[Genetic and prenatal diagnosis of a pregnant women with mental retardation].

OBJECTIVE: To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies. METHODS: G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus. RESULTS: The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week. CONCLUSION: Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype.

Carboxyl ester lipase is highly conserved in utilizing maternal supplied lipids during early development of zebrafish and human.

Carboxyl ester lipase (Cel), is a lipolytic enzyme secreted by the pancreas, which hydrolyzes various species of lipids in the gut. Cel is also secreted by mammary gland during lactation and exists in breast milk. It facilitates dietary fat digestion and absorption, thus contributing to normal infant development. This study aimed to examine whether the Cel in zebrafish embryos has a similar role of maternal lipid utilization as in human infants, and how Cel contributes to the utilization of yolk lipids in zebrafish. The cel1 and cel2 genes were expressed ubiquitously in the blastodisc and yolk syncytial layer before 24 hpf, and in the exocrine pancreas after 72 hpf. The cel1 and cel2 morphants exhibited developmental retardation and yolk sac retention. The total cholesterol, cholesterol ester, free cholesterol, and triglyceride were reduced in the morphants' body while accumulated in the yolk (except triglyceride). The FFA content of whole embryos was much lower in morphants than in standard controls. Moreover, the delayed development in cel (cel1/cel2) double morphants was partially rescued by FFA and cholesterol supplementation. Delayed and weakened cholesterol ester transport to the brain and eyes was observed in cel morphants. Correspondingly, shrunken midbrain tectum, microphthalmia, pigmentation-delayed eyes as well as down-regulated Shh target genes were observed in the CNS of double morphants. Interestingly, cholesterol injections reversed these CNS alterations. Our findings suggested that cel genes participate in the lipid releasing from yolk sac to developing body, thereby contributing to the normal growth rate and CNS development in zebrafish.

Genetic considerations in the prenatal diagnosis of overgrowth syndromes.

Large (>90%) for gestational age (LGA) fetuses are usually identified incidentally. Detection of the LGA fetus should first prompt the provider to rule out incorrect dates and maternal diabetes. Once this is done, consideration should be given to certain overgrowth syndromes, especially if anomalies are present. The overgrowth syndromes have significant clinical and molecular overlap, and are associated with developmental delay, tumors, and other anomalies. Although genetic causes of overgrowth are considered postnatally, they are infrequently diagnosed prenatally. Here, we review prenatal sonographic findings in fetal overgrowth syndromes, including Pallister-Killian, Beckwith-Wiedemann, Sotos, Perlman, and Simpson-Golabi-Behmel. We also discuss prenatal diagnosis options and recurrence risks.

Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1).

Preadipocyte factor-1 (Pref-1) is a transmembrane protein highly expressed in preadipocytes. Pref-1 expression is, however, completely abolished in adipocytes. The extracellular domain of Pref-1 undergoes two proteolytic cleavage events that generate 50 and 25 kDa soluble products. To understand the function of Pref-1, we generated transgenic mice that express the full ectodomain corresponding to the large cleavage product of Pref-1 fused to human immunoglobulin-gamma constant region. Mice expressing the Pref-1/hFc transgene in adipose tissue, driven by the adipocyte fatty acid-binding protein (aP2, also known as aFABP) promoter, showed a substantial decrease in total fat pad weight. Moreover, adipose tissue from transgenic mice showed reduced expression of adipocyte markers and adipocyte-secreted factors, including leptin and adiponectin, whereas the preadipocyte marker Pref-1 was increased. Pref-1 transgenic mice with a substantial, but not complete, loss of adipose tissue exhibited hypertriglyceridemia, impaired glucose tolerance, and decreased insulin sensitivity. Mice expressing the Pref-1/hFc transgene exclusively in liver under the control of the albumin promoter also showed a decrease in adipose mass and adipocyte marker expression, suggesting an endocrine mode of action of Pref-1. These findings demonstrate the inhibition of adipogenesis by Pref-1 in vivo and the resulting impairment of adipocyte function that leads to the development of metabolic abnormalities.

Genetic disorders in the GH IGF-I axis in mouse and man.

Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.

Aflatoxin exposure in utero causes growth faltering in Gambian infants.

BACKGROUND: Growth faltering in West African children has previously been associated with dietary exposure to aflatoxins, particularly upon weaning. However, in animal studies in utero exposure to low levels of aflatoxin also results in growth faltering. OBJECTIVE: This study investigated the effect of in utero aflatoxin exposure on infant growth in the first year of life in The Gambia. METHODS: Height and weight were measured for 138 infants at birth and at regular monthly intervals for one year. Aflatoxin-albumin (AF-alb) adduct level was measured in maternal blood during pregnancy, in cord blood and in infants at age 16 weeks. RESULTS: The geometric mean AF-alb levels were 40.4 pg/mg (range 4.8-260.8 pg/mg), 10.1 pg/mg (range 5.0-189.6 pg/mg) and 8.7 pg/mg (range 5.0-30.2 pg/mg) in maternal, cord and infant blood, respectively. AF-alb in maternal blood was a strong predictor of both weight (P = 0.012) and height (P = 0.044) gain, with lower gain in those with higher exposure. A reduction of maternal AF-alb from 110 pg/mg to 10 pg/mg would lead to a 0.8 kg increase in weight and 2 cm increase in height within the first year of life. CONCLUSIONS: This study shows a strong effect of maternal aflatoxin exposure during pregnancy on growth in the first year of life and thus extends earlier observations of an association between aflatoxin exposure during infancy and growth faltering. The findings imply value in targeting intervention strategies at early life exposures.

Genotype-phenotype correlations of 39 patients with Cornelia De Lange syndrome: the Dutch experience.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly syndrome characterised by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioural problems, and malformations of the upper extremities. Recently mutations in NIPBL, the human homologue of the Drosophila Nipped-B gene, were found to cause CdLS. Mutations have been found in 39% of reported cases. METHODS: Patients were enrolled in the study and classified into one of four groups based on clinical examination: classic, mild, possible, or definitively not CdLS. Three dimensional photography was taken of 20 subjects, and compared between groups. Behaviour was assessed with specific attention to autism. We searched for mutations in NIPBL and correlated genotype with phenotype. RESULTS: : We found mutations in 56% of cases. CONCLUSIONS: Truncating mutations were generally found to cause a more severe phenotype but this correlation was not absolute. Three dimensional facial imaging demonstrated the potential for classifying facial features. Behavioural problems were highly correlated with the level of adaptive functioning, and also included autism. No correlation of behaviour with the type of mutation was found.

Combined Effects of Gestational Phthalate Exposure and Zinc Deficiency on Steroid Metabolism and Growth.

Disruption of steroid hormone signaling has been implicated independently in the developmental abnormalities resulting from maternal phthalate plasticizer exposure and developmental zinc deficiency. This study investigated if secondary zinc deficiency may result from dietary exposure to a low level of di-2-ethylhexyl phthalate (DEHP) through gestation and if this could be associated with altered steroid metabolism. The interaction between marginal zinc nutrition and DEHP exposure to affect pregnancy outcome, zinc status, and steroid metabolism was also assessed. For this purpose, rats were fed a diet containing an adequate (25 mg/kg) or marginal (10 mg/kg) level of zinc without or with DEHP (300 mg/kg) from gestation day (GD) 0 until GD 19. Steroid profiles were measured in dam liver, plasma, adrenal glands, and in fetal liver by UPLC/MS-MS. In dams fed the adequate zinc diet, DEHP exposure decreased maternal weight gain and led to hepatic acute-phase response and zinc accumulation. The latter could compromise zinc availability to the fetus. DEHP and marginal zinc deficiency caused several adverse effects on the maternal and fetal steroid profiles. Interactions between DEHP exposure and marginal zinc deficient nutrition affected 17OH pregnenolone and corticosterone, while pregnenolone levels were specifically affected by DEHP exposure. Maternal marginal zinc deficiency specifically affected maternal progesterone and aldosterone, and presented evidence of increased androgen aromatization activity in maternal and fetal tissues. Results stress the potential major impact of mild DEHP exposure on maternal/fetal steroid metabolism that can be potentiated by nutritional and chronic disease states leading to zinc deficiency.

Glypican-6 promotes the growth of developing long bones by stimulating Hedgehog signaling.

Autosomal-recessive omodysplasia (OMOD1) is a genetic condition characterized by short stature, shortened limbs, and facial dysmorphism. OMOD1 is caused by loss-of-function mutations of glypican 6 (GPC6). In this study, we show that GPC6-null embryos display most of the abnormalities found in OMOD1 patients and that Hedgehog (Hh) signaling is significantly reduced in the long bones of these embryos. The Hh-stimulatory activity of GPC6 was also observed in cultured cells, where this GPC increased the binding of Hh to Patched 1 (Ptc1). Consistent with this, GPC6 interacts with Hh through its core protein and with Ptc1 through its glycosaminoglycan chains. Hh signaling is triggered at the primary cilium. In the absence of Hh, we observed that GPC6 is localized outside of the cilium but moves into the cilium upon the addition of Hh. We conclude that GPC6 stimulates Hh signaling by binding to Hh and Ptc1 at the cilium and increasing the interaction of the receptor and ligand.

Malnutrition and some related factors in primary school children, Semnan, Iran.

BACKGROUND: Malnutrition places a direct and indirect burden on individuals, especially children and communities. Malnutrition or growth failure can occur because of various reasons. This study aimed to determine the prevalence of thinness, underweight, stunting, and their related factors in students aged 6-12 years in Semnan province, central Iran. PARTICIPANTS AND METHODS: Using multistage sampling, a total of 2195 primary students in Semnan province, between November 2012 and March 2013, were selected randomly and the prevalences of wasting, underweight, and stunting among the students were estimated. Students' weights were measured using a Burer digital scale (Germany), with an accuracy of 100 g. Students' heights were measured using a nonstretchable tape measure. The BMI was calculated. Using the CDC 2000 standards, values less than the fifth percentile of BMI, weight-for-age, and height-for-age were defined as thinness, underweight, and stunting, respectively. RESULTS: In the total sample, 12.5, 9.2, and 9.0% of the students, respectively, were affected by thinness, underweight, and stunting. Lack of access to a computer increased the odds ratio (OR) of thinness by 1.38 times [OR=1.38, 95% confidence interval (CI): 1.06-1.78, P=0.015). Other variables (including age) did not show a significant association with the prevalence of thinness. Similarly, of all the variables studied, only access to a computer showed a significant association with the prevalence of underweight (OR=1.37, 95% CI: 1.02-1.84, P=0.036). The prevalence of stunting was associated significantly with a history of parasitic infection (OR=2.32, 95% CI: 1.53-3.51, P<0.001) and living in rural areas (OR=1.57, 95% CI: 1.15-2.16, P=0.005). CONCLUSION: The prevalence of malnutrition among students is high. Hence, families and stakeholders must pay special attention to various measures including healthcare services to improve the condition. Education, health, and support programs must be strengthened and continued.

The association between short stature and sensorineural hearing loss.

In order to test the Thrifty Phenotype Hypothesis on hearing, data from two cross-sectional studies on hearing were re-evaluated. The data sets comprised 500 18-year-old conscripts, and 483 noise-exposed male employees. Sensorineural hearing loss (SNHL) was over-represented among conscripts with a short stature (odds ratio=2.2) or hearing loss in the family (odds ration=4.2), but not among noise-exposed conscripts (odds ratio=0.9-1.3). Among noise-exposed short employees, hypertension and age exhibited a negative impact on high frequency hearing thresholds, while among tall employees hypertension had no effect on hearing and the influence of age was less pronounced (p<0.01 for body height; p<0.02 for age, hypertension and the interaction between body height and hypertension; p<0.05 for the interaction between body height and age). This suggests that mechanisms linked to fetal programming and growth retardation and/or insulin-like growth factor 1 levels during fetal life, such as a delayed cell cycle during the time window when the cochlea develops, may cause SNHL in adulthood.

More on human immunodeficiency virus embryopathy.

Eight patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, ranging in age from 4 to 33 months, were evaluated for the presence of dysmorphic features recently described as human immunodeficiency virus embryopathy. Birth data and growth charts were available. Growth failure, a prominent box-like head, large wide eyes, and a well-formed philtrum were seen in the majority of patients. The significance of hypertelorism, obliquity of eyes, long palpebral fissures, blue scleras, depressed bridge of nose, and prominent upper vermilion border is discussed.

Severe anomalies associated with ring chromosome 7.

A newborn infant with the polyasplenia sequence, intrauterine growth retardation, cutaneous nevi, and minor anomalies was found to have mosaicism for ring chromosome 7. This patient's anomalies are markedly different from those of previous patients reported with this cytogenetic anomaly.

Mice lacking a CDK inhibitor, p57Kip2, exhibit skeletal abnormalities and growth retardation.

p57Kip2, one of the cyclin-dependent kinase (CDK) inhibitors, has been suggested to be a tumor suppressor candidate. To elucidate its biological roles in mouse development and tumorigenesis, we created p57Kip2-deficient mice. The p57Kip2-deficient mice exhibited a cleft palate and defective bone formation resulting in severe dyspnea. Most of the p57Kip2-deficient mice died within 24 h after birth, while about 10% of them survived beyond the weaning period. All of the surviving mice showed severe growth retardation. The males showed immaturity of the testes, prostate and seminal vesicles, and the females showed vaginal atresia, immaturity of the uterus, and an increased number of atretic follicles. Although Yan et al. and Zhang et al. have already reported p57Kip2-deficient mice, they could not investigate the phenotypes of the surviving p57Kip2-deficient mice. Also, most of the symptoms of Beckwith-Wiedemann syndrome could not be reproduced in the mutant mice. Embryonic fibroblasts prepared from p57Kip2-deficient mice showed no differences in the proliferation rate and saturation density, suggesting that G1 arrest is largely independent of p57Kip2 function. Our results suggest that p57Kip2 plays a critical role in development, but do not support the hypothesis that the p57Kip2 gene is a tumor-suppressor gene or is responsible for Beckwith-Wiedemann syndrome.

[Epiphyseal points of the fetal knee. The impact of growth disorders on bone maturation]. / Points épiphysaires du genou du foetus. Retentissement des troubles de la croissance sur la maturation osseuse.

The radiological appearance of bone maturity can be used as a criterion for fetal maturity. This examination with limited irradiation to the fetus is an alternative to amniocentesis. The practice of the latter is not without risk. The authors carried out 194 examinations of the contents of the uterus to look at the epiphyses of the knee between the 34th and 40th week of amenorrhoea. The found three groups: 1) those with normal development; 2) those with delayed development and 3) those with more advanced development. They did not find significant correlation between small-for-dates growth and bony maturity. On the other hand, where there was increased growth of the fetus in cases where maternal diabetes was excluded there was demonstrated that bony maturity accelerated with the presence of Béclard's point from the 34th week onwards. With such great variation in the dates of the appearance of points of ossification the presence of epiphyseal points in the knee cannot be taken as a criterion to establish fetal maturity nor the minimum duration of the pregnancy.

Postnatal growth defects in mice with constitutive depletion of central serotonin.

Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (-95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2(-/-) mouse line and VMAT2(sert-cre) mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2(pet1-cre)) in 5-HT raphe neurons leading to partial (-75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2(sert-cre) mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2(sert-cre) and Tph2(-/-) mice, but not in the VMAT2(pet1-cre) mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.

Maternal smoking during pregnancy and offspring growth in childhood: 1993 and 2004 Pelotas cohort studies.

OBJECTIVE: To explore the effects of maternal smoking during pregnancy on offspring growth using three approaches: (1) multiple adjustments for socioeconomic and parental factors, (2) maternal-paternal comparisons as a test of putative intrauterine effects and (3) comparisons between two birth cohort studies. METHODS: Population-based birth cohort studies were carried out in Pelotas, Brazil, in 1993 and 2004. Cohort members were followed up at 3, 12, 24 and 48 months. Multiple linear regression analysis was used to examine the relationships between maternal and paternal prenatal smoking and offspring anthropometric indices. In the 2004 cohort, the association of smoking with trunk length, leg length and leg-to-sitting-height ratio at 48 months was also explored. RESULTS: Maternal smoking during pregnancy was associated with reduced z scores of length/height-for-age at each follow-up in both cohorts and reduced leg length at 48 months in the 2004 cohort. Children older than 3 months born to smoking women showed a higher body mass index-for-age z score than children of non-smoking women. CONCLUSIONS: The results of this study strongly support the hypothesis that maternal smoking during pregnancy impairs linear growth and promotes overweight in childhood.

Height at 2 and 5 years of age in children born very preterm: the EPIPAGE study.

OBJECTIVES: To evaluate growth for children born very preterm with particular focus on those born small-for-gestational age (SGA) or with ex utero growth restraint (GR), and to identify risk factors for short stature at 5 years of age. STUDY DESIGN: Population-based study of children born at less than 33 completed weeks of gestation (Étude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE)). Short stature was defined as height <-2SD on WHO growth curves. Ex utero GR was considered to have occurred in children with appropriate size for gestational age at birth and with a height and/or weight below -2SD at 2 years of corrected age. Logistic regression models were used to test associations between risk factors and short stature. RESULTS: The authors measured height at 5 years of age for 1,597 of 2,193 children (73%), 5.6% (95% CI 4.6 to 6.9) of whom were diagnosed as having a short stature. Height was measured at 2 and 5 years of age in 1417 children. Among these, 24% of those born SGA and 36% of those with ex utero GR (p=0.002) had a short stature at 5 years. Predictors of short stature were SGA or birth length <-2SD, maternal height ≤ 160 cm, gestational age <29 weeks and systemic corticosteroids. Breastfeeding at discharge decreased the risk of short stature. CONCLUSIONS: Short stature at 5 years of age is common in children born preterm. The highest incidence was observed in the group with ex utero GR. Systemic steroids have a long-term impact on growth and should be used with caution. Breastfeeding at discharge appeared to be protective.