RESUMEN
AIM: To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin-like growth factor I receptor gene (IGF1R). METHODS: Children with short stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analysed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation-dependent probe amplification analysis. RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G > T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G > A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26-0.60) and 0.64 (range: 0.32-0.86) after 1 and 2 years of treatment, respectively. CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
Asunto(s)
Trastornos del Crecimiento , Hormona del Crecimiento/uso terapéutico , Microcefalia , Receptor IGF Tipo 1 , Estatura , Niño , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Heterocigoto , Humanos , Factor I del Crecimiento Similar a la Insulina , Microcefalia/tratamiento farmacológico , Microcefalia/genética , Mutación , Receptor IGF Tipo 1/genéticaRESUMEN
PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels are associated with cardiovascular risk. To investigate PCSK9 and Lp(a) levels of children born after assisted reproduction technologies (ART) compared with naturally conceived (NC) controls. METHODS: In this exposure-matched cohort study, 73 racial-, sex-, and age-matched children (mean age 98 ± 35 months) of ART (intracytoplasmic sperm injection [ICSI] n = 33, classic in vitro fertilization [IVF] n = 40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (< 8 years, 8-10 years, ≥ 10 years). RESULTS: In the overall population, PCSK9 levels were related to total cholesterol, low-density lipoprotein, and systolic blood pressure, while Lp(a) levels were related to age, apolipoprotein-B, birth weight, height, waist-to-hip ratio, insulin resistance, insulin, and high-sensitivity C-reactive protein. No significant differences were observed regarding lipid biomarkers between ART and NC children. However, a significant interaction was found between age groups and conception method (p < 0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring. IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, p = 0.010) and NC children (12.3 vs. 8.3 mg/dl, p = 0.048). CONCLUSIONS: We show that PCSK9 levels increase with age in ART children, indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results indicate that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a).
Asunto(s)
Enfermedades Cardiovasculares/sangre , Lipoproteína(a)/sangre , Proproteína Convertasa 9/sangre , Técnicas Reproductivas Asistidas/efectos adversos , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Niño , Preescolar , Femenino , Fertilización In Vitro/efectos adversos , Humanos , Resistencia a la Insulina/genética , Masculino , Factores de Riesgo , Inyecciones de Esperma Intracitoplasmáticas/efectos adversosRESUMEN
BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.
Asunto(s)
Negro o Afroamericano , Hispánicos o Latinos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/fisiopatología , Adolescente , Niño , Femenino , Humanos , Masculino , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/etnología , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
UNLABELLED: Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 years referred to the National Institutes of Health (NIH) from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of four children (three females and one male), aged 7.5-15.5 years (mean age 11.2 years) with length of disease 2-4 years, were recorded among 160 (2.5 %) children seen at or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two) or after leaving NIH (two). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances, and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (one), ectopic corticotropin production (one), and primary adrenal hyperplasia (one). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor. CONCLUSIONS: Despite the advances in early diagnosis and treatment of pediatric CS, a 2.5 % mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and treat accordingly.
Asunto(s)
Síndrome de Cushing/mortalidad , Adolescente , Niño , Preescolar , Síndrome de Cushing/diagnóstico , Femenino , Humanos , Masculino , Estudios Retrospectivos , Estados UnidosRESUMEN
BACKGROUND: Hepcidin is a peptide hormone that plays a key role in regulating iron absorption from the small intestine and body iron distribution. Alterations in hepcidin concentrations have been associated with chronic inflammatory conditions or inherited diseases of iron metabolism. The aim of our study was to evaluate healthy children in order to define normal reference range of serum hepcidin concentrations. The universal use of a reliable commercial ELISA kit gives the ability to compare our results with those from previous studies. METHODS: We evaluated 180 healthy children (88 boys, mean age: 67.55 ± 39.26 months, median: 60, range: 24-156 months) aged 2-12 years, using an immunoassay kit. RESULTS: Hepcidin median values were 46.94 ng/ml for boys and 46.79 ng/ml for girls. No significant differences were observed between boys and girls. There seem to be significantly higher values of hepcidin in older children (10-12 years old). This trend was constant and statistically significant in boys after gender and age group stratification. Although this trend was more prominent in girls, it was not statistically significant. CONCLUSIONS: This study aims at setting up reference values for serum hepcidin concentrations in healthy pediatric population by using a well-established laboratory kit. The difference in hepcidin concentrations in older children could be attributed to different growth rates. Additionally, differences between values in adults and children could reflect alterations in iron metabolism between those two age groups.
Asunto(s)
Envejecimiento/sangre , Hepcidinas/sangre , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Inmunoensayo , Masculino , Valores de Referencia , Estadísticas no ParamétricasRESUMEN
During the development of the appendicular skeleton, the cartilaginous templates undergo hypertrophic differentiation and remodels into bone, except for the cartilage most adjacent to joint cavities where hypertrophic differentiation and endochondral bone formation are prevented, and chondrocytes instead form articular cartilage. The mechanisms that prevent hypertrophic differentiation and endochondral bone formation of the articular cartilage have not been elucidated. To explore the role of the synovial microenvironment in chondrocyte differentiation, osteochondral allografts consisting of articular cartilage, epiphyseal bone, and growth plate cartilage from distal femoral epiphyses of inbred Lewis rats expressing enhanced green fluorescent protein from a ubiquitous promoter were transplanted either in inverted or original (control) orientation to matching sites in wildtype littermates, thereby allowing for tracing of transplanted cells and their progenies. We found that no hypertrophic differentiation occurred in the growth plate cartilage ectopically placed at the joint surface. Instead, the transplanted growth plate cartilage, with time, remodeled into articular cartilage. This finding suggests that the microenvironment at the articular surface inhibits hypertrophic differentiation and supports articular cartilage formation. To explore this hypothesis, rat chondrocyte pellets were cultured with and without synoviocyte-conditioned media. Consistent with the hypothesis, hypertrophic differentiation was inhibited and expression of the articular surface marker lubricin (Prg4) was dramatically induced when chondrocyte pellets were exposed to synovium- or synoviocyte-conditioned media, but not to chondrocyte- or osteoblast-conditioned media. Taken together, we present evidence for a novel mechanism by which synoviocytes, through the secretion of a factor or factors, act directly on chondrocytes to inhibit hypertrophic differentiation and endochondral bone formation and promote articular cartilage formation. This mechanism may have important implications for articular cartilage development, maintenance, and regeneration.
RESUMEN
OBJECTIVE: Perichondrium autotransplants have been used to reconstruct articular surfaces destroyed by infection or trauma. However, the role of the transplanted perichondrium in the healing of resurfaced joints has not been investigated. DESIGN: Perichondrial and periosteal tissues were harvested from rats hemizygous for a ubiquitously expressed enhanced green fluorescent protein (EGFP) transgene and transplanted into full-thickness articular cartilage defects at the trochlear groove of distal femur in wild-type littermates. As an additional control, cartilage defects were left without a transplant (no transplant control). Distal femurs were collected 3, 14, 56, 112 days after surgery. RESULTS: Tracing of transplanted cells showed that both perichondrium and periosteum transplant-derived cells made up the large majority of the cells in the regenerated joint surfaces. Perichondrium transplants contained SOX9 positive cells and with time differentiated into a hyaline cartilage that expanded and filled out the defects with Col2a1-positive and Col1a1-negative chondrocytes and a matrix rich in proteoglycans. At later timepoints the cartilaginous perichondrium transplants were actively remodeled into bone at the transplant-bone interface and at post-surgery day 112 EGFP-positive perichondrium cells at the articular surface were positive for Prg4. Periosteum transplants initially lacked SOX9 expression and despite a transient increase in SOX9 expression and chondrogenic differentiation, remained Col1a1 positive, and were continuously thinning as periosteum-derived cells were incorporated into the subchondral compartment. CONCLUSIONS: Perichondrium and periosteum transplanted to articular cartilage defects did not just stimulate regeneration but were themselves transformed into cartilaginous articular surfaces. Perichondrium transplants developed into an articular-like, hyaline cartilage, whereas periosteum transplants appeared to produce a less resilient fibro-cartilage.
Asunto(s)
Cartílago Articular , Animales , Condrocitos , Condrogénesis , Cartílago Hialino , Periostio , RatasRESUMEN
BACKGROUND/OBJECTIVES: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency. METHODS: The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex. RESULTS: Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter. CONCLUSIONS: These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.
Asunto(s)
Agrecanos/genética , Brazo , Estatura , Trastornos del Crecimiento , Haploinsuficiencia , Heterocigoto , Adolescente , Adulto , Brazo/crecimiento & desarrollo , Brazo/patología , Niño , Preescolar , Femenino , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Trastornos del Crecimiento/fisiopatología , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
CONTEXT: Assisted reproduction technologies (ART), classic in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) are increasingly used. Several studies have demonstrated an unfavorable cardiometabolic profile of the ART offspring. Proteomics is a state-of-the-art technology used for the identification of early biomarkers of disease. OBJECTIVES: To investigate the proteomic profile of children born after ICSI compared with naturally conceived (NC) controls in search of cardiometabolic risk markers. DESIGN: Cross-sectional case-control study: qualitative, comparative proteomic plasma analysis. SETTING: Pediatric Endocrinology and IVF Outpatient Clinics, University of Athens and the Biomedical Research Foundation of the Academy of Athens. PARTICIPANTS: Forty-two sex- and age-matched couples of ICSI and NC children were assessed. Ten pairs additionally matched for birth weight and twin/single pregnancies were submitted to proteomic analysis. INTERVENTION: Medical history, clinical examination, and blood biochemical, hormonal, and proteomic analyses. MAIN OUTCOME MEASURES: (1) Differences in auxological and laboratory data between groups. (2) Differences in plasma proteomic profile in 10 individual pairs and pooled samples. RESULTS: The ICSI group had shorter gestation, more cesarean sections, smaller birth weight/length, and advanced maternal age. No major differences were observed regarding biochemical markers. Proteomic analysis revealed 19 over- and three underexpressed proteins in ICSI. Most overexpressed proteins are implicated in acute-phase reaction, blood coagulation, complement pathway activation, and iron and lipid metabolism, suggesting a subclinical unfavorable cardiometabolic profile. CONCLUSIONS: This study applies proteomics in ICSI-conceived children, providing evidence for an early adverse cardiometabolic profile and supporting the necessity of their long-term monitoring.
RESUMEN
Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN, the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.
RESUMEN
CONTEXT: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. OBJECTIVE: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. PATIENTS AND METHODS: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. RESULTS: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. CONCLUSIONS: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
Asunto(s)
Agrecanos/genética , Enanismo/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antropometría/métodos , Braquidactilia/genética , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Enanismo/tratamiento farmacológico , Femenino , Crecimiento/genética , Hormona del Crecimiento/uso terapéutico , Heterocigoto , Humanos , Lactante , Degeneración del Disco Intervertebral/genética , Desplazamiento del Disco Intervertebral/genética , Masculino , Persona de Mediana Edad , Osteocondritis Disecante/congénito , Osteocondritis Disecante/genética , Linaje , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC). METHODS: Data from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for > 6 months. Confirmed compliance with vandetanib (67-150 mg/m(2)/day) and LT was a necessary inclusion criterion. RESULTS: While on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p = 0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m(2)/day (±24) to 116 mcg/m(2)/day (±24) was required in order to resume normative TSH levels (p = 0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up. CONCLUSIONS: In our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n = 2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00514046.
RESUMEN
CONTEXT: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. OBJECTIVE: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. METHODS: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. RESULTS: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). CONCLUSIONS: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
Asunto(s)
Mutación de Línea Germinal , Hiperaldosteronismo/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética , Adulto , Empalme Alternativo/genética , Proteínas del Dominio Armadillo , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Glucocorticoides/metabolismo , Humanos , Hiperaldosteronismo/metabolismo , Masculino , Persona de Mediana Edad , Mutación Missense , Estudios RetrospectivosRESUMEN
BACKGROUND: There have been increasing indications about an epigenetically-based elevated predisposition of assisted reproductive technology (ART) offspring to insulin resistance, which can lead to an unfavorable cardio-metabolic profile in adult life. However, the relevant long-term systematic molecular studies are limited, especially for the IntraCytoplasmic Sperm Injection (ICSI) method, introduced in 1992. In this study, we carefully defined a group of 42 prepubertal ICSI and 42 naturally conceived (NC) children. We assessed differences in their metabolic profile based on biochemical measurements, while, for a subgroup, plasma metabolomic analysis was also performed, investigating any relevant insulin resistance indices. METHODS & RESULTS: Auxological and biochemical parameters of 42 6.8±2.1 yrs old ICSI-conceived and 42 age-matched controls were measured. Significant differences between the groups were determined using univariate and multivariate statistics, indicating low urea and low-grade inflammation markers (YKL-40, hsCRP) and high triiodothyronine (T3) in ICSI-children compared to controls. Moreover, plasma metabolomic analysis carried out for a subgroup of 10 ICSI- and 10 NC girls using Gas Chromatography-Mass Spectrometry (GC-MS) indicated clear differences between the two groups, characterized by 36 metabolites linked to obesity, insulin resistance and metabolic syndrome. Notably, the distinction between the two girl subgroups was accentuated when both their biochemical and metabolomic measurements were employed. CONCLUSIONS: The present study contributes a large auxological and biochemical dataset of a well-defined group of pre-pubertal ICSI-conceived subjects to the research of the ART effect to the offspring's health. Moreover, it is the first time that the relevant usefulness of metabolomics was investigated. The acquired results are consistent with early insulin resistance in ICSI-offspring, paving the way for further systematic investigations. These data support that metabolomics may unravel metabolic differences before they become clinically or biochemically evident, underlining its utility in the ART research.