MPS on 3.6 mL plasma from pregnant mothers could potentially provide the diagnosis of CAH, noninvasively, before the ninth week of gestation. Only affected female fetuses will thus be treated. Our strategy represents a generic approach for noninvasive prenatal testing for an array of autosomal recessive disorders.

Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene () cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.

This International Consensus Guideline was developed by experts in the field of 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. Besides, it presents long-term consequences of SGA birth and new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, and 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 cardio-metabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at age of 3-4 years, should be referred for diagnostic work-up. 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 0.033–0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3-4 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.

<b><i>Background/Aims:</i></b> Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. <b><i>Methods:</i></b> During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as &amp;#x3c;10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline. <b><i>Results:</i></b> In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. <b><i>Conclusion:</i></b> We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of &amp;#x3c; 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

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