evidence of transependymal flow or aqueductal stenosis (Fig. 2). The massa intermedia was prominent, suggestive of fusion. The optic nerves, chiasm, and tracts were all hypoplastic. A cord-expanding intramedullary collection of cerebrospinal fluid (CSF) was present from the inferior aspect of C-6 to T-2 (Fig. 2C). There was no evidence of cerebellar ectopia. In 1997, Reish and colleagues1 described the possibility of a new Xlinked syndrome, BRESEK/BRESHECK, named after the acronym that reflects the findings: brain anomalies, retardation of mentality and growth, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear deformity and deafness, eye hypoplasia, cleft palate, cryptorchidism, and kidney dysplasia/hypoplasia. Our patient exhibited brain anomalies, mental and growth retardation, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, and eye hypoplasia similar to the findings described by Reish, et al. The presence of an intramedullary CSF collection appears to be yet another manifestation of this syndrome, without apparent clinical significance in early childhood.

Postnatal Head Growth Deficit Among Premature Infants Parallels Retinopathy of Prematurity and Insulin-like Growth Factor-1 Deficit

We hypothesized that in premature infants, retinal vascular growth retardation between birth and postmenstrual age of approximately 30 to 32 weeks that initiates retinopathy of prematurity is paralleled by brain growth retardation. In a prospective longitudinal study, we measured postnatal head growth, retinopathy of prematurity stage, protein and energy intake, severity of illness and serum insulin-like growth factor-1 levels in 58 preterm infants (mean gestational age at birth: 27.6 weeks) from birth until postmenstrual age of approximately 40 weeks. Premature infant head growth decelerates dramatically after birth until postmenstrual age of approximately 30 weeks. Head growth retardation coincides with retinal vascular growth suppression. Accelerated growth follows between post menstrual ages of approximately 30 to 32 weeks and approximately 40 weeks. The degree of head growth retardation up to postmenstrual age of 31 weeks corresponds to the degree of retinopathy of prematurity and to the degree of suppression of serum levels of insulin-like growth factor-1. At postmenstrual age of 31 weeks, if a child's head circumference SD is below -2.5, then the probability of also developing at least stage 3 retinopathy of prematurity increases fivefold compared with head circumference above -2.5 SD (32% vs 6%) suggesting parallel processes in brain and retina. Serum insulin-like growth factor-1 levels correlate positively with head circumference SD score and with the degree of retinopathy of prematurity. The correlation between head and retinal growth is consistent with insulin growth factor-1 being one of the postnatal growth factors involved in this multifactorial process and also suggests that factors that contribute to retinopathy of prematurity during this critical period may also affect neurological dysfunction. Additional studies are required to establish this connection.

Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis

All Down syndrome (DS) children have different degrees of developmental disabilities, developmental delay, and developmental brain abnormalities associated with CNS maturation delay and cortical dysgenesis. We have examined 780 occipitofrontal circumferences (OFC), mean and +/- SD, of DS children from birth to age 5 years. Also, gross and microscopic neuropathological studies in the same age group were performed, with special attention to brain weight (BW), shape, myelin formation, cortical organization of 101 DS and 80 non-DS individuals; ultrastructural studies were also performed on selective cases (five DS and five non-DS). The OFC was plotted on Nellhause curves and showed microcranium after mid-infancy in most cases. Twenty percent of DS children had an OFC in the lower normal range. The brain shape in DS newborn infants was the same as in non-DS infants, but after 3-5 months of age in DS infants the antero-posterior diameter was found to be shorter than in non-DS infants. Narrowness of the superior temporal gyrus was noted in 34 of 101 (33%) of DS brains. Microscopic examination showed myelination delay in 22.5% DS and only in 6.8% non-DS children. Morphometric studies in DS cases from birth showed fewer neurons (20-50% less), lower neuronal densities, and neuronal distribution, especially of cortical layers II and IV. Ultrastructurally in DS, the synaptic density, synaptic length, and contact zones were found to be abnormal. The retardation of brain growth, maturation delay, and cortical dysgenesis present in DS children most likely are regulated by the extra chromosome 21, but the gene responsible for the abnormalities remains to be determined.