Clinical management and outcome of head and neck paragangliomas (HNPGLs): A single centre retrospective study.

CONTEXT: Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined. OBJECTIVE: To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities. METHODS: Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023. RESULTS: There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04). CONCLUSION: The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes.

Mothers' experiences of a lifestyle intervention for weight reduction 12 months after gestational diabetes mellitus: Qualitative findings from the PAIGE2 study.

The standardised pooled prevalence of gestational diabetes mellitus (GDM) globally is approximately 14 %, a reflection of increasing rates of obesity in women of childbearing age. Lifestyle interventions to reduce GDM and subsequent type 2 diabetes (T2D) have been deemed a research priority but are challenging to perform and have variable success rates. The PAIGE2 study was a pragmatic lifestyle randomised controlled trial for women with GDM and body mass index ≥25 kg/m2, which began during pregnancy and continued for one year postnatally. The primary outcome was weight loss 12 months postnatally compared with mothers receiving standard maternity care. Qualitative results are presented from end of study focus groups conducted amongst intervention mothers to gather feedback and determine acceptability of the PAIGE2 intervention. In total, 19 mothers participated in five virtual focus groups. Content analysis explored general study experience, longer term changes to lifestyle and suggested improvements of intervention components including monthly phone calls, motivational text messages, Fitbit experience, Slimming World, and study contact timings. Overall, most mothers found the individual PAIGE2 intervention components enjoyable, although opinions differed as to which were the most effective. Several mothers claimed the intervention helped them make long-term changes to their behaviours. A common suggested improvement was the establishment of a local group where mothers could share their experiences. In conclusion, most mothers deemed the intervention acceptable, and felt that with minor enhancements, it could be utilised as an effective tool to support weight loss after pregnancy and reduce future risk of obesity and T2D.

A pragmatic lifestyle intervention for overweight and obese women with gestational diabetes mellitus (PAIGE2): A parallel arm, multicenter randomized controlled trial study protocol.

Background: The global epidemic of type 2 diabetes (T2D) and obesity has been translated into pregnancy, with approximately 18% of women being diagnosed worldwide with Gestational Diabetes Mellitus (GDM). Whilst preventive strategies have proven effective in the non-pregnant context, attrition rates are high and there is an urgent need to develop a customized, pragmatic lifestyle intervention for women both during and after pregnancy. Diet and exercise modification, behavioral support, and Commercial Weight Management Organizations have been strongly recommended to aid postpartum weight reduction for mothers with previous GDM, subsequently reducing their risk of developing obesity and T2D. This study, informed by a previous pilot study, aims to determine the effectiveness of a pragmatic pregnancy and postpartum lifestyle modification program for overweight women with previous GDM (PAIGE2) to reduce body weight at 12 months postpartum. Methods/design: This paper summarizes the protocol for the PAIGE2 study, which has been developed based on results from a pilot study (PAIGE). A six center, two parallel arm, 12-month, randomized controlled trial will be conducted across Northern Ireland and the Republic of Ireland (3 centers each), involving 340 women with GDM and body mass index ≥25 kg/m2 recruited during pregnancy. The lifestyle intervention involves a one-hour virtual educational program (to take place at 32-36 weeks gestation). Postpartum, the intervention will include monthly phone calls, weekly motivational text messages, weekly step counts, and referral for three months to a Commercial Weight Management Organization (Slimming World). The control arm will receive usual care as offered by the local maternity hospital. The primary outcome is weight loss at 12 months postpartum. Study visits for anthropometric and clinical measurements, fasting blood samples, questionnaires pertaining to health, wellbeing and physical activity will take place at 6 weeks, 6- and 12-months postpartum. Focus groups will be conducted with intervention mothers' post-intervention to determine the acceptability of the study design including utility of a Commercial Weight Management Organization, feasibility of remote patient contact, family involvement and patient satisfaction. Discussion: The PAIGE2 study will address the gaps in previously conducted research and, if positive, has the potential to have major public health implications for the prevention of future GDM and subsequent T2D. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04579016?term=NCT04579016&draw=2&rank=1, identifier NCT04579016.

First-trimester glycaemic markers as predictors of gestational diabetes and its associated adverse outcomes: A prospective cohort study.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with excessive fetal growth in later gestation. Recent data suggest accelerated growth may begin before 28 weeks' gestation when GDM is typically diagnosed. The identification of pregnancies at risk of early fetal growth would enable early intervention. We assessed the use of early pregnancy HbA1c in predicting excessive fetal growth. RESEARCH DESIGN AND METHODS: Women were recruited at antenatal booking from a major maternity unit in the UK. HbA1c was measured at <14 weeks gestation in 1243 women at risk of GDM as defined by UK NICE risk factors of whom 1115 underwent OGTT. Women with previous GDM were excluded. Comprehensive fetal ultrasound was performed at 28 weeks' gestation alongside 75 g OGTT in 976 of these women. GDM was defined using WHO criteria. Pregnancy outcomes were extracted from the regional maternity care database. RESULTS: Two hundred and thirty-six women screened positive for GDM. At diagnosis, GDM pregnancies demonstrated higher adjusted fetal weight percentile than non-GDM pregnancies: (51.8 vs. 46.3, p = 0.008). This was driven by increases in the fetal abdominal circumference percentile in GDM compared with non-GDM pregnancies (55.3 vs. 46.2, p = <0.001). Early pregnancy HbA1c was higher in the GDM versus non-GDM group: (35.7 mmol/mol vs. 32.9 mmol/mol p = <0.01). A threshold for predicting excessive fetal growth was not identified in this cohort. CONCLUSIONS: Accelerated fetal growth is evident prior to the diagnosis of GDM. There remains a need for suitable methods of early identification of pregnancies at high risk for early accelerated fetal growth due to GDM. First-trimester HbA1c was not useful in identifying these pregnancies. NOVELTY STATEMENT: WHAT IS ALREADY KNOWN?: Recent research suggests excessive growth associated with GDM may begin prior to 28 weeks' gestation, when GDM is typically tested for WHAT THIS STUDY HAS FOUND?: Pregnancies affected by GDM are already subject to accelerated fetal growth in comparison to non-GDM pregnancies by way of higher estimated fetal weight and fetal abdominal circumference Neither first-trimester HbA1c nor plasma glucose was useful predictors of these outcomes WHAT ARE THE IMPLICATIONS OF THIS STUDY?: Highlights the emergence of excessive growth prior to detection of GDM Reinforces need for suitable methods of identifying such pregnancies in earlier gestation.

Iodine status of teenage girls on the island of Ireland.

PURPOSE: The trace element iodine is a vital constituent of thyroid hormones. Iodine requirements increase during pregnancy, when even mild deficiency may affect the neurocognitive development of the offspring. Urinary iodine concentration (UIC) is the means of assessing iodine status in population surveys; a median UIC of 100-199 µg/L is deemed sufficient in a non-pregnant population. Milk is the main dietary source of iodine in the UK and Ireland. METHODS: We surveyed the iodine status of 903 girls aged 14-15 years in seven sites across the island of Ireland. Urine iodine concentration was measured in spot-urine samples collected between March 2014 and October 2015. Food group intake was estimated from iodine-specific food-frequency questionnaire. Milk-iodine concentration was measured at each site in summer and winter. RESULTS: The median UIC overall was 111 µg/L. Galway was the only site in the deficient range (median UIC 98 µg/L). All five of the Republic of Ireland sites had UIC ≤ 105 µg/L. In the two sites surveyed twice, UIC was lower in summer vs winter months [117 µg/L (IQR 76-165) vs 130 µg/L (IQR 91-194) (p < 0.01)]. Milk samples collected from Galway and Roscommon had a lower mean iodine concentration than those from Derry/Londonderry (p < 0.05). Milk intake was positively associated with UIC (p < 0.001). CONCLUSIONS: This is the largest survey of its kind on the island of Ireland, which currently has no iodine-fortification programme. Overall, the results suggest that this young female population sits at the low end of sufficiency, which has implications if, in future, they enter pregnancy with borderline status.

Twenty-four-hour growth hormone profiling in the assessment of acromegaly.

OBJECTIVES AND BACKGROUND: Recent guidelines recommend insulin-like growth factor (IGF-1), random growth hormone (GH) and nadir GH on an oral glucose tolerance test (OGTT) for assessment of acromegaly. At this Regional Centre, the 24-hour GH profile has also been used. DESIGN PATIENTS AND MEASUREMENTS: We evaluated 57 GH profiles from 34 patients from 2008 to 2012. Samples were drawn every 2 hour and matched with 0800 GH, nadir GH after OGTT and IGF-1. RESULTS: Correlations between the mean 13-point profiles and mean 5-point profile, OGTT nadir and 0800 GH were as follows: r = .99, .99 and .90, respectively (P < .01 for all). The correlation between the mean 13-point profiles and IGF-1 was r = .32 P = .02.Of 5 patients with very high 0800 GH preoperatively (≥20 µg/L), mean 13-point GH reduced by 88%-99% postoperatively. IGF-1 did not normalize in these patients, and all required extra treatment. Preoperatively, all patients had concordant 0800 GH and IGF-1. Postoperatively, 6 patients had 0800 GH <1 µg/L and high IGF-1; only 2 of these had a 13-point mean >1 µg/L, but 5 required further treatment. CONCLUSIONS: Growth hormone profiling is not necessary for assessing the majority of patients with acromegaly if there is confidence in the local IGF-1 assay. When undertaken, a 5-point profile is adequate. In patients with very high 0800 GH, 24-hour profiling was useful in demonstrating partial therapeutic success but did not alter management. Further work is needed to explore the possible role of GH profiling in stratifying patients with discordant IGF-1 and GH results.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.

Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as G protein-coupled receptors (GPCRs). AP2, a heterotetramer of α, ß, µ and σ subunits, links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membrane-associated cargo proteins. Here we show that missense mutations of AP2 σ subunit (AP2S1) affecting Arg15, which forms key contacts with dileucine-based motifs of CCV cargo proteins, result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular calcium homeostasis disorder affecting the parathyroids, kidneys and bone. We found AP2S1 mutations in >20% of cases of FHH without mutations in calcium-sensing GPCR (CASR), which cause FHH1. AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. Thus, our results identify a new role for AP2 in extracellular calcium homeostasis.

Identification of a second kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows localization to a <3.5 megabase pair region on chromosome 19q13.3.

CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogenous disorder that consists of three defined types, FHH1, FHH2, and FHH3 whose chromosomal locations are 3q21.1, 19p, and 19q13, respectively. FHH1, caused by mutations of the calcium-sensing receptor (CASR), occurs in more than 65% of patients, whereas the abnormalities underlying FHH2 and FHH3, which have each been described in single North American kindreds, are unknown. OBJECTIVE: The aim of this study was to determine the basis of FHH in a proband, who did not have CASR mutations, and her kindred. PATIENTS AND METHODS: The proband was a 43-yr-old woman who presented with a corrected serum calcium of 2.74 mmol/liter (normal = 2.15-2.55 mmol/liter), a serum PTH of 47 pg/ml (normal = 10-65 pg/ml), and a urinary calcium clearance:creatinine clearance of 0.006. She did not have a CASR mutation within the coding region and splice sites, and 24 members from three generations of her kindred were ascertained and investigated for serum abnormalities and cosegregation with polymorphic loci from chromosomes 3q21.1 and 19q13 using leukocyte DNA. RESULTS: Sixteen members were hypercalcemic with normal or elevated serum PTH concentrations and mild hypophosphatemia, features consistent with FHH3. Use of microsatellite and single nucleotide polymorphic loci from chromosome 19q13.3 demonstrated cosegregation with FHH in the kindred, with a peak LOD score = 5.98 at 0% recombination with D19S412. Analysis of recombinants mapped FHH to a 3.46-Mbp interval flanked centromerically by single nucleotide polymorphism rs1990932 and telomerically by D19S604. CONCLUSIONS: FHH3 may explain the calcium homeostasis disorder in those FHH patients who do not have CASR mutations.

Postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is characterised by the development of excessive tachycardia on standing with maintained blood pressure. We report a case of POTS in a 20-year-old girl with type 1 diabetes who presented with a 3-week history of lethargy, fatigue and orthostatic intolerance. Examination revealed a postural rise in heart rate of over 50 bpm with maintained blood pressure. This was associated with symptoms of light-headedness. Cardiac structure and function as assessed by ECG and ECHO were normal as was thyroid and adrenal function. POTS was confirmed with tilt table testing. Treatment was initiated with increased fluid intake, fludrocortisone and bisoprolol with improvement. POTS is a disabling condition which can significantly limit a patient's activities and working capacity and should be considered in a young, otherwise well patient who presents with orthostatic intolerance and a postural rise in heart rate.