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Correction to: Genetics in Medicine 22:2020 https://doi.org/10.1038/s41436-019-0743-3 published online 17 January 2020. An incorrect reference was cited in the fourth sentence of the Results section. The correct citation should have been Al-Gazali LI, Hamid Z, Hertecant J et al. An autosomal recessive syndrome of choanal atresia, hypothelia/athelia and thyroid gland anomalies overlapping Bamforth syndrome, ANOTHER syndrome and methimazole embryopathy. Clin Dysmorphol 2002;2:79–85. This has now been corrected in both the PDF and HTML versions of the Article.

Context\ud \ud Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).\ud \ud \ud \ud Objective\ud \ud To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.\ud \ud \ud \ud Design\ud \ud 12-year prospective, observational study.\ud \ud \ud \ud Participants & Setting\ud \ud We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.\ud \ud \ud \ud Interventions & Outcome\ud \ud AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).\ud \ud \ud \ud Results\ud \ud Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).\ud \ud \ud \ud Conclusions\ud \ud Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype–phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families.

Hoe zorgen we dat een beleidsmaatregel effect heeft in de praktijk? Hoe zorgen we dat organisaties werken volgens aanbevolen richtlijnen? Het programma was toch bewezen effectief, waarom zie ik in de praktijk dan geen effect?

Context:Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.Objective:To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members.Design:This was an observational, longitudinal study conducted over 7 years.Setting:International collaborative study conducted at referral centers for pituitary diseases.Participants:FIPA families (n = 216) and sporadic young-onset (≤30 y) pituitary adenoma patients (n = 404) participated in the study.Interventions:We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant.Main Outcome Measure(s):We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis.Results:Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening.Conclusions:A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Providers of youth care encounter problems with the implementation of interventions. This dissertation aimed to gain insight into factors that lead to successful and sustainable implementation of interventions in youth care. The first part of the dissertation provides a definition and a theoretical model that incorporates the main concepts related to implementation. Implementation is considered to be a systematic approach with the aim of a successful and sustainable implementation of an intervention. Regarding the success of implementation, specific attention is paid to the distinction between (1) implementation in the narrow sense – to carry out the intervention as intended, designated as program integrity - and (2) implementation in a broad sense - to achieve the intended outcomes. Through the following four steps a planned and phased approach is guaranteed: (1) define the desired outcome in a narrow and broad sense, (2) analyze the determinants (3) select strategies and (4) monitor, evaluate and adjust the process. Interviews with experts show that although various implementation activities were used in practice, these activities do not seem to be selected very systematically. The second part of the dissertation shows the ‘implementation monitor’, a schematic representation of an implementation process of a particular intervention in a specific organization. The monitor can be used to design, conduct, analyze and present research on implementation. This part also focuses on psychometric quality of two research instruments, the Decision Determinants Questionnaire (DDQ) and the questionnaire ‘Vragenlijst Kerncomponenten’. The DDQ measures readiness to change of employees in an organization. The ‘Vragenlijst Kerncomponenten’ is designed to gain insight into skills of youth care professionals and as a tool to discuss these skills between the professionals and their supervisors. In the third part of the dissertation contains two empirical studies on implementation. Firstly, the implementation of the intervention ‘Methodiek Ambulante Hulp’ within Jeugdformaat. Data were collected using questionnaires and structured interviews with 253 clients, 59 professionals and their supervisors. This study gave insight into the process of implementing an intervention. Furthermore, it shows relevant correlations between determinants of that implementation process and implementation in the narrow sense (program integrity) and in the broad sense (child outcomes). Secondly, a study on the implementation in the narrow sense of the intervention ‘Deltamethode Gezinsvoogdij’, a method for family guardianship at Bureau Jeugdzorg. The dissertation ends with a discussion, containing conclusions regarding the research questions, a summary of main findings for research and practice, limitations of the study and implications for further research and for the practice of youth care in the Netherlands. Amongst other findings, it is argued that the evidence for determinants of successful implementation is scarce, that this dissertation shows that implementation is a complex process in which various characteristics influence how the process proceeds and that an intervention can only help children and parents if it fits the needs of the client and if providers of the intervention are properly supervised. To conclude: implementation of an intervention should be well-thought

Een mooi omschreven interventie die uiteindelijk niet meer van de boekenplank komt. Een praktisch protocol dat alleen de binnenkant van een bureaulade te zien krijgt. Herkenbaar? Waarschijnlijk wel. Want ondanks de groeiende aandacht voor effectieve interventies in de jeugdzorg verloopt de invoering in de praktijk vaak moeizaam. Een goed gepland implementatieproces vergroot de kans op succes.

Effectieve en duurzame implementatie van jeugdzorginterventies is een belangrijke schakel om te komen tot effectieve jeugdzorg. Aangezien er geen kennis beschikbaar is over effectieve implementatie van interventies in de jeugdzorg, is er een literatuurstudie verricht naar effectieve implementatie van interventies in de gezondheidszorg, het onderwijs en het bedrijfsleven. Er is gebruik gemaakt van reviews, metastudies en primaire studies die zijn gepubliceerd in (inter)nationale wetenschappelijke tijdschriften, maar ook van rapporten en verslagen van organisatie in Nederland die zich met implementatievraagstukken bezighouden. In dit rapport wordt beschikbare kennis uit onderzoek en theorie toepasbaar gemaakt op de situatie in de jeugdzorg, zodat deze kennis benut kan worden voor een succesvol verloop van implementatietrajecten.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to alpha helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access) Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.