Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Endocrine Late Effects in Childhood Cancer Survivors.

Childhood cancer management has improved considerably over the years, leading to a significant improvement in survival of up to 80%. However, childhood cancer survivors are at the highest risk of developing sequelae resulting from treatment, with endocrine complications being frequently observed among survivors. Multiple predisposing factors for endocrine sequelae have been identified, including age at diagnosis, treatment received, radiation, tumor type, and genetic polymorphisms, which could explain the individual predisposition to develop drug toxicity. Novel agents targeting tumor growth and immune checkpoint inhibitors have recently become the cornerstone for the treatment of different cancers, triggering a myriad of immune-related endocrinopathies. Endocrine sequelae of cancer therapy will have an impact on not only childhood but also on the survival and quality of life of these highly complex patients. Therefore, lifelong monitoring of childhood cancer survivors at risk of endocrine diseases is paramount. Encouraging oncologists and endocrinologists to develop new follow-up and early detection guidelines that minimize sequelae among these patients has become a priority, promoting integration between pediatric and adult units since many sequelae may manifest only after years to decades of follow-up.

Evaluación de la función tiroidea en el recién nacido pretérmino o de muy bajo peso / Assessment of thyroid function in the preterm and/or very low birth weight newborn

El Programa de cribado o detección precoz del hipotiroidismo congénito es uno de los mayores avances logrados en Pediatría. Las hormonas tiroideas son imprescindibles para el desarrollo y la maduración cerebral, que continúan en la etapa neonatal. Las alteraciones de la función tiroidea en niños prematuros y con bajo peso en los primeros meses de vida origina lesiones irreversibles en el sistema nervioso central y es una de las causas más frecuentes y evitables de retraso mental. El diagnóstico en el periodo neonatal es difícil, por lo que requiere estudio analítico para poder efectuar el tratamiento adecuado.La relevancia de este problema justifica su difusión a todas las áreas de Pediatría. El objetivo principal, evitar el daño cerebral en estos pacientes. Otros aspectos para optimizar el desarrollo adecuado de estos niños con todos los controles periódicos necesarios y lograr la inclusión del diagnóstico de las alteraciones tiroideas durante la estancia en unidades neonatales y en los primeros meses de vida precisan implementar los recursos de los centros sanitarios y continuar avanzando según los conocimientos actuales.En el presente documento nos centraremos en el cribado de los recién nacidos pretérmino (< 32 semanas de gestación) o con muy bajo peso para la edad gestacional (1.500-1.000 g muy bajo peso al nacer, o<1.000 g peso extremadamente bajo al nacer) y la protocolización de evaluación de función tiroidea en prematuros.Actualizamos los procedimientos diagnósticos, las pruebas imprescindibles y complementarias requeridas, la etiología y los diagnósticos diferenciales en esta patología. (AU)

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment.The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge.In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000g VLBW or <1000g) and the function evaluation protocol thyroid in premature babies.We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology. (AU)

Assessment of thyroid function in the preterm and/or very low birth weight newborn.

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment. The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge. In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000 g VLBW or <1000 g) and the function evaluation protocol thyroid in premature babies. We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology.

[Assessment of thyroid function in the preterm and/or very low birth weight newborn]. / Evaluación de la función tiroidea en el recién nacido pretérmino o de muy bajo peso.

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment. The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge. In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500-1000g VLBW or <1000g) and the function evaluation protocol thyroid in premature babies. We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology.

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

OBJECTIVE: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas. DESIGN: We performed a multicenter retrospective study. PATIENTS: 24 patients bearing large GH-producing tumours. MEASUREMENTS: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression. RESULTS: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P Ë‚ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity. CONCLUSIONS: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.

Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants.

CONTEXT: Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. OBJECTIVE: The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. PATIENTS AND METHODS: Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown. RESULTS: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. CONCLUSIONS: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.

Recomendaciones para el diagnóstico y seguimiento del feto y del recién nacido hijo de madre con patología tiroidea autoinmune / Recommendations for the diagnosis and follow up of the foetus and newborn child born to mothers with autoimmune thyroid disease

El objetivo de este documento es revisar las recomendaciones actuales en el manejo del hijo de madre con patología autoinmune tiroidea. En este 2017 se ha publicado la guía de la Asociación Americana de Tiroides para el diagnóstico y manejo de la enfermedad tiroidea durante el embarazo y el posparto. En dicha guía se establecen 97 recomendaciones y se propone un algoritmo de diagnóstico y tratamiento del hipotiroidismo gestacional. También en este último año se ha publicado una amplia revisión sobre el abordaje fetal y neonatal del hijo de madre con enfermedad de Graves. Se insiste en la trascendencia de la determinación de anticuerpos maternos frente al receptor de TSH en la segunda mitad del embarazo para estratificar adecuadamente el riesgo en el neonato

The objective of this document is to review the current recommendations in the management of the foetus and the newborn child born to mothers with autoimmune thyroid disease. In 2017, the American Thyroid Association published guidelines for the diagnosis and management of thyroid disease during pregnancy and post-partum. In this guide, 97 recommendations were made, and an algorithm for the diagnosis and treatment of gestational hypothyroidism was proposed. Also, in this last year, a wide review was been published on the foetal and neonatal approach of the child of a mother with Graves’ disease. The importance of the determination of maternal antibodies against thyrotropin receptor in the second half of pregnancy is stressed, in order to adequately stratify the risk in the neonate

[Recommendations for the diagnosis and follow up of the foetus and newborn child born to mothers with autoimmune thyroid disease]. / Recomendaciones para el diagnóstico y seguimiento del feto y del recién nacido hijo de madre con patología tiroidea autoinmune.

The objective of this document is to review the current recommendations in the management of the foetus and the newborn child born to mothers with autoimmune thyroid disease. In 2017, the American Thyroid Association published guidelines for the diagnosis and management of thyroid disease during pregnancy and post-partum. In this guide, 97 recommendations were made, and an algorithm for the diagnosis and treatment of gestational hypothyroidism was proposed. Also, in this last year, a wide review was been published on the foetal and neonatal approach of the child of a mother with Graves' disease. The importance of the determination of maternal antibodies against thyrotropin receptor in the second half of pregnancy is stressed, in order to adequately stratify the risk in the neonate.

Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency.

CONTEXT: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. OBJECTIVE: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. RESULTS: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. CONCLUSION: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.

Secuelas endocrinológicas en supervivientes de cáncer infantil / Endocrine sequelae in childhood cancer survivors

La evolución en los tratamientos oncológicos ha supuesto un aumento de la supervivencia del cáncer infantil cercana al 80% a 5 años, por lo que 1/500 adultos jóvenes será un superviviente. Las secuelas endocrinas son las más comunes y afectan al 40-60%, siendo las más frecuentes las alteraciones del crecimiento y la disfunción gonadal y tiroidea. Los pacientes con tumores del sistema nervioso central, leucemias y linfomas son los que presentan más secuelas, y estas dependen del tipo de cáncer, su localización, la edad de diagnóstico y el protocolo de tratamiento; las terapias de mayor riesgo son la radioterapia craneal y el trasplante de progenitores hematopoyéticos. Dado este elevado riesgo, las guías internacionales recomiendan a los endocrinólogos evaluar prospectivamente a los supervivientes. Algunas de las alteraciones endocrinas no se manifestarán hasta la vida adulta, por lo que debemos crear programas de transición, así como ser activos en la investigación para reducir las secuelas endocrinas de los tratamientos del cáncer (AU)

Thanks to the advances in cancer treatment, the five-year survival rate after childhood cancer has increased up to 80%. Therefore 1/500 young adults will be a survivor. Endocrine sequelae are most common, affecting 40-60% of survivors. The most frequent sequelae include growth failure and gonadal and thyroid diseases. Sequelae occur more frequently in survivors from central nervous system tumors, leukemia, and lymphoma. Their development will depend on the type of cancer, its location, age at diagnosis, and treatment administered. Treatments associated to more endocrine sequels are cranial radiotherapy and hematopoietic cell transplantation. Because of the high prevalence of endocrine sequelae, international guidelines recommend endocrinologists to prospectively evaluate the survivors. As some of these endocrine changes will not develop until adult life, transition programs should be implemented, and active investigation should be made to decrease the endocrine consequences of cancer treatment (AU)

Endocrine sequelae in childhood cancer survivors. / Secuelas endocrinológicas en supervivientes de cáncer infantil.

Thanks to the advances in cancer treatment, the five-year survival rate after childhood cancer has increased up to 80%. Therefore 1/500 young adults will be a survivor. Endocrine sequelae are most common, affecting 40-60% of survivors. The most frequent sequelae include growth failure and gonadal and thyroid diseases. Sequelae occur more frequently in survivors from central nervous system tumors, leukemia, and lymphoma. Their development will depend on the type of cancer, its location, age at diagnosis, and treatment administered. Treatments associated to more endocrine sequels are cranial radiotherapy and hematopoietic cell transplantation. Because of the high prevalence of endocrine sequelae, international guidelines recommend endocrinologists to prospectively evaluate the survivors. As some of these endocrine changes will not develop until adult life, transition programs should be implemented, and active investigation should be made to decrease the endocrine consequences of cancer treatment.

Pituitary dysfunction after traumatic brain injury: are there definitive data in children?

In the past decade, several studies in adults and children have described the risk of pituitary dysfunction after traumatic brain injury (TBI). As a result, an international consensus statement recommended follow-up on the survivors. This paper reviews published studies regarding hypopituitarism after TBI in children and compares their results. The prevalence of hypopituitarism ranges from 5% to 57%. Growth hormone (GH) and ACTH deficiency are the most common, followed by gonadotropins and thyroid-stimulating hormone. Paediatric studies have failed to identify risk factors for developing hypopituitarism, and therefore we have no tools to restrict screening in severe TBI. In addition, the present review highlights the lack of a unified follow-up and the fact that unrecognised pituitary dysfunction is frequent in paediatric population. The effect of hormonal replacement in patient recovery is important enough to consider baseline screening and reassessment between 6 and 12 months after TBI. Medical community should be aware of the risk of pituitary dysfunction in these patients, given the high prevalence of endocrine dysfunction already reported in the studies. Longer prospective studies are needed to uncover the natural course of pituitary dysfunction, and new studies should be designed to test the benefit of hormonal replacement in metabolic, cognitive and functional outcome in these patients.

Pituitary dysfunction after traumatic brain injury in children: is there a need for ongoing endocrine assessment?

BACKGROUND: Hypopituitarism has been widely described in adults after traumatic brain injury (TBI); however, the available data in paediatric populations are scarce. Here, we report the results of a prospective, long-term study in children, adolescents and young adults. STUDY GROUP: Thirty-seven children (age, 2 months to 19·9 years) of 51 eligible patients were followed for 1 year. Clinical and baseline endocrine variables were assessed in all 3 and 12 months after TBI; children ≥ 6 years underwent two stimulation tests (glucagon stimulation and megatest). RESULTS: In the group ≥6 years, 11 of 23 patients (47·8%) had a subnormal GH peak 3 months after TBI that persisted in 8 of 23 patients (34%) after 1 year. The GH response showed no correlation with injury severity (GCS, Marshall classification). Growth velocity was normal in all patients, except for one. Body mass index (BMI) SDS increased significantly in the group with low GH response. A suboptimal cortisol was observed in 10 of 23 subjects, which normalized in all but three, 1 year thereafter. All patients but one showed a pubertal response to GnRH testing. No clinical or hormonal abnormalities were detectable in children <6 years. CONCLUSION: Our results recommend to prospectively follow children after TBI: firstly, because the impairment of pituitary function cannot be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. Prospective clinical trials are needed before recommending a systematic screening after TBI and/or GH therapy either in postpubertal children or in prepubertal children who grow normally.

Triple A syndrome in a patient with genetic growth hormone insensitivity: phenotypic effects of two genetic disorders.

BACKGROUND: Primary growth hormone insensitivity (GHI) and triple A syndrome are rare autosomal recessive disorders. CASE REPORT: The patient, a 12-year-old boy from consanguineous parents, was referred for short stature at the age of 7 years (height: -5.4 SD score). He had low serum insulin-like growth factor I (IGF-I) and IGF binding protein 3 and a blunted IGF-I response to recombinant human GH; molecular analysis of the GH receptor disclosed a homozygous A(-1)→G(-1) at the 5' pseudoexon 6Ψ splice site. Recombinant IGF-I therapy (mecasermin, Increlex®, twice daily) initiated at the age of 9 years resulted in an increase of height velocity (HV) from 4.0 to 9.5 cm/year. At the age of 10.5 years, he presented with asthenia, anorexia, weight loss, a decrease in HV and very low cortisol levels; adrenal insufficiency was confirmed and glucocorticoid therapy was initiated. Subsequent peripheral motor neuropathy, achalasia and alacrima raised the suspicion of triple A syndrome, which was confirmed by the presence of a homozygous R194X mutation in the AAAS gene. CONCLUSION: This unusual combination of diseases, to our knowledge, has not been reported to date. Although the patient responded to recombinant IGF-I therapy for GHI, we hypothesize that the treatment could have had an inhibitory effect on 11ß-hydroxysteroid dehydrogenase type 1 activity, thereby reducing the availability of cortisol and precipitating adrenal insufficiency.

Insulin resistance after precocious pubarche: relation to PAI-1-675 4G/5G polymorphism, and opposing influences of prenatal and postnatal weight gain.

OBJECTIVE: The common promoter -675 4G/5G insertion/deletion polymorphism (indel) in the plasminogen activator inhibitor-1 (PAI-1) gene has been associated with quantitative components of the metabolic syndrome. We hypothesized that this polymorphism is associated with precocious pubarche (PP), a population known to be at risk for hyperinsulinaemic hyperandrogenism. DESIGN: A cross-sectional, hospital-based study. PATIENTS: A total of 115 control and 182 PP Catalan girls and young women. MEASUREMENTS: Subjects were genotyped for the -675 4G/5G indel in the PAI-1 gene. Insulin resistance and insulin secretion were estimated by the homeostasis model assessment. RESULTS: Genotype frequencies for the PAI-1-675 4G/5G indel (4G4G, 4G5G and 5G5G) were similar in control and PP subjects (24%vs. 27%, 50%vs. 47%, and 26%vs. 26%, respectively; P = 0.85) and these frequencies were in Hardy-Weinberg equilibrium. The 5G allele, however, was associated with insulin resistance in both postmenarcheal control and PP subjects (P < 0.01 for pooled postmenarcheal subjects, N = 122). The coexistence with the at-risk genotype of both a low birthweight (standard deviation score, SDS < -1.0) and a high body mass index (BMI) at time of the study (SDS > +1.0) resulted in a noteworthy increase (P < 0.001) in insulin resistance. CONCLUSION: The common promoter -675 4G/5G indel of the PAI-1 gene is not associated with PP but, in Catalan young women, the 5G allele enhances the risk for insulin resistance imposed by the sequence of a low birth weight (LBW) and a high BMI.

The tumour necrosis factor (TNF)-alpha-308GA promoter polymorphism is related to prenatal growth and postnatal insulin resistance.

OBJECTIVE: Variation in the tumour necrosis factor gene, (TNF) has been associated with insulin resistance traits. We questioned whether the TNF-308G/A polymorphism is associated with birthweight and insulin resistance in children born small for gestational age (SGA), a patient population known to be at risk for insulin resistance. DESIGN: A cross-sectional, hospital-based study assessing insulin sensitivity in SGA children. PATIENTS: One hundred and ninety-eight school-age children born either SGA (n=90, age 7.4+/- 4.5 years) or appropriate for gestational age (AGA, n=108, age 8.7+/- 4.0 years). MEASUREMENTS: All children were genotyped for the TNF-308G/A polymorphism; a biochemical profile was also performed in prepubertal SGA (n=58) and AGA (n=57) subjects. RESULTS: Genotype frequencies for the TNF-308G/A single nucleotide polymorphisms (SNPs) (GG and GA/AA) differed between SGA and AGA children (86%vs. 72% and 14%vs. 28%, respectively; P=0.025). The GG genotype was associated with lower birthweight and birth length (2747.0+/- 23.3 g vs. 2851.0+/- 45.7 g, P=0.045, and 47.0+/- 0.2 cm vs. 48.2+/- 0.4 cm, P=0.011, respectively) and, in AGA but not in SGA children, with higher systolic blood pressure [103.3 (95% confidence interval (CI) 96.4-110.2) mmHg vs. 92.8 (84.9-100.7) mmHg; P=0.028], higher blood glucose [4.8 (4.7-5.0) mmol/l vs. 4.5 (4.3-4.8) mmol/l; P=0.042] and higher homeostasis model assessment for insulin resistance (HOMA-IR) index [1.4 (1.1-1.7) vs. 0.9 (0.4-1.3); P=0.005]. In multivariate analysis, the TNF-308GG genotype was an independent predictor of HOMA-IR during childhood, explaining 8% of its variance. CONCLUSION: SGA children show increased frequency of the TNF-308G allele, an allele that is associated with prenatal growth and with postnatal insulin resistance. The TNF-308G/A polymorphism may have implications in the growth and metabolic abnormalities that characterise SGA children.

Both intrauterine growth restriction and postnatal growth influence childhood serum concentrations of adiponectin.

OBJECTIVE: Insulin resistance has been linked to intrauterine growth restriction; adiponectin is a strong determinant of insulin sensitivity. We aimed at studying the contributions of birthweight and insulin sensitivity to circulating adiponectin in children born small for gestational age (SGA). DESIGN: Cross-sectional, hospital-based study dealing with insulin sensitivity in SGA children. PATIENTS: Thirty-two prepubertal children born SGA (age 5.4 +/- 2.9 years) and 37 prepubertal children born appropriate for gestational age (AGA, age 5.9 +/- 3.0 years). MEASUREMENTS: Serum levels of fasting glucose, serum lipids, insulin (immunometric assay) and adiponectin concentrations (ELISA) were assessed, and insulin resistance (IR) and insulin secretion (beta-cell) were calculated by the homeostasis model of assessment (HOMA). RESULTS: SGA children had similar HOMA-IR, HOMA-beta-cell and adiponectin concentrations than AGA children. However, in a separate analysis of subjects older than 3 years of age, SGA children showed higher HOMA-IR after adjusting for sex, age and body mass index (BMI) standard deviation score (SDS). Circulating adiponectin was higher in SGA children [adjusted means: 14.5 mg/l (95% CI 12.9-16.1) and 18.7 mg/l (95% CI 17.0-20.3) for AGA and SGA children, respectively; P < 0.0001]. Further analysis revealed that the group of overweight SGA (arbitrarily defined as being in the higher quartile for the BMI SDS distribution in the sample) had decreased serum concentrations of adiponectin, compared to lean SGA children [adjusted means: 12.9 mg/l (95% CI 9.3-16.5) vs. 19.0 (95% CI 16.8-21.3), respectively; P = 0.001]. In a multiple regression model, HOMA-IR and SGA status explained 35% and 15% of adiponectin variance, respectively. CONCLUSIONS: Prenatal growth restriction is associated with insulin resistance but relatively increased adiponectin concentrations, provided overweight does not ensue. The contributions of circulating adiponectin to the increased risks for developing insulin resistance and type-2 diabetes in formerly SGA subjects merit further studies.