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This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < −2.5 SDS at age 2 years or < −2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

Accelerated early growth and early timing of puberty or pubertal variant have been noticed as risk factors for metabolic syndrome, more frequently observed in children born small for gestational age (SGA) or children with premature adrenarche (PA). Children with SGA, especially if they make an accelerated catch-up growth in early life, carry a higher risk for long-term metabolic consequences, such as type 2 diabetes, insulin resistance, and cardiovascular diseases. Furthermore, multiple studies support that these children, either born SGA or with a history of PA, may have earlier pubertal timing, which is also associated with various metabolic risks. This review aims to summarize the recent studies investigating the association between early infantile growth, the timing of puberty, and metabolic risks to expand our knowledge and gain more insight into the underlying pathophysiology.

Pubertal children with significant growth retardation represent a considerable therapeutic challenge. In growth hormone (GH) deficiency, and in those without identifiable pathologies (idiopathic short stature), the impact of using GH is significantly hindered by the relentless tempo of bone age acceleration caused by sex steroids, limiting time available for growth. Estrogen principally modulates epiphyseal fusion in females and males. GH production rates and growth velocity more than double during puberty, and high-dose GH use has shown dose-dependent increases in linear growth, but also can raise insulin-like growth factor I concentrations supraphysiologically, and increase treatment costs. Gonadotropin-releasing hormone analogs (GnRHas) suppress physiologic puberty, and when used in combination with GH can meaningfully increase height potential in males and females while rendering adolescents temporarily hypogonadal at a critical time in development. Aromatase inhibitors (AIs) block androgen to estrogen conversion, slowing down growth plate fusion, while allowing normal virilization in males and stimulating longitudinal bone growth via androgen receptor effects on the growth plate. Here, we review the physiology of pubertal growth, estrogen and androgen action on the epiphyses, and the therapeutic impact of GH, alone and in combination with GnRHa and with AIs. The pharmacology of potent oral AIs, and pivotal work on their efficacy and safety in children is also reviewed. Time-limited use of AIs is a viable alternative to promote growth in pubertal males, particularly combined with GH. Use of targeted growth-promoting therapies in adolescence must consider the impact of sex steroids on growth plate fusion, and treatment should be individualized.

Introduction Functional hypothalamic amenorrhea (HA) is commonly associated with increased exercise or decreased caloric intake and often with stress. We have previously demonstrated an increased burden of rare sequence variants (RSVs) in genes involved in GnRH ontogeny and upstream regulation in women with HA, but the role of metabolic and stress signaling to the GnRH neuronal system is poorly defined in this population. Methods The study included 100 women with a confirmed diagnosis of HA. The control cohort consisted of 468 women (aged 45­­-65 years) drawn from the NIH ClinSeq® Project. Exome sequencing was performed on peripheral blood genomic DNA. A subset of 72 genes was analyzed that have been shown to: 1) link metabolic or stress with reproductive phenotypes or 2) integrate metabolic and stress pathways with control of GnRH secretion. Joint genotyping of case and control samples was performed using the GATK GenotypeGVCFs function, locus-filtering using the VariantRecalibrator function, and genotype refinement using CalculateGenotypePosteriors with computation of median depths. Median depth positions Results HA patients exhibited an increased burden of RSVs in metabolism genes vs. controls (AS p=0. 043; CS p=0.105). The total number of RSVs per gene highlighted differences between HA and controls for the following genes: ADAMTSL1, GRINA, GRIN1, HCRTR1, TENM3, and NOS1 (AS p Conclusions These data suggest that RSVs in genes involved in phenotypes or signaling pathways that link metabolism to GnRH secretion may predispose to development of HA in the setting of decreased energy balance, but not for stress-related genes. GRINA and GRIN1 are important components of glutamate signaling that facilitate both appetite and GnRH secretion either directly or through kisspeptin. HCRTR1 plays a similar role in linking appetite and GnRH secretion while NOS1, which facilitates kisspeptin signaling, may be protective. This work highlights the need for further studies to understand the potential roles of ADAMTSL1 and TENM3 as risk factors for HA. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight.Prospective observational.Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups.Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders.Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI.Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

Congenital generalized lipodystrophy (CGL) is a genetic disorder charaterized by total body fat loss. The extent of fat loss is usually associated with the severity of the disease and patients typically develop metabolic complications such as hypertriglyceridemia, hepatic steatosis, insulin resistance, and diabetes mellitus. Mutations in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes are known to cause CGL. We report a new case of CGL but where no genetic aetiology has yet been identified in the known genes that cause CGL. The patient is a female child born at 36 weeks gestation with a birth weight os 2.57 kg. Soon after birth she was diagnosed clinically with CGL with both the DEXA and MRI scans showing severely diminished adipose tissue and 0% body fat respectively. She had severe failure to thive and developed diabetes mellitus, hyperlipidaemia, hypertrophic cardiomyopathy, severe scalp seborrheic dermatitis and hepatic steotosis. At 2 years of age her weight was only 3.7kg and she died from an upper respiratory tract infection. Whole exome sequencing and trio analysis did not find any mutations or copy number variants (CNV) in the AGPAT2, BSCL2, CAV1, and CAVIN1 genes associated with CGL. De-novo variants were found in the genes PCNT, PDE4DIP and STAT3 which need further functional validation. This case suggests that other possibly novel genetic mechanisms may be responsible for the CGL observed in this patient. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Objective To describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants. Design Observational study. Methods Probands’ phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports. Results Cases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): −2.8 (0.9) and −3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: −4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference −3.0 (range: −4.7 to −1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process. Conclusions Patients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Background: The combination of growth hormone (GH) and aromatase inhibitors (AI) improves linear growth in severely short adolescent boys; however, the effects of this intervention on quality of life (QoL) are unknown. This study assesses whether GH, AI, or their combination impacts the QoL of adolescent males with idiopathic short stature (ISS) from both the adolescent and the parent perspective. Method: A randomized open-label comparator trial was conducted in 76 pubertal males with ISS who received AI, GH, or AI/GH for 24 months. The condition-specific Quality of Life in Short Stature Youth questionnaire was used to assess QoL. Results: QoL scores were low at baseline in the children’s and parents’ reports. Within-group testing showed that total QoL scores increased significantly at 24 months in the GH and AI/GH group but not the AI group in the children’s report, whereas it increased in all of the groups in the parents’ report. Increases in QoL scores were associated with an increase in height SDS. Conclusions: Treatment with GH and AI/GH was associated with improved QoL scores as measured from both the patients’ and the parents’ perspectives, suggesting that the improved growth resulting from the use of these growth-promoting therapies has beneficial psychosocial effects in adolescent males with ISS followed for 24 months.

Background In addition to increasing linear growth, improvement in health-related quality of life (HRQOL) is an important endpoint in the treatment of short statured youth. Hence, condition-specific psychometric valid instruments that adequately assess HRQOL are needed. We aimed to confirmatorily examine the psychometric performance of the Quality of Life in Short Stature Youth (QoLISSY) questionnaire used in a previously reported prospective randomized open-label trial. Methods This trial compared treatment of idiopathic short stature (ISS) in 76 adolescent males with either oral aromatase inhibitors (AIs), subcutaneous daily growth hormone (GH) or a combination treatment (AI/GH) for at least 2 years, demonstrating improvements in HRQOL with the GH and AI/GH interventions. HRQOL was assessed from the child’s and parent’s perspectives with the short stature-specific QoLISSY and the generic KIDSCREEN questionnaires before and 24 months into treatment. Scale scores and psychometric properties were examined regarding reliability and validity of the QoLISSY questionnaire using the dataset from the published trial. Results The QoLISSY questionnaire showed high internal consistency and satisfactory criterion, convergent and known-groups validity. Scale scores were evenly distributed with no major floor or ceiling effects. Responsiveness analyses suggest that the QoLISSY questionnaire detects significant changes in HRQOL after 2 years of treatment with growth-promoting therapies in children with short stature from both the child’s and parent’s perspectives. Conclusions The QoLISSY questionnaire is a psychometrically sound, reliable and valid instrument that can explore the experiences associated with short stature, track HRQOL changes over time and in response to treatment, and highlight HRQOL domains that can be improved through intervention.

Among patients with Turner Syndrome (TS), premature ovarian failure is a main feature. Recently published consensus guidelines recommend that transdermal (TD) estradiol is the preferred route for estrogen replacement. Studies related to ultrasound (US) measurements during estrogen replacement in TS patients using estradiol (17β E2) and correlating uterine growth with estrogen metabolites are limited.To compare uterine morphology and hormonal changes depending on route of administration of 17β E2 (oral vs. TD) in a small population of girls with TS.11 hypogonadal girls with TS (mean (SE) age 14.5 ± 1.4 years; BMI -0.98 ± -1.0 SDS) who participated in a larger study on the effects of oral versus TD 17β E2 agreed to do a sub-study on the effect of the form of 17β E2 treatment on uterine size.17β E2 was given orally or TD for 12 months, titrated to doses up to 2 mg orally or 100 μg TD to achieve normal estradiol levels. Subjects received monthly progesterone for 1 week for withdrawal bleeding. At baseline, 6 and 12 months, a pelvic ultrasound was performed while on estradiol only.Uterine morphology and endometrial thickness increased comparably in both groups. E2 concentrations were comparable at 12 months between both groups but E1 and E1S were lower in TD group at 12 months.According to our experience, in a group of TS patients randomized to oral vs TD 17β E2 and monitored with trans-abdominal US, both groups achieved similar increases in uterine size comparable to normal women. To confirm our observation a larger sample and a longer evaluation period is needed.

Deletions in the SHOX gene are the most frequent genetic cause of Leri-Weill syndrome and Langer mesomelic dysplasia, which are also present in idiopathic short stature.To describe the molecular and clinical findings observed in 23 of 45 non-consanguineous Chilean patients with different phenotypes related to SHOX deficiency.Multiplex ligation-dependent probe amplification was used to detect the deletions; the SHOX coding region and deletion-flanking areas were sequenced to identify point mutations and single-nucleotide polymorphisms (SNPs).The main genetic defects identified in 21 patients consisted of deletions; one of them, a large deletion of800 kb, was found in 8 patients. Also, a smaller deletion of350 kb was observed in 4 patients. Although we could not precisely determine the deletion breakpoint, we were able to identify a common haplotype in 7 of the 8 patients with the larger deletion based on 22 informative SNPs.These results suggest that the large deletion-bearing allele has a common ancestor and was either introduced by European immigrants or had originated in our Amerindian population. This study allowed us to identify one recurrent deletion in Chilean patients; also, it contributed to expanding our knowledge about the genetic background of our population.

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage.

OBJECTIVE Proinflammatory advanced glycation end products (AGEs) found in thermally processed foods correlate with serum AGEs (sAGEs) and promote type 1 and type 2 diabetes in mice. Herein we assess the relationship of maternal blood and food AGEs to circulating glycoxidants, inflammatory markers, and insulin levels in infants up to age 1 year. RESEARCH DESIGN AND METHODS AGEs (Nε-carboxymethyllysine [CML] and methylglyoxal derivatives) were tested in sera of healthy mothers in labor (n = 60), their infants, and infant foods. Plasma 8-isoprostane, fasting glucose, insulin, leptin, and adiponectin levels were assessed in 12-month-old infants. RESULTS Significant correlations were found between newborn and maternal serum CML (sCML) (r = 0.734, P = 0.001) serum methylglyoxal derivatives (sMGs) (r = 0.593, P = 0.001), and 8-isoprostanes (r = 0.644, P = 0.001). Infant adiponectin at 12 months negatively correlated with maternal sCML (r = −0.467, P = 0.011), whereas high maternal sMGs predicted higher infant insulin or homeostasis model assessment (P = 0.027). Infant sAGEs significantly increased with the initiation of processed infant food intake, raising daily AGE consumption by ∼7.5-fold in year 1. CONCLUSIONS Maternal blood and food-derived AGEs prematurely raise AGEs in children to adult norms, preconditioning them to abnormally high oxidant stress and inflammation and thus possibly to early onset of disease, such as diabetes.

Pediatric and adolescent reproductive endocrine disorders represent a myriad of diseases including cryptorchidism, male and female sex steroid deficiencies, precocious puberty, and polycystic ovarian syndrome. While there are many traditional therapeutic interventions, some disorders now benefit from new medications or formulations. In this article, we review the most commonly used pharmacological therapies for these disorders and discuss treatment controversies and toxicities.

To test the hypothesis that increased fluid intake increases the urine free cortisol, we prescribed 5 liters of fluid intake per day or a normal fluid intake according to a randomized cross-over design in six normal volunteers. Each period lasted 5 days, with a 2-day washout period of normal fluid intake between the two periods. Urine free cortisol, 17-hydroxycorticosteroids, and creatinine were measured daily during each study period, and the average value over each 5-day period was calculated for each subject. High fluid intake caused a significant increase in the mean urine free cortisol [126 +/- 33 (SD) vs. 77 +/- 18 micrograms/day, P0.005]. The frequency of urine free cortisol results that exceeded the upper normal limit of 95 micrograms/day was also much higher during high fluid intake (23/30 vs. 6/30, P0.005). By contrast, urine 17-hydroxycorticosteroids (high fluid vs. normal fluid: 5.3 +/- 1.5 vs. 5.0 +/- 1.7 mg/day, respectively, P = not significant) and urine creatinine (1.51 +/- 0.48 vs. 1.45 +/- 0.37 g/day, P = not significant) did not differ between the two study periods. We conclude that high fluid intake (5 liters/day) increases free cortisol excretion without an increase in urine 17-hydroxycorticosteroids. Thus, mild to moderate increases in urine cortisol excretion may not indicate hypercortisolism in individuals who have a high fluid intake and urine volume.

Both vitamin A deficiency and excess cause abnormalities of linear growth. Since vitamin A is a retinoid precursor, we hypothesized that retinoids act in the growth plate to regulate longitudinal bone growth. To test this hypothesis, we administered a single oral dose (300 mg/kg) of all-trans retinoic acid (RA) to 5-week old rats. RA decreased the height of the proximal tibial growth plate by 66% (vs. vehicle-treated rats, p