Summary Primary hyperparathyroidism (PHPT) is characterised by the overproduction of parathyroid hormone (PTH) due to parathyroid hyperplasia, adenoma or carcinoma and results in hypercalcaemia and a raised or inappropriately normal PTH. Symptoms of hypercalcaemia occur in 20% of patients and include fatigue, nausea, constipation, depression, renal impairment and cardiac arrythmias. In the most severe cases, uraemia, coma or cardiac arrest can result. Primary hyperparathyroidism in pregnancy is rare, with a reported incidence of 1%. Maternal and fetal/neonatal complications are estimated to occur in 67 and 80% of untreated cases respectively. Maternal complications include nephrolithiasis, pancreatitis, hyperemesis gravidarum, pre-eclampsia and hypercalcemic crises. Fetal complications include intrauterine growth restriction; preterm delivery and a three to five-fold increased risk of miscarriage. There is a direct relationship between the degree of severity of hypercalcaemia and miscarriage risk, with miscarriage being more common in those patients with a serum calcium greater than 2.85 mmol/L. Neonatal complications include hypocalcemia. Herein, we present a case series of three women who were diagnosed with primary hyperparathyroidism in pregnancy. Case 1 was diagnosed with multiple endocrine neoplasia type 1 (MEN1) in pregnancy and required a bilateral neck exploration and subtotal parathyroidectomy in the second trimester of her pregnancy due to symptomatic severe hypercalcaemia. Both case 2 and case 3 were diagnosed with primary hyperparathyroidism due to a parathyroid adenoma and required a unilateral parathyroidectomy in the second trimester. This case series highlights the work-up and the tailored management approach to patients with primary hyperparathyroidism in pregnancy. Learning points: Primary hyperparathyroidism in pregnancy is associated with a high incidence of associated maternal fetal and neonatal complications directly proportionate to degree of maternal serum calcium levels. Parathyroidectomy is the definitive treatment for primary hyperparathyroidism in pregnancy and was used in the management of all three cases in this series. It is recommended when serum calcium is persistently greater than 2.75 mmol/L and or for the management of maternal or fetal complications of hypercalcaemia. Surgical management, when necessary is ideally performed in the second trimester. Primary hyperparathyroidism is genetically determined in ~10% of cases, where the likelihood is increased in those under 40 years, where there is relevant family history and those with other related endocrinopathies. Genetic testing is a useful diagnostic adjunct and can guide treatment and management options for patients diagnosed with primary hyperparathyroidism in pregnancy, as described in case 1 in this series, who was diagnosed with MEN1 syndrome. Women of reproductive age with primary hyperparathyroidism need to be informed of the risks and complications associated with primary hyperparathyroidism in pregnancy and pregnancy should be deferred and or avoided until curative surgery has been performed and calcium levels have normalised.
MODY is a rare form of diabetes caused by impaired insulin production attributable to autosomal dominant monogenic mutations. It is an important diagnosis as it results in a treatment change for 25% of patients, allows for the screening of 1 st degree relatives and identifies patients who have MODY subtypes associated with reduced rates of micro- and macro-vascular complications. Diagnosing MODY is challenging and several MODY risk factor calculators have been proposed to guide rational genetic testing. The aim of this study was to retrospectively apply the MODY risk factor calculators to patients with diagnosed MODY who attended the diabetes service at a tertiary hospital in the West of Ireland to identify the most accurate calculator in predicting MODY in this patient cohort. MODY risk factor calculators in the literature focus on young age at diagnosis, low BMI and low HbA1c as defining features of MODY. Ellard, Bellanne-Chantelot et al. (2008) proposed age at diagnosis ≤25, BMI <30 and HbA1c ≤58.8 mmol/L as the recommended criteria for genetic testing in MODY, and this captured 6/21 (28.57%) patients with MODY in our cohort. Thanabalasingham, Pal et al. (2012) proposed age at diagnosis ≤30, BMI <30 and HbA1c ≤63.9 mmol/L, which accounted for 8/21 (38.1%) of our MODY patients. The MODY Probability Calculator proposed by Shields et al. (2012) was developed using logistic regression to determine the probability of MODY. Variables include current age, age at diagnosis, sex, treatment with insulin, time to insulin treatment, BMI, HbA1c and parental history of diabetes. The MODY Probability Calculator cannot be directly compared to the other calculators, as it does not define clinical criteria in a binary fashion but assigns a weighting to each factor. Patients have to be aged ≤35 at diagnosis for this calculator to be applied, which resulted in the exclusion of 3/22 patients in our cohort. 9/22 (40.9%) patients had a positive predictive value (PPV) of >50%, which conferred a 0.47/100 false negative rate and a 3/100 false positive rate if used as the basis for referring for genetic testing. 5/22 (22.73%) patients had a PPV of >75%, which conferred a 0.9/100 false negative rate and a 1.2/100 false positive rate, which is highly sensitive and specific. 12/22 (54.55%) patients had a PPV of >20%, which conferred a 0.14/100 false negative rate and a 16.8/100 false positive rate. This work demonstrates that the MODY Probability Calculator currently achieves the best balance of sensitivity / specificity in diagnosing patients with MODY. Nevertheless, a significant portion (10/22) of known MODY patients were not identified. Limitations include excluding patients aged >35 at diagnosis and excluding patients with a strong family history of diabetes who do not have an affected parent. These calculators are diagnostic adjuncts in the Endocrinologist’s toolbox to stratify MODY risk but do not replace clinical judgement.
Introduction Primary hyperparathyroidism (PHPT) in pregnancy is rare, with a reported incidence of <1%. It is associated with serious maternal and foetal complications, and is genetically determined in ~10% of cases. Confirming a genetic diagnosis can guide management of inherited PHPT, and enables screening for syndrome-related diseases. This case series highlights the role of genetic testing in the tailored management of patients with PHPT in pregnancy. Clinical cases Case 1 is a 20 year old female who was diagnosed with PHPT at 5 weeks gestation after presentation with nausea. She was hypercalcaemic (2.78 mmol/L at diagnosis; 2.98 mmol/L pre-parathyroidectomy), had negative neck ultrasonography and a MEN1 mutation (exon 2, c.236_237del, p.(Pro79fs)) on genetic testing in pregnancy. After initial management with oral and IV rehydration, her severe symptomatic hypercalcaemia required treatment with open neck exploration and a 3 gland parathyroidectomy in the 2 nd trimester. The standard surgical approach of a 3.5 gland parathyroidectomy was avoided due to the risk of inducing hypoparathyroidism. Intra-operative PTH dropped 53.8% post 3 gland parathyroidectomy. Parathyroid hyperplasia on histology was consistent with the diagnosis of MEN1 syndrome. The patient’s symptoms resolved post-operatively and foetal investigations are normal at 28 weeks gestation. She is receiving close obstetric follow-up including 3-weekly foetal growth scans due to the increased risk of IUGR. She was counseled on her increased risk of pancreatic and pituitary tumours and her 1 st degree relatives are undergoing genetic screening. Case 2 is a 40 year old female with a known diagnosis of PHPT who was awaiting parathyroidectomy prior to pregnancy. She was hypercalcaemic (2.78 mmol/L at 7 weeks; 2.99 mmol/L pre-parathyroidectomy), and had a lower left parathyroid adenoma on ultrasound and pre-pregnancy SPECT-CT. Genetic testing was not performed as she was 40 at diagnosis and had no contributory family history. After failure of conservative management, parathyroidectomy of the left superior parathyroid gland was performed in the 2 nd trimester. Histology results confirmed a left inferior parathyroid adenoma, concordant with the radiological findings. Her symptoms improved post-operatively; she is receiving close obstetric follow-up. Clinical lessons Genetic testing enables the management of PHPT to be tailored appropriately. It can better inform the surgical approach; including the need for subtotal parathyroidectomy and bilateral neck exploration in those cases at risk of multiple parathyroid gland disease, as demonstrated in our case with MEN1. Finally this case series demonstrates that surgical management of PHPT should be considered for select cases in pregnancy and thus far no maternal or foetal complications have arisen in these featured cases following surgical intervention.
Background: A better understanding of the influence of genetic factors on the response to lifestyle interventions in people with obesity may allow the development of more personalised, effective and efficient therapeutic strategies. We sought to determine the influence of six obesity-related genetic risk scores on the magnitude of weight lost by patients with severe obesity who completed a dietary intervention. Methods: In this single-centre prospective cohort study, participants with severe and complicated obesity who completed a 24-week, milk-based meal replacement programme were genotyped to detect the frequency of common risk alleles for obesity and type 2 diabetes-related traits. Genetic risk scores (GRS) for six of these traits were derived. Participants with a potentially deleterious monogenic gene variant were excluded from the analysis. Results: In 93 patients completing the programme who were not carrying a known obesity-related gene mutation, 35.5% had diabetes, 53.8% were female, mean age was 51.4 ± 11 years, mean body mass index was 51.5 ± 8.7 and mean total weight loss percent at 24 weeks was 16 ± 6.3%. The waist–hip ratio (WHR) GRS was inversely associated with percentage total weight loss at 24 weeks (adjusted β for one standard deviation increase in WHR GRS −11.6 [−23.0, −0.3], p = 0.045), and patients in the lowest tertile of WHR GRS lost more weight. Conclusions: Patients with severe and complicated obesity with a genetic predisposition to central fat accumulation had less weight loss in a 24-week milk-based meal replacement programme, but there was no evidence for influence from the five other obesity-related genetic risk scores on the response to dietary restriction.
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