Genetic analysis of IRF6, a gene involved in craniofacial midline formation, in relation to pituitary and facial morphology of patients with idiopathic growth hormone deficiency.

INTRODUCTION: Growth hormone is secreted by the pituitary gland, which forms part of the craniofacial midline. IRF6 encodes a transcription factor involved in the development of the craniofacial midline and mutations in IRF6 are known to disturb craniofacial development. Craniofacial and pituitary development are closely related. After whole exome sequencing revealed a new mutation in IRF6 in a family with Idiopathic Growth Hormone Deficiency (IGHD), we screened the remainder of our IGHD cohort for mutations in this gene and related their genotypes to pituitary and craniofacial morphology. MATERIALS AND METHODS: We sequenced all coding exons and exon-intron boundaries of IRF6 in 81 patients with IGHD. We performed a multiplex ligation-dependent probe amplification (MLPA) in order to exclude copy number variations in IRF6. We analyzed facial measurements taken from standardized digital pictures of 48 patients. RESULTS: We found two new variants and eleven polymorphisms. Apart from the new mutation found in the index family (p.Arg233Cys), we found one other new heterozygous missense mutation in IRF6 (Pro456Ser). p.Arg233Cys was reported as extremely rare in exome databases (1 allele out of 120.852 alleles sequenced), strictly conserved among species and was predicted deleterious by all variant predictor programs. Pro456Ser was predicted to be benign. MLPA did not reveal any exon deletions or duplications in any of the patients. CONCLUSION: This is the first report of IRF6 analysis in an IGHD cohort. We found one new mutation which, based on in silico analysis, could be of functional relevance. However, we did not find any mutations in the other patients. Therefore, we conclude that IRF6 defects are rare in IGHD patients and further research should focus on new candidate genes.

We mind your step: understanding and preventing drop-out in the transfer from paediatric to adult tertiary endocrine healthcare.

Introduction: Transition from paediatric to adult endocrinology can be challenging for adolescents, their families and healthcare professionals. Previous studies have shown that up to 25% of young adults with endocrine disorders are lost to follow-up after moving out of paediatric care. This poses a health risk for young adults, which can lead to serious and expensive medical acute and long-term complications. Methods: In order to understand and prevent dropout, we studied electronic medical records of patients with endocrine disorders. These patients were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our hospital in 2013-2014 and should have made the transfer to adult care at the time of the study. Results: Of 387 adolescents, 131 had an indication for adult follow-up within our university hospital. Thirty-three (25%) were lost to follow-up. In 24 of them (73%), the invitation for the adult OPC had never been sent. We describe the failures in logistic processes that eventually led to dropout in these patients. Conclusion: We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Of all dropouts, 73% could be attributed to the failure of logistic steps. In order to prevent these dropouts, we provide practical recommendations for patients and paediatric and adult endocrinologists.

[A man with pain in epigastrio]. / Een man met pijn in epigastrio.

A 22-year-old man was admitted to the hospital with epigastric pain. At first the diagnosis 'pneumonia' was made, based on a chest X-ray. CT-thorax revealed herniation of the colon in a diaphragmatic rupture, which was caused by an old stab wound.