Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

OBJECTIVE: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis. PATIENTS AND DESIGN: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%). CONCLUSIONS: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.

Co-Existence of Congenital Adrenal Hyperplasia and Bartter Syndrome due to Maternal Uniparental Isodisomy of HSD3B2 and CLCNKB Mutations.

INTRODUCTION: We present a patient with co-existence of 3ß-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency and Bartter syndrome, a unique dual combination of opposing pathologies that has not been reported previously in the literature. CASE: A female infant (46,XX) born at 34/40 weeks' gestation, weighing 2.67 kg (-1.54 standard deviation score) to non-consanguineous parents presented on day 4 of life with significant weight loss. Subsequent investigations revealed hyponatraemia, hypochloraemia, metabolic alkalosis, elevated 17-hydroxyprogesterone, ACTH, and renin. Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation. Due to the persistence of the hypochlo-raemic and hypokalemic alkalosis, an underlying renal tubulopathy was suspected. Sequence analysis of a targeted tubulopathy gene panel revealed a homozygous deletion in CLCNKB, consistent with Bartter syndrome type 3. The mother was found to be heterozygous for both mutations in -HSD3B2 and CLCNKB, and the father was negative for both. Single-nucleotide polymorphism microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB. DISCUSSION: Identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental disomy, especially if the phenotype is unusual, potentially encompassing more than one disorder. The persistence of hypokalemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with a form of CAH in which aldosterone production is severely impaired, challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

BACKGROUND: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication. CASE REPORTS: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH. CONCLUSIONS: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.

Atrioventricular block: an unusual complication of Graves' disease.

We report the case of a 10-year-old girl treated with atenolol and carbimazole for tachycardia and hypertension associated with Graves' disease who developed symptomatic 2:1 heart block. 2:1 heart block resolved following cessation of atenolol, reduction in carbimazole dose and treatment of suspected tonsillitis. First-degree atrioventricular block persisted, but gradually normalised following improvement in thyroid status.

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

Feasibility study of automated overnight closed-loop glucose control under MD-logic artificial pancreas in patients with type 1 diabetes: the DREAM Project.

BACKGROUND: Artificial pancreas systems may offer a potential major impact on the normalization of metabolic control and preventing hypoglycemic events. This study aims to establish near-normal overnight glucose control and reduce the risk of nocturnal hypoglycemia using the MD-Logic Artificial Pancreas (MDLAP), an algorithm that was developed by our research group. This inpatient feasibility study is the first step towards implementing an overnight closed-loop MDLAP system at the patient's home. SUBJECTS AND METHODS: Seven patients with type 1 diabetes (three adolescents and four adults; mean±SD age, 20.6±4.7 years; duration of diabetes, 9.6±2.6 years; body mass index, 24.3±3.9 kg/m(2); and glycated hemoglobin, 7.8±0.8%) participated in a total of 14 closed-loop overnight sessions. Each participant underwent two closed-loop inpatient sessions starting at dinner alone and at dinner following exercise. The closed-loop inpatient sessions were compared with data derived from nights spent at home with an open-loop system in a similar scenario to the study protocol. RESULTS: The mean percentage of time spent in the near normal glucose range of 63-140 mg/dL was 83±16%, and the median (interquartile range) was 85% (78-92%) for the overnight closed-loop sessions compared with 34±31% and 27% (6-57%) in the homecare open-loop setting, respectively. During the overnight closed-loop sessions at dinner alone 92±9% of the sensor values ranged within target range, compared with 73±19% for the sessions following exercise (P=0.03). No hypoglycemic (<63 mg/dL) events occurred during the closed-loop sessions. CONCLUSION: Closed-loop insulin delivery under MDLAP is a feasible and safe solution to control overnight glycemia.

Stressful weight loss.

This paper describes a patient initially diagnosed with autoimmune thyroiditis who undergoes a diagnostic and investigatory journey.