BackgroundFetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied.Methodology/Principal FindingsOver the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/−1.2 vs +0.58 +/−1.17 SD in FGR−) resulting in the restoration of BMI and of fat mass to values similar to FGR−, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/−1.41 vs 2.63+/−1 ng/ml in FGR−).ConclusionEarly catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction.
Adult peak bone mass is related to birth weight, suggesting it could be affected by fetal growth pattern. Small-forgestational-age (SGA) newborns have lower bone mineral content (BMC), but what about adapted-for-gestational-age (AGA) newborns with fetal growth restriction? The purpose of the study was to determine the respective role of birth weight and fetal growth pattern on BMC. Full-term newborns from SGA high-risk pregnancies were included (n ϭ 185). Estimated fetal weight percentiles were measured monthly from mid-gestation to birth, and restricted fetal growth (FGR) was defined as a loss by more than 20 percentiles. BMC was measured at birth, using dual x-ray absorptiometry. Newborns were SGA (n ϭ 56) or AGA (n ϭ 129). Newborns with FGR (n ϭ 111) were AGA (n ϭ 71) or SGA (n ϭ 41). BMC was significantly lower in SGA than AGA (1.48 Ϯ 0.02 vs. 1.87 Ϯ 0.04 g/cm) and lower when FGR irrespective of birth weight (1.66 g/cm Ϯ 0.03 vs. 1.89 g Ϯ 0.05). In multivariate analysis, FGR and SGA were significant and independent predictors of low BMC. In conclusion, fetal growth pattern affects BMC not only in SGA infants but also when birth weight is maintained in the normal range. T he peak bone mass of an individual depends upon growth and mineralization during the first two decades of life. However, a proportion of the variance of bone mineral content (BMC) found in the general population cannot be explained by genetic factors or childhood environment (1,2). Epidemiologic studies have suggested that part of this residual variation might be explained by the growth pattern in infancy (3) and probably during fetal development. Linear fetal growth is high during the last two trimesters of pregnancy, and fetal bone mineralization increases toward the end of pregnancy (4). Previous studies on a small number of newborns have shown that being born small for gestational age (SGA) was for a strong determinant of bone metabolism. BMC is lower in SGA infants at birth and is associated with a decrease in osteocalcin plasma level, suggesting that fetal mineralization is affected by fetal growth pattern (5,6). Moreover, prospective data in adult subjects indicate that bone mass and BMC are associated with birth weight after adjustment for environmental factors and body size at the time of investigation (7). However, birth weight results from fetal growth in utero. In addition, to gestational age and gender, other pregnancy characteristics, such as maternal height and weight before pregnancy, parity and ethnicity account for a large part of variation in fetal growth velocity and weight at birth. On the one hand, small babies who are small simply as a result of adaptation to maternal size can be separated from those who have suffered from restricted fetal growth (FGR). On the other hand, infants with appropriate for gestational age (AGA) birth weight can fail to reach their genetic potential of growth because of a real FGR. Birth weight by itself is not sufficient to identify FGR then. It has recently been shown that customi...
Fetal growth restriction induces changes in body composition and metabolism suggestive of a higher insulin sensitivity independently from BW itself, reflecting adaptive changes to an adverse fetal nutritional environment.
ObjectiveThe molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step.MethodsCoDE-seq is based on an augmented WES method, using probes distributed uniformly throughout the genome. CoDE-seq was validated in 40 patients for whom chromosomal DNA microarray was available. CNVs and mutations were assessed in 82 children/young adults with suspected Mendelian obesity and/or intellectual disability and in their parents when available (ntotal = 145).ResultsCoDE-seq not only detected all of the 97 CNVs identified by chromosomal DNA microarrays but also found 84 additional CNVs, due to a better resolution. When compared to CoDE-seq and chromosomal DNA microarrays, WES failed to detect 37% and 14% of CNVs, respectively. In the 82 patients, a likely molecular diagnosis was achieved in >30% of the patients. Half of the genetic diagnoses were explained by CNVs while the other half by mutations.ConclusionsCoDE-seq has proven cost-efficient and highly effective as it avoids the sequential genetic screening approaches currently used in clinical practice for the accurate detection of CNVs and point mutations.
Lafora disease (LD) is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. LD leads to accumulation of insoluble, abnormal, glycogen–like structures called Lafora bodies (LBs). It is caused by mutations in the gene encoding glycogen phosphatase (EPM2A) or the E3 ubiquitin ligase malin (EPM2B/NHLRC1). These two proteins are involved in an intricate, however, incompletely elucidated pathway governing glycogen metabolism. The formation of EPM2A and malin signaling complex promotes the ubiquitination of proteins participating in glycogen metabolism, where dysfunctional mutations lead to the formation of LBs. Herein, we describe a 13-years-old child with LD due to a NHLRC1 (c.386C > A, p.Pro129His) mutation, who has developed diabetes mellitus and was treated with metformin. We discuss how basic mechanisms of LD could be linked to β-cell dysfunction and insulin resistance.
Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by early onset of severe rickets, with a complete triad of clinical, biochemical and skeletal abnormalities. Homozygous or heterozygous mutations in the vitamin D receptor (VDR) gene leading to complete or partial target organ resistance to the action of 1α, 25-dihydroxyvitamin D3 (the active form of vitamin D) are responsible for HVDRR. Theoretically the therapeutic goal is to overcome this tissue resistance, and to normalize calcium and phosphate homeostasis. Practically, the treatment could be oriented to correct the secondary hyperparathyroidism to avoid long-term negative impact on bone health. The conventional therapeutic strategy (high-dose calcium plus active vitamin D metabolites) gives variable responses in magnitude and duration. We report a case of HVDRR with heterozygous mutation in the VDR gene, neonatal alopecia, and a severe clinical phenotype diagnosed at the age of 30 months who showed unsatisfactory response to traditional therapy. The short-term responsiveness to cinacalcet was encouraging, with adequate correction of phosphate-calcium homeostasis and significant improvement of clinical and radiological status at 6 months of treatment.
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