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Hicks K.A.,Section of Diabetes and Endocrinology | Kushner J.A.,Baylor College of Medicine | Heptulla R.,Yeshiva University | Ham J.N.,Baylor College of Medicine
Journal of Pediatric Endocrinology and Metabolism

Although KCNJ11 mutations of the KATP channel within the β cell are known to prevent insulin secretion and cause permanent neonatal diabetes mellitus, the genotype-phenotype correlation continues to be of clinical interest. We report the clinical outcomes in monozygotic twins with neonatal diabetes due to heterozygous mutations in KCNJ11 at R201H. The twins demonstrated concordant clinical outcomes after transitioning from insulin to oral sulfonylurea therapy at 4 months of age. Both twins remained on sulfonylurea therapy while achieving similar growth, development, and metabolic goals. They exhibit marked sensitivity to sulfonylurea therapy with current dosing at 0.05 and 0.06 mg/kg per day at age 5 years which deviates from the approximate maintenance dose of 0.4 mg/kg per day at the time of transition and subsequent follow-up. Metabolic control provided by low-dose sulfonylurea therapy is likely due to early age at transition from insulin to sulfonylurea therapy and possible preservation of endogenous insulin secretion. Source

Tryggestad J.B.,Section of Diabetes and Endocrinology | Li S.,University of Oklahoma | Chernausek S.D.,Section of Diabetes and Endocrinology
Journal of Medical Case Reports

Introduction. Arhinia, congenital absence of the nose, is a rare malformation. We present the third reported case of arhinia accompanied by hypogonadism and demonstrate that this is due to gonadotropin deficiency. Case presentation. A 13-year-old Caucasian boy with congenital arhinia presented for evaluation of delayed puberty and micropenis. We examined genes known to be associated with hypogonadotropic hypogonadism for mutations and performed a chromosomal microarray to assess copy number variation. Conclusion: No mutations in KAL1, FGFR1, PROK2, PROKR2, FGF8, CHD7 and GnRHR were identified in our patient and there were no copy number variations observed that would explain the phenotype. Though studies are limited in such patients, we suggest that hypogonadotropic hypogonadism is associated with arhinia and that the two entities likely result from a common genetic cause that affects early nasal development and gonadotropin-releasing hormone neuron formation or migration. © 2013 Tryggestad et al; licensee BioMed Central Ltd. Source

Adlan M.A.,Section of Diabetes and Endocrinology
Current diabetes reviews

Impaired glucose tolerance and diabetes mellitus are a manifestation of several well recognised endocrine disorders. Hyperglycaemia subsides upon removal of the underlying cause in these conditions - usually a hormone secreting tumour. We describe two subjects who were cured of their poorly controlled diabetes mellitus following surgical removal of a phaeochromocytoma and a cortisol secreting adrenal adenoma and review the mechanisms underlying glucose intolerance in endocrine disorders. The reported incidence of diabetes is variable in these conditions and may range between 2-95%. The severity is also variable as some affected individuals have only minor glucose intolerance while others have frank symptomatic diabetes mellitus which forms a major manifestation of their illness. The mechanisms causing hyperglycaemia are (a) insulin resistance, (b) increased hepatic glucose production and output, (c) decreased insulin production and release and (d) increased intestinal glucose absorption. Multiple intermediate mechanisms which include electrolyte perturbations and hormone receptor and post receptor mediated effects are responsible for these abnormalities. An understanding of these mechanisms and diagnostic strategies is important as these may be used to advantage in managing these patients. We describe some of these in greater detail below. Source

Kamath C.,Section of Diabetes and Endocrinology | Young S.,RSR Limited | Kabelis K.,RSR Limited | Sanders J.,RSR Limited | And 5 more authors.
Clinical Endocrinology

Context Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies. Patient An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. Measurements and Results Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. Conclusions The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function. © 2012 Blackwell Publishing Ltd. Source

Kamath C.,Section of Diabetes and Endocrinology | Govindan J.,Section of Diabetes and Endocrinology | Premawardhana A.D.,Section of Diabetes and Endocrinology | Wood S.J.,Section of Diabetes and Endocrinology | And 3 more authors.
Clinical Medicine, Journal of the Royal College of Physicians of London

Lithium (Li) may cause multiple endocrinopathies, including hypercalcaemia, thyroid dysfunction and nephrogenic diabetes insipidus (NDI), but rarely in the same patient. The management of NDI remains a challenge. We report on a patient on long-term Li who had simultaneous NDI (paired serum and urine samples had abnormal osmolalities, typical of NDI, and treatment with parenteral desmopressin failed to affect urinary volume and serum osmolality), 'destructive' thyroiditis (hyperthyroidism, absent radioiodine uptake and absent thyrotrophin receptor antibodies) and primary hyperparathyroidism (compatible biochemistry, urine calcium excluding 'set point' anomalies and hypocalciuric hypercalcaemia, and normal parathyroid imaging). The thyroiditis resolved spontaneously and hypercalcaemia responded to reduction of Li dose. The NDI was unresponsive to amiloride, thiazides and ibuprofen in combination. However, urine output was reduced by 50% when a high dose of oral desmopressin was given. We conclude that Li-induced multiple endocrinopathy remains rare and, although NDI is difficult to manage, high dose oral desmopressin should be tried when other medications fail. © Royal College of Physicians, 2013. Source

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