Context Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

Objective: Comparison of studies on remission rates in pediatric Graves’ disease is complicated by lack of uniformity in treatment protocols, remission definition, and follow-up duration. We performed a systematic review on remission rates in pediatric Graves’ disease and attempted to create uniformity by recalculating remission rates based on an intention-to-treat analysis. Methods: PubMed and Embase were searched in August 2020 for studies on patients with Graves’ disease: (i) 2 to 18 years of age, (ii) initially treated with methimazole or carbimazole for at least 18 months, (iii) with a follow-up duration of at least 1 year after cessation of methimazole or carbimazole. All reported remission rates were recalculated using an intention-to-treat analysis. Results: Of 1890 articles, 29 articles consisting of 24 patient cohorts were included with a total of 3057 patients (82.6% female). Methimazole or carbimazole was initially prescribed in 2864 patients (93.7%). Recalculation based on intention-to-treat analysis resulted in an overall remission rate of 28.8% (829/2880). Pooled remission rates based on treatment duration were 23.7, 31.0, 43.7, and 75% respectively after 1.5–2.5 years, 2.5–5 years, 5–6 years (two studies), and 9 years (single study) treatment duration. The occurrence of adverse events was 419 in 2377 patients (17.6%), with major side effects in 25 patients (1.1%). Conclusions: Using a standardized calculation, the overall remission rate in methimazole-treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate. However, evidence is limited and further research is necessary to investigate the efficacy of longer treatment durations.

Background: Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader–Willi-like, Silver–Russell-like or as a Silver–Russell spectrum disorder. Methods: This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader–Willi-like from December 2018 to January 2022. Results: Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS −2.03 (−3.22; −1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect. Conclusions: Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader–Willi syndrome (PWS) and Silver–Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.

Context: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age–adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives. Objective: We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study. Methods: Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis. Results: A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days). Conclusion: Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time.

Developmental delay, epilepsy and neonatal diabetes Permanent neonatal diabetes mellitus Standard deviation score Sulfonylurea receptor (1/2) Gloyn AL, Pearson ER, Antcliff JF et al (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849 CAS Article PubMed Google Scholar Babenko AP, Polak M, Cavé H et al (2006) Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 355:456–466 CAS Article PubMed Google Scholar Proks P, Arnold AL, Bruining J et al (2006) A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 15:1793–1800 CAS Article PubMed Google Scholar Shimomura K, Horster F, de Wet H et al (2007) A novel mutation causing DEND syndrome; a treatable channelopathy of pancreas and brain. Neurology 69:1342–1349 CAS Article PubMed Google Scholar Pearson ER, Flechtner I, Njølstad PR et al (2006) Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 355:467–477 CAS Article PubMed Google Scholar Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT (2008) Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diab Care 31:204–209 CAS Article Google Scholar Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ (2006) Improved motor development and good long-term glycemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia 49:2559–2563 CAS Article PubMed Google Scholar Slingerland AS, Hurkx W, Noordam K et al (2008) Sulfonylurea therapy improves cognition in a patient with V59M KCNJ11 mutation. Diabet Med 25:277–281 CAS Article PubMed Google Scholar Conti LR, Radeke CM, Shyng SL, Vandenberg CA (2001) Transmembrane topology of the sulfonylurea receptor SUR1. J Biol Chem 276:41270–41278 CAS Article PubMed Google Scholar Download references We thank I. Bertram and J. de Randamie for technical assistance. The authors declare that there is no duality of interest associated with this manuscript. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Department of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Centre, PO Box 22660, 1100 DD, Amsterdam, The Netherlands N. Zwaveling-Soonawala, T. Vulsma & A. S. van Trotsenburg Department of Pediatric Neurology, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands E. E. Hagebeuk Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK A. S. Slingerland Laboratory of Pediatric Endocrinology, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands C. Ris-Stalpers You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Correspondence to N. Zwaveling-Soonawala. Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Reprints and Permissions Zwaveling-Soonawala, N., Hagebeuk, E.E., Slingerland, A.S. et al. Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation. Diabetologia 54, 469–471 (2011). https://doi.org/10.1007/s00125-010-1981-8 Download citation Received: 04 August 2010 Accepted: 22 October 2010 Published: 26 November 2010 Issue Date: February 2011 DOI: https://doi.org/10.1007/s00125-010-1981-8

Objective: To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD). Design: Nationwide, cross-sectional study. Methods: Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing. Results: During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively). Conclusion: Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis.