Clinical Features, Genotype-Phenotype Correlations and Treatment Outcomes in Children and Adolescents with Multiple Endocrine Neoplasia Type 1: An International Cohort Study

Omair A. Shariq1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, PhilippaPrentrice3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3 1Nuffield Department of Surgical Sciences, University of Oxford, UK2Department of Surgery, Mayo Clinic, Rochester, MN3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK4Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK5Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.6Department of Surgery, Medical University of Vienna, Vienna, Austria.7Centre for Endocrine Surgery, Great Ormond Street Hospital for Children, London, UK8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN9Oxford Clinical Trials Research Unit, Botnar Research Centre, Oxford, UK Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by parathyroid, pituitary and duodenopancreatic neuroendocrine tumours (DP-NETs). Knowledge regarding manifestations and outcomes is largely derived from adult cohorts. Thus, we investigated the occurrence and treatment of MEN1 manifestations in children and adolescents, and also explored potential genotype-phenotype correlations. Methods Eighty MEN1 patients who underwent childhood/adolescent tumour surveillance at 5 international referral centres were included. Fisher’s exact, Wilcoxon rank-sum and Kaplan-Meier tests were used to compare proportions, continuous variables and recurrence-free survival, respectively. Results Fifty-six patients (70%) developed an MEN1 manifestation before 19 years, at a median age of 14 years (range: 6-18 years). Primary hyperparathyroidism occurred in 46/56 patients (82.1%), 33 (72%) of whom underwent parathyroidectomy. Less-than-subtotal (<3-gland) parathyroidectomy resulted in worse recurrence/persistence-free survival vs subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months vs not reached; P=0.005). Twenty-one patients (37.5%) developed DP-NETs (non-functioning [n=15], insulinomas [n=8], and gastrinoma [n=1]), 12 (57.1%) underwent surgery and 3 (14.3%) had metastases (hepatic [n=2] and lymph node [n=1]). Compared to patients without DP-NETs, those with DP-NETs at <19 years were more likely to harbour MEN1 mutations disrupting the menin-JunD interaction domain (80% vs 51.9%; P=0.0459). Pituitary tumours developed in 18/56 patients (32%) and were mostly dopamine agonist-responsive prolactinomas. Conclusions Morbidity from MEN1 manifestations occurs during childhood and adolescence in 70% of patients. Less-than-subtotal parathyroidectomy leads to high failure rates. DP-NETs are the second most common manifestation in this age group and may be more frequent in patients with mutations that disrupt menin-JunD binding.

Spring-assisted posterior vault expansion—a single-centre experience of 200 cases

Purpose Children affected by premature fusion of the cranial sutures due to craniosynostosis can present with raised intracranial pressure and (turri)brachycephalic head shapes that require surgical treatment. Spring-assisted posterior vault expansion (SA-PVE) is the surgical technique of choice at Great Ormond Street Hospital for Children (GOSH), London, UK. This study aims to report the SA-PVE clinical experience of GOSH to date. Methods A retrospective review was carried out including all SA-PVE cases performed at GOSH between 2008 and 2020. Demographic and clinical data were recorded including genetic diagnosis, craniofacial surgical history, surgical indication and assessment, age at time of surgery (spring insertion and removal), operative time, in-patient stay, blood transfusion requirements, additional/secondary (cranio)facial procedures, and complications. Results Between 2008 and 2020, 200 SA-PVEs were undertaken in 184 patients (61% male). The study population consisted of patients affected by syndromic (65%) and non-syndromic disorders. Concerns regarding raised intracranial pressure were the surgical driver in 75% of the cases, with the remainder operated for shape correction. Median age for SA-PVE was 19 months (range, 2–131). Average operative time for first SA-PVE was 150 min and 87 for spring removal. Median in-patient stay was 3 nights, and 88 patients received a mean of 204.4 ml of blood transfusion at time of spring insertion. A single SA-PVE sufficed in 156 patients (85%) to date (26 springs still in situ at time of this analysis); 16 patients underwent repeat SA-PVE, whilst 12 underwent rigid redo. A second SA-PVE was needed in significantly more cases when the first SA-PVE was performed before age 1 year. Complications occurred in 26 patients with a total of 32 events, including one death. Forty-one patients underwent fronto-orbital remodelling at spring removal and 22 required additional cranio(maxillo)facial procedures. Conclusions Spring-assisted posterior vault expansion is a safe, efficient, and effective procedure based on our 12-year experience. Those that are treated early in life might require a repeat SA-PVE. Long-term follow-up is recommended as some would require additional craniomaxillofacial correction later in life.