Postnatal Growth Delay Research Articles

A de novo mutation of ADAMTS8 in a patient with Wiedemann–Steiner syndrome

BackgroundWiedemann–Steiner syndrome (WDSTS) is a rare autosomal dominant disorder caused by mutations in the KMT2A gene and is usually characterized by hairy elbows, short stature, developmental delay, intellectual disability and obvious facial dysmorphism.Case presentationHere, we report a 5-year-old girl with clinical features similar to WDSTS, including postnatal growth delay, retarded intellectual development, and ocular hypertelorism. Through whole-exome sequencing (WES), a frameshift variant of KMT2A was found in the patient but not in her parents’ genomic DNA. By bioinformatics analysis, the KMT2A variant was demonstrated to be the top candidate pathogenic variant for the clinical phenotype consistent with WDSTS. Moreover, a duplication of exon 1 in ADAMTS8 (belonging to the zinc metalloproteinase family) was found in the genomic DNA of this patient, which may be responsible for the characteristics that are different from those of WDSTS, including early teething, rapid tooth replacement, and dysplastic enamel.ConclusionsFrom the above results, we propose that in our patient, the frameshift variant in KMT2A is the main reason for the WDSTS phenotype, and the unreported mutation in ADAMTS8 may be the candidate reason for other characteristics that are different from those of WDSTS. Therefore, this study not only provides a new KMT2A variant associated with WDSTS but is also a reminder that combined mutations may be present in a case with more characteristics than those seen in WDSTS.

Novel pyrroline-5-carboxylate reductase 2 (PYCR2) mutation in an Iranian patient with hypomyelinating leukodystrophy: findings of molecular and in silico investigations

BackgroundHypomyelinating leukodystrophy (HLD) is a specific group of leukodystrophies and is characterized by progressive postnatal growth delay that represents a type of clinically overlapping but genetically heterogeneous diseases with autosomal recessive inheritance. Loss-of-function mutations in PYCR2 are one of the main causes of HLD type 10 (HLD10), which is identified by cerebral hypomyelination, inadequate growth, brain atrophy, and movement abnormality. This study aimed to investigate the molecular etiology of HLD10 disorder in an Iranian patient from a consanguineous marriage family.ResultsThe DNA samples were extracted from the patient, a 9-year-old girl, and her parents. Whole-exome sequencing was conducted for these samples and the results were eventually confirmed and segregated via Sanger sequencing. Our findings demonstrated a novel homozygous frameshift mutation in PYCR2 gene, c.135dup (NM_013328.4). The heterozygous state of this variant was confirmed in parents. Additionally, this mutation was predicted to exhibit damaging effects through protein sequence alteration.ConclusionsSuch findings are of importance for understanding the underlying pathogenicity mechanisms and for improving genetic counseling knowledge of HLD patients for families.

Congenital syphilis in a preterm newborn with gastrointestinal disorders and postnatal growth restriction

BackgroundCongenital syphilis (CS) depends on the placental transmission of Treponema pallidum (TP) spirochetes from an infected mother to fetus during pregnancy. It shows a wide clinical variability with cutaneous and visceral manifestations, including stillbirths, neonatal death, and asymptomatic cases. Preterm infants with CS may have more severe features of disease than the term ones, due to the combined pathogenic effect of both CS and prematurity.Case presentationWe report on a female preterm (32+6 weeks of gestation) newborn showing most of the typical CS manifestations, in addition to gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth restriction. The mother resulted positive at the syphilis screening test of the first trimester of pregnancy, but she did not undergo any treatment. At birth, our newborn was VDRL positive (antibody titer four times higher compared to the mother), and she was treated with intravenous benzathine benzylpenicillin G for 10 days (50,000 IU/Kg three times per day). Poor tolerance to enteral nutrition (abdominal distension, increased biliary type gastric secretions) was observed. A barium enema X-Ray identified a colon stenosis within the descending tract. However, the poor general conditions due to a concurrent fungal sepsis did not allow to perform any surgical procedure, and a conservative approach with total parenteral nutrition was started. The following evolution was marked by difficulties in enteral feeding including refusal of food and vomiting, to which also contributed the neurological abnormalities related to a perinatal asphyxia, and the affective deprivation for the physical absence of the mother during hospitalization. At 5 months of age, after the introduction of an amino acid-based formula (Neocate LCP Nutricia ®), an improvement of enteral feeding was observed, with no further and significantly decreased episodes of abdominal distension and vomiting respectively, and regular stool emission. A psychological support offered to the family allowed a more stable bond between the mother and her baby, thus providing a significant additional benefit to food tolerance and growth. She was discharged at 5 months of age, and included in a multidisciplinary follow-up. She at present shows global growth delay, and normal development apart from mildly increased tone of lower limbs.ConclusionsOur report highlights less common clinical CS manifestations like gastrointestinal disorders including feeding difficulties, colon stenosis and malabsorption leading to postnatal growth delay. Moreover, it underlines how prematurity may worsen the clinical evolution of such congenital infection, due to the additional pathogenic effect of possible associated diseases and/or conditions like sepsis, hypoxic/ischemic injury, or use of drugs. CS may be observed also in high-income countries, with high rates of antenatal screening and availability of prenatal treatment. A multidisciplinary network must be guaranteed to the affected subjects, to ensure adequate care and improve the quality of life for patients and their families.

Clinical evaluation of rare copy number variations identified by chromosomal microarray in a Hungarian neurodevelopmental disorder patient cohort

BackgroundNeurodevelopmental disorders are genetically heterogeneous pediatric conditions. The first tier diagnostic method for uncovering copy number variations (CNVs), one of the most common genetic etiologies in affected individuals, is chromosomal microarray (CMA). However, this methodology is not yet a routine molecular cytogenetic test in many parts of the world, including Hungary. Here we report clinical and genetic data of the first, relatively large Hungarian cohort of patients whose genetic testing included CMA.MethodsClinical data were retrospectively collected for 78 children who were analyzed using various CMA platforms. Phenotypes of patients with disease-causing variants were compared to patients with negative results using the chi squared/Fisher exact tests.ResultsA total of 30 pathogenic CNVs were identified in 29 patients (37.2%). Postnatal growth delay (p = 0.05564), pectus excavatum (p = 0.07484), brain imaging abnormalities (p = 0.07848), global developmental delay (p = 0.08070) and macrocephaly (p = 0.08919) were more likely to be associated with disease-causing CNVs.ConclusionOur results allow phenotypic expansion of 14q11.2 microdeletions encompassing SUPT16H and CHD8 genes. Variants of unknown significance (n = 24) were found in 17 patients. We provide detailed phenotypic and genetic data of these individuals to facilitate future classification efforts, and spotlight two patients with potentially pathogenic alterations. Our results contribute to unraveling the diagnostic value of rare CNVs.

IDF21-0574 Type 1 Diabetes onset and COVID-19 infection in a child with Sanjad Sakati Syndrome: a case from Kuwait

Background: Sanjad Sakati Syndrome (SSS) is an autosomal recessive multisystem disorder characterized by congenital hypoparathyroidism, prenatal and postnatal growth and mental delay, dysmorphic features, and hypocalcemia seizures. It has not been linked with autoimmune disorders such as Type 1 Diabetes (T1D). Viral infections may play a role in triggering the development of T1D. Contracting SARS-CoV-2 virus may induce an autoimmune response by damaging the pancreatic β cells and accelerate the onset of T1D. To the best of our knowledge, no case studies of SSS has been reported to develop T1D were reported. Aim: To present a child with SSS who was newly diagnosed with T1D and SARS-CoV-2 infection (COVID-19). Method: Data on the patient were extracted from the Childhood Onset Diabetes electronic Registry (CODeR) in Kuwait. Results: The child was diagnosed early in life with SSS by tubulin-specific chaperone E (TBCE) gene mutation. The child is under multidisciplinary care and managed by alphacalcidol treatment. In May 2021, she presented with a history of fever, cough, polyuria, polydipsia, and poor appetite which lasted for 6 days. On investigations, random blood sugar level was 22 mmol/l and HbA1c level was 10%. There was no evidence of diabetic ketoacidosis. Autoantibodies to glutamic acid decarboxylase (GAD) and thyroperoxidase antibodies (TPO) were positive, with normal thyroid function results. Serum insulin and c-peptide levels were low (0.93 miu/ml, 28 pmol/l respectively). Thus, T1D diagnosis was made, and insulin therapy was started. No family history of diabetes was reported. On admission, the child tested positive for SARS-CoV-2 PCR and had positive contacts with family members with COVID-19 infection. As per WHO COVID-19 infection severity criteria, the child’s condition was classified as mild. She was discharged home with no short-term sequelae of COVID-19 infection; diabetes and dietary education was provided. Discussion: To the best of our knowledge, this is the first case reported in literature of a patient with SSS who presented with T1D onset along with COVID-19 infection. Viral infections such as SARS-CoV-2 virus may trigger the development of autoimmune diseases such as T1D. Exploring the relationship between COVID-19 infection and T1D onset is needed for better understand the effect of COVID-19 infection and outcome on pediatric patients with comorbidities. Further explorations are also needed to study the relationship of SSS and autoimmune disorders as well; to fully appreciate the impact on such patients.

Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome.

Warburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.We reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.

Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome.

Background and PurposeWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.MethodsWe applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.ResultsWe reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.ConclusionsWES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.

Jacobsen syndrome and neonatal bleeding: report on two unrelated patients

IntroductionIn 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified.Patients’ presentationWe report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations.ConclusionsPresent newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

Clinical and Nutritional Determinants of Extrauterine Growth Restriction Among Very Low Birth Weight Infants.

PurposeTo identify the clinical and nutritional factors associated with extrauterine growth restriction (EUGR) among very low birth weight infants (VLBW) in a tertiary hospital in Jordan.Patients and MethodsWe conducted a retrospective analysis of all VLBW infants admitted at King Abdullah University Hospital between July 2015 and June 2020. Clinical factors, nutritional intake, and growth parameters were collected and analyzed. A multilogistic regression model was applied to identify factors associated with EUGR.ResultsOf the 247 VLBW infants included in analysis, 112 (45%) were males, 30 (12%) were below 1000 g, and 72 (29%) were small for gestational age (SGA). EUGR was diagnosed in 198 (80%) at discharge. The rates of EUGR among SGA and non-SGA infants were 97% and 73%, respectively. The EUGR infants had a higher gestational age (30.7 vs 29.8 weeks, p=0.04), a lower birth weight (1209 vs 1300 g, p=0.005), a longer ventilatory support (5.7 vs 2.2 days, p=0.03), a higher incidence of sepsis (23% vs 10%, p=0.05), and a longer hospitalization (46 vs 38 days, p=0.03). With multilogistic regression model, the factors associated with EUGR include small-for-gestational age (AOR 9, 95% C.I. 2, 50), >3-day delay in feeding initiation (AOR 3.8, 95% C.I. 1.2,10), >14-day delay in achieving full feeds (AOR 3.3, 95% C.I. 1.2, 8), <3 g/kg of protein intake on the 8th day (AOR 2.1, 95% C.I. 1.1, 4.1), <100 kcal/kg of total caloric intake on the 15th day (AOR 3.8, 95% C.I. 1.6, 8.9), and occurrence of sepsis (AOR 3, 95% C.I. 1.1, 9).ConclusionThe rate of EUGR in our unit is high. In addition to being SGA at birth, sepsis and suboptimal protein and caloric intake in the first two weeks of life were significantly associated with this complication. A more aggressive enteral and parenteral nutritional approach is needed to minimize postnatal growth delay.

"Females Are Not Just 'Protected' Males": Sex-Specific Vulnerabilities in Placenta and Brain after Prenatal Immune Disruption.

Current perceptions of genetic and environmental vulnerabilities in the developing fetus are biased toward male outcomes. An argument is made that males are more vulnerable to gestational complications and neurodevelopmental disorders, the implication being that an understanding of disrupted development in males is sufficient to understand causal mechanisms that are assumed to be similar but attenuated in females. Here we examine this assumption in the context of immune-driven alterations in fetal brain development and related outcomes in female and male mice. Pregnant C57BL/6 mice were treated with low-dose lipopolysaccharide at embryonic day 12.5. Placental pathology, acute fetal brain inflammation and hypoxia, long-term changes in adult cortex cytoarchitecture, altered densities and ratio of excitatory (Satb2+) to inhibitory (parvalbumin+) neuronal subtypes, postnatal growth, and behavior outcomes were compared between male and female offspring. We find that while males experience more pronounced placental pathology, fetal brain hypoxia, depleted PV and Satb2+ densities, and social and learning-related behavioral abnormalities, females exhibit unique acute inflammatory signaling in fetal brain, postnatal growth delay, opposite alterations in cortical PV densities, changes in juvenile behavior, delayed postnatal body growth, and elevated anxiety-related behavior as adults. While males are more severely impacted by prenatal immune disruption by several measures, females exposed to the same insult exhibit a unique set of vulnerabilities and developmental consequences that is not present in males. Our results clearly outline disparate sex-specific features of prenatal vulnerability to inflammatory insults and warn against the casual extrapolation of male disease mechanisms to females.

SAT-285 Role of Chromosome Microarray in Identifying a Genetic Cause of Undervirilized External Genitalia and Growth Delay in an Infant: 6p Duplication Associated with Short Stature and Micropenis

THE CASE 4 mo M born at term 7lbs 7.5oz, 19.5 inches via C-section, referred for micropenis found during evaluation for circumcision. No history of hypoglycemia. Of note, dad is s/p hypospadias repair and is short at 5th %ile. PE showed short stature, length at 3rd %ile (-1.91 SDS), wt 53rd %ile, HC 76th %ile. Stretched penile length 1.5 cm (-2.5 SDS = 1.9cm), testes 1.5 cm each, normal. Periorbital hemangioma noted. Otherwise normal exam. Chromosome microarray showed a 6.1 Mb duplication of the terminal region of 6p, pathogenic; and a 222 kb deletion of terminal 17p (felt to have no clinical significance). Patient referred to Genetics. Parental testing showed balanced translocation in dad's chromosome 46,XY,t(6;17)(p25.1;p13.1)]. GH, TSH, FT4, LH, FSH, AMH levels normal. Total Testosterone 68 ng/dL. CAH-6 panel within expected limits. Testosterone therapy 50mg/mo x 3mos initiated to improve penile length. DISCUSSION Workup of underlying cause of male undervirilization is challenging. More often than not, a definitive diagnosis remains elusive. The current case underlines the invaluable contribution of chromosomal microarray in this endeavor. Duplication of distal fragment of chromosome 6p is extremely rare, with <50 cases reported thus far. There are several genes located in this region, and as expected, case reports thus far have a wide phenotypic variability. Common features include pre-/postnatal growth delay, developmental disability, congenital malformations of the heart, kidneys, eyes. However to our knowledge, this is the first report of a patient with 6p25pter with micropenis. Of note, a patient with 6p25pter + 22q11.2pter trisomies was reported to have penile chordee and cryptorchidism (Scarborough, et al, 1986). Patienit's dad has history of hypospadias as well, suggesting a correlation between this specific mutation and undervirilized male external genitalia. Review of 26 OMIM genes contained in the reported abnormal region showed scant known data about these genes. However, gene transcripts from 5 of these OMIM genes (DUSP22, FAM50B, HUS1B, FOXQ1, SERPINB9) were shown to be highly expressed in the testis +/- brain in humans/animals, suggesting a possible role that these genes play in male genital development. CONCLUSION A genetic cause of micropenis is often hard to establish. We report a case associated with a pathogenic duplication of the terminal region of 6p chromosome. To our knowledge, no such case has been previously reported. This rare chromosome abnormality does have other associated medical complications for which he needs to be monitored. The crucial role of chromosome microarray in picking up such abnormalities in workup of undevirilization is emphasized. More research is needed to elucidate the mechanism by which the affected genes influence male genital development.

Ring chromosome 15 \u2013 cytogenetics and mapping arrays: a case report and review of the literature

BackgroundRing chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and mental and motor problems among others. Only 97 clinical cases of ring chromosome 15 syndrome have been reported since 1966 and a common phenotype for these patients has not been established.Case presentationThe present case report describes a 15-month-old girl from the Amazon region of Ecuador, of Mestizo ancestry, who after cytogenetic tests showed a 46,XX,r(15) karyotype in more than 70% of metaphases observed. Her parents were healthy and non-related. The pregnancy was complicated and was positive for intrauterine growth retardation. Her birth weight was 1950 g, her length was 43.5 cm, and she had a head circumference of 29.3. In addition to postnatal growth delay, she had scant frontal hair, small eyes, hypertelorism, low-set of ears, flattened nasal bridge, anteverted nostrils, down-turned mouth, three café au lait spots, and delayed dentition.ConclusionsDespite the frequency of some phenotypes expressed in the different clinical cases reviewed and the present case, a common phenotype for patients with ring 15 could not be determined and it is restricted to the region of the chromosome lost during the ring formation.

The Postnatal Growth Delay in Preterm Infants and Survey of the Causative (Risk) Factors

Purpose: To analyze the factors which are associated with growth delay and malnutrition in preterm infants during first year of life. Conclusion: Evaluation data of monofactor analyze in group of low body weight (LBW) infants showed statistically significant correlation of growth delay (GD) with late gestosis of pregnancy (OR-3,56), IUGR in a newborn (OR-4,40), formula feeding (OR-9,69) and anemia of a newborn (OR5,73). To optimize health care in preterm infants it is necessary to consider the factors which correlate with GD and give the recommendations how to prevent or treat pathological and deficit conditions. Conclusion: Evaluation data of monofactor analyze in group of low body weight (LBW) infants showed statistically significant correlation of growth delay (GD) with late gestosis of pregnancy (OR-3,56), IUGR in a newborn (OR-4,40), formula feeding (OR-9,69) and anemia of a newborn (OR5,73). To optimize health care in preterm infants it is necessary to consider the factors which correlate with GD and give the recommendations how to prevent or treat pathological and deficit conditions.Purpose: To analyze the factors which are associated with growth delay and malnutrition in preterm infants during first year of life. Conclusion: Evaluation data of monofactor analyze in group of low body weight (LBW) infants showed statistically significant correlation of growth delay (GD) with late gestosis of pregnancy (OR-3,56), IUGR in a newborn (OR-4,40), formula feeding (OR-9,69) and anemia of a newborn (OR5,73). To optimize health care in preterm infants it is necessary to consider the factors which correlate with GD and give the recommendations how to prevent or treat pathological and deficit conditions.

The Postnatal Growth Delay in Preterm Infants and Survey of the Risk Factors

The aim was to analyze the factors that are associated with growth delay (GD) and malnutrition in preterm infants during the first year of life. The trial included 150 preterm children. The data of life history and anthropometry were studied. The trial showed statistically significant correlation of GD in preterm babies with intrauterine growth restriction, prolonged respiratory care and tube feeding, formula feeding, anemia of prematurity, and severe asphyxia at birth. To optimize health care in preterm infants, it is necessary to consider the factors that correlate with GD and give the recommendations how to prevent or treat pathological and deficit conditions.

Effects of Growth Hormone on Bone.

Describe the effects of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on the skeleton. The GH and IGF-1 axis has pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. GH deficiency leads to decreased bone turnover, delayed statural growth in children, low bone mass, and increased fracture risk in adults. GH replacement improves adult stature in GH deficient children, increases bone mineral density (BMD) in adults, and helps to optimize peak bone acquisition in patients, during the transition from adolescence to adulthood, who have persistent GH deficiency. Observational studies suggest that GH replacement may mitigate the excessive fracture risk associated with GH deficiency. Acromegaly, a state of GH and IGF-1 excess, is associated with increased bone turnover and decreased BMD in the lumbar spine observed in some studies, particularly in patients with hypogonadism. In addition, patients with acromegaly appear to be at an increased risk of morphometric-vertebral fractures, especially in the presence of active disease or concurrent hypogonadism. GH therapy also has beneficial effects on statural growth in several conditions characterized by GH insensitivity, including chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing (SHOX) gene mutations, and Noonan syndrome. GH and IGF-1 have important roles in skeletal physiology, and GH has an important therapeutic role in both GH deficiency and insensitivity states.

Wolf–Hirschhorn Syndrome and Epilepsy: An Overview

The Wolf–Hirschhorn syndrome (WHS, OMIM194190) is a contiguous gene deletion syndrome of the distal part of the short arm of chromosome 4 (4p16 region) characterized by a distinctive facial appearance, intrauterine and postnatal growth delay, intellectual disability, and seizures. The WHS clinical spectrum is complex and variable. Typically, more than 90% of WHS-related patients begin seizures in the first 3 years of life. In these cases, most of the epilepsy is well controlled, and over half of the patients stopped having seizures after adolescence. Etiology and/or genetics of their seizures were unclear. The clinical data on the association between epilepsy and chromosomal abnormalities is likely to improve our understanding of the functions and mechanisms of genes related to epilepsy. Future studies would be needed for a deeper understanding of WHS.

Trisomy 1q41-qter and monosomy 3p26.3-pter in a family with a translocation (1;3): further delineation of the syndromes.

BackgroundTrisomy 1q and monosomy 3p deriving from a t(1;3) is an infrequent event. The clinical characteristics of trisomy 1q41-qter have been described but there is not a delineation of the syndrome. The 3p25.3-pter monosomy syndrome (MIM 613792) characteristics include low birth weight, microcephaly, psychomotor and growth retardation and abnormal facies.Case presentationA 2 years 8 months Mexican mestizo male patient was evaluated due to a trisomy 1q and monosomy 3p derived from a familial t(1;3)(q41;q26.3). Four female carriers of the balanced translocation and one relative that may have been similarly affected as the proband were identified. The implicated chromosomal regions were defined by microarray analysis, the patient had a trisomy 1q41-qter of 30.3 Mb in extension comprising about 240 protein coding genes and a monosomy 3p26.3-pter of 1.7 Mb including only the genes CNTN6 (MIM 607220) and CHL1 (MIM 607416), which have been implicated in dendrite development. Their contribution to the phenotype, regarding the definition of trisomy 1q41-qter and monosomy 3p26.3-pter syndromes are discussed.ConclusionWe propose that a trisomy 1q41-qter syndrome should be considered in particular when the following characteristics are present: postnatal growth delay, macrocephaly, wide fontanelle, triangular facies, frontal bossing, thick eye brows, down slanting palpebral fissures, hypertelorism, flat nasal bridge, hypoplasic nostrils, long filtrum, high palate, microretrognathia, ear abnormalities, neural abnormalities (in particular ventricular dilatation), psychomotor developmental delay and mental retardation. Our patient showed most of these clinical characteristics with exception of macrocephaly, possibly due to a compensatory effect by haploinsufficiency of the two genes lost from 3p. The identification of carriers has important implications for genetic counseling as the risk of a new born with either a der(3) or der(1) resulting from an adjacent-1 segregation is of 25% for each of them, as the products of adjacent-2 or 3:1 segregations are not expected to be viable.

Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.

Respiratory failure, cleft palate and epilepsy in the mouse model of human Xq22.1 deletion syndrome

Chromosomal segmental deletion is a frequent cause of human diseases. A familial 1.1 Mb deletion of human chromosome Xq22.1 associates with epilepsy, cleft palate and developmental defects in heterozygous female patients. Here, we describe a mouse mutant with a targeted deletion of the syntenic segment of the mouse X chromosome that phenocopies the human syndrome. Male mice with a deletion of a 1.1 Mb Nxf2-Nxf3 X-chromosomal segment exhibit respiratory failure, neonatal lethality and cleft palate. In female mice, heterozygosity for the deletion manifests cleft palate, early postnatal lethality, postnatal growth delay and spontaneous seizures in surviving animals, apparently due to X-chromosome inactivation. Furthermore, loss of a 0.35 Mb subregion containing Armcx5, Gprasp1, Gprasp2 and Bhlhb9 is sufficient to cause the Xq22.1 syndrome phenotype. Our results support that the 1.1 Mb deletion of human Xq22.1 is the genetic cause of the associated syndrome.