Aims/hypothesis
The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent ...neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in
KCNJ11
(which encodes the inwardly rectifying potassium channel Kir6.2).
Methods
We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to
KCNJ11
mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg
−1
day
−1
glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in
Xenopus
oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer.
Results
In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA
1c
from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (
p
= 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years,
p
= 0.032). There was no difference in pre-transfer HbA
1c
(
p
= 0.87), weight-for-age
z
scores (SD score;
p
= 0.12) or sex (
p
= 0.17).
Conclusions/interpretation
Transfer from insulin is successful for most
KCNJ11
patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous ...studies suggested that people with
PNDM require lower sulfonylurea doses and have milder neurological features than those with
PNDM. However, these studies were short-term and included combinations of
-PNDM and
-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated
-PNDM.
We studied all 24 individuals with
PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.
Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 range 4.1-13.2 years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA
7.2% vs. 5.7%,
= 0.0004) and remained excellent long-term (1-year vs. 10-year HbA
5.7% vs. 6.5%,
= 0.04),
= 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide,
= 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).
Sulfonylurea treatment of
-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.
Summary
Objective
Patients with hyperthyroidism lacking autoimmune features but showing diffuse uptake on thyroid scintigram can have either Graves’ disease or germline activating TSH receptor (TSHR) ...mutation. It is important to identify patients with activating TSHR mutation due to treatment implication, but the overlapping clinical features with Graves’ disease make it difficult to discriminate these two conditions without genetic testing. Our study aimed to assess the potential of systematic TSHR mutation screening in adults with hyperthyroidism, showing diffuse uptake on thyroid scintigraphy but absence of TSH receptor antibodies (TRAb) and clinical signs of autoimmunity.
Design
A cross‐sectional study of Caucasian adults with hyperthyroidism, managed at three endocrine centres in the South West, UK, from January 2006 to April 2017.
Methods
We recruited 78 adult Caucasian patients with hyperthyroidism showing diffuse uptake on 99mTc‐pertechnetate thyroid scintigraphy but without TRAb and other autoimmune clinical features of Graves’ disease (such as thyroid‐associated ophthalmopathy or dermopathy). Genomic DNA of these patients was analysed for variants in the TSHR gene.
Results
Genetic analysis identified 11 patients with four variants in TSHR p.(Glu34Lys), p.(Asp36His), p.(Pro52Thr) and p.(Ile334Thr). None of these variants were pathogenic according to the American College of Medical Genetics and Genomics guideline.
Conclusions
Activating TSHR mutations are a rare cause of nonautoimmune adult hyperthyroidism. Our study does not support the routine genetic testing in adult patients with hyperthyroidism showing diffuse uptake on scintigraphy but negative TRAb and lacking extrathyroidal manifestations of Graves’ disease.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aims/hypothesis
The majority of infants with neonatal diabetes mellitus present with severe ketoacidosis at a median of 6 weeks. The treatment is very challenging and can result in severe ...neurological sequelae or death. The genetic defects that cause neonatal diabetes are present from birth. We aimed to assess if neonatal diabetes could be diagnosed earlier by measuring glucose in a dried blood spot collected on day 5 of life.
Methods
In this retrospective case–control study we retrieved blood spot cards from 11 infants with genetically confirmed neonatal diabetes (median age of diagnosis 6 range 2–112 days). For each case we also obtained one (
n
= 5) or two (
n
= 6) control blood spot cards collected on the same day. Glucose was measured on case and control blood spot cards. We established a normal range for random glucose at day 5 of life in 687 non-diabetic neonates.
Results
All 11 neonates with diabetes had hyperglycaemia present on day 5 of life, with blood glucose levels ranging from 10.2 mmol/l to >30 mmol/l (normal range 3.2–6.0 mmol/l). In six of these neonates the diagnosis of diabetes was made after screening at day 5, with the latest diagnosis made at 16 weeks.
Conclusions/interpretation
Neonatal diabetes can be detected on day 5 of life, preceding conventional diagnosis in most cases. Earlier diagnosis by systematic screening could lead to prompt genetic diagnosis and targeted treatment, thereby avoiding the most severe sequelae of hyperglycaemia in neonates.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chylothorax after coronary artery bypass grafting is a rare complication and leads to increased mortality and morbidity. Because of the rarity of this complication, its management is debatable. We ...present the case of a 41 years old male patient who had a left sided chylothorax after coronary artery bypass grafting. The patient was managed conservatively with low fat diet and drainage of the chylothorax. A thorough search of the literature published on the subject was done and treatment strategies employed by various authors were studied. Various treatment options are conservative management with chest tube drainage, octreotide and low-fat diet or diet containing medium chain triglycerides. Invasive options are video assisted thoracoscopy and thoracotomy with or without ligation of thoracic duct. An account of the management strategies employed by various authors is presented in this report.
Key Clinical Message
A 60‐year‐old man with a pre‐existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the ...first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult.
A 60‐year‐old man with a pre‐existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
11 patients were referred to our Molecular Genetics Department at the Royal Devon and Exeter Hospital between 2000-2012 with a physician's diagnosis of remitting diabetes. Our aim was to identify ...patients with remitting diabetes whose clinical presentation is not explained by any known aetiology of diabetes.
We obtained longitudinal clinical data on all 11 patients from the hospital records. All patients were aged between 0.5 and 35 years at diagnosis. We applied clinical criteria derived from the literature to establish 1) definite diabetes, 2) diabetes initially severe-requiring treatment with insulin, 3) remission of diabetes, and 4) exclusion of known causes of remitting diabetes.
10 out of 11 patients had an alternative explanation for their remission or a clear diagnosis was not identified. We identified a single patient with idiopathic remitting diabetes using these criteria. The patient was a white Caucasian female diagnosed aged 15 with symptoms of diabetes, laboratory glucose of 21.2 mmol/L and HbA1c 134 mmol/mol. Her BMI was 23.6 kg/m2. She was treated with basal bolus insulin but discontinued two years after diagnosis due to hypoglycaemia. 13 years post diagnosis, she had a normal oral glucose tolerance test during pregnancy (fasting glucose 4.5 mmol/L, 2 hr glucose 4.8 mmol/L) and an HbA1c of 30 mmol/mol. This patient does not appear to have Type 1 or Type 2 diabetes, and furthermore does not fit into current classifications of diabetes.
Idiopathic remitting diabetes is rare but does exist. Strict clinical criteria are important to ensure patients have a robust clinical diagnosis. Identification of more patients with idiopathic remitting diabetes will enable further study of the clinical course of this syndrome. Applying these strict criteria will allow the identification of patients with remitting diabetes to assess its aetiology.
Full text
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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