Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study.

Objective: To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study. Methods: Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups. Results: Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01). Conclusion: This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity.

Normocalcemic primary hyperparathyroidism is an early stage of primary hyperparathyroidism according to fibroblast growth factor 23 level.

Introduction: Normocalcemic primary hyperparathyroidism is a variant of primary hyperparathyroidism with consistently normal albumin-adjusted or free-ionized calcium levels. It may be an early stage of classic primary hyperparathyroidism or could represent primary kidney or bone disorder characterized by permanent elevation of PTH level. Aim of the study: The study aims to compare the FGF-23 levels in patients with PHPT, NPHPT, and normal calcium and PTH levels. Methods: Our study included patients who were referred to the endocrinology clinic with a presumptive diagnosis of primary hyperparathyroidism, an isolated increased level of PTH, or reduced bone densitometry. For each patient, we performed blood analysis of FGF-23, calcium, phosphate, vitamin D [25(OH)D3], estimated glomerular filtration rate (eGFR), bone turnover markers, and urine analysis for calcium/creatinine ratio. Results: Our study included 105 patients. Thirty patients with hypercalcemic hyperparathyroidism (HPHPT group), thirty patients with elevated PTH and normal calcium levels (NPHPT group), and 45 patients with normal calcium and PTH levels in the control group. FGF 23 level was 59.5± 23 pg/ml in the NPHPT group, 77 ± 33 pg/ml in the HPHPT group, and 49.7 ± 21.7 pg/ml in the control group (p=0.012). The phosphate level was lowest in the HPHPT group: 2.9 ± 0.6 vs 3.5 ± 0.44 in the NPHPT and 3.8 ± 0.5 in the control groups (p=0.001). No differences were found in eGFR, 25(OH)D3, C-terminal telopeptide type I collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) levels, and bone densitometry scores between the three study groups. Conclusion: Our findings suggest that NPHPT is an early stage of PHPT. Further studies are needed to determine the role of FGF-23 and its usefulness in NPHPT.

Central diabetes insipidus: a late sequela of BNT162b2 SARS-CoV-2 mRNA vaccine?

BACKGROUND: The development of an effective vaccine is a powerful tool to contain the global spread of coronavirus disease 2019 (COVID-19). Still, it raises potential safety concerns about the subsequent enhancement of associated immunopathology. Increasing evidence shows that the endocrine system, including the hypophysis, may be involved in COVID-19. Moreover, occasional but increasing reports of endocrine disorders involving the thyroid have been reported after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Among them, a few cases encompass the pituitary. Here we report a rare case of central diabetes insipidus following SARS-CoV-2 vaccination. CASE PRESENTATION: We report a 59-year-old female patient with a 25-year history of Crohn's disease in long-term remission, who presented with sudden onset of polyuria eight weeks after administration of an mRNA SARS-CoV-2 vaccination. Laboratory evaluation was consistent with isolated central diabetes insipidus. Magnetic resonance imaging displayed involvement of the infundibulum and the posterior hypophysis. Eighteen months after the vaccination, she is still under desmopressin treatment and had stable pituitary stalk thickening on magnetic resonance imaging. Although Crohn's disease-associated hypophysitis has been reported, it is scarce. In the absence of other recognizable causes of hypophysitis, we believe the involvement of the hypophysis in our patient may have been triggered by the SARS-CoV-2 vaccine. CONCLUSIONS: We report a rare case of central diabetes insipidus potentially associated with SARS-CoV-2 mRNA vaccination. Further studies are needed to understand better the mechanisms underlying autoimmune endocrinopathies development in the context of COVID-19 infection and SARS-CoV-2 vaccination.

Blood glucose control with different treatment regimens in type 2 diabetes patients hospitalized with COVID-19 infection: A retrospective study.

Coronavirus disease (COVID-19) is closely associated with hyperglycemia and a worse prognosis in patients with a previous diagnosis of type 2 diabetes mellitus. A few studies investigated the effects of diabetes treatment regimens in these patients during hospitalization. Here, we evaluate the impact of insulin and non-insulin therapy on glucose control in patients with type 2 diabetes admitted with COVID-19. This is a retrospective study including 359 COVID-19 patients with type 2 diabetes. Patients were divided into 2 groups according to diabetes treatment during hospitalization. The first group included patients treated with insulin only, and the second group patients treated with other antidiabetic agents with or without insulin. Average blood glucose was higher in the insulin-only treatment group (201 ± 66 mg/dL vs 180 ± 71 mg/dL, P = .004), even after excluding mechanically ventilated patients (192 ± 69 vs 169 ± 59 mg/dL, P = .003). In patients with moderate severity of COVID-19, average blood glucose was also significantly higher in the insulin-only treated group (197 ± 76 vs 168 ± 51 mg/dL, P = .001). Most patients (80%) in the combination treatment group received metformin. Moderately affected COVID-19 patients with type 2 diabetes could safely be treated with antihyperglycemic medications with or without insulin.

Ectopic Cushing's syndrome in a patient with metastatic Merkel cell carcinoma: A case report.

BACKGROUND: Ectopic Cushing syndrome (ECS) is a rare condition commonly associated with neuroendocrine tumors (NET), mainly bronchial carcinoids. The association of paraneoplastic syndrome with Merkle cell carcinoma (MCC) is limited to individual case reports. CASE SUMMARY: In this article we report an unusual and striking presentation of ECS in a patient with known metastatic MCC. An elderly patient presented with new onset severe hypertension, hyperglycemia and hypokalemia, muscle wasting, and peripheral edema. A diagnosis of adrenocorticotropic hormone dependent, non-pituitary, Cushing syndrome was established. Medical therapy inhibiting adrenal function was promptly started but unfortunately the patient survived only a few days after diagnosis. CONCLUSION: The occurrence of an aggressive form of ECS in patients with NET should be recognized as an ominous event. To our knowledge, the association of this complication in a patient with MCC had not been reported.

New Insights on Effects of Glucocorticoids in Patients With SARS-CoV-2 Infection.

OBJECTIVE: Since January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients. METHODS: To review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury. RESULTS: In our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs. CONCLUSION: For clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.

Severe hypercalcemia in a patient with chronic lymphocytic leukemia and non-small cell lung carcinoma: A case report.

RATIONALE: Hypercalcemia is a common finding in patients with advanced-stage cancers. Paraneoplastic hypercalcemia is commonly associated with dismal prognoses, with survival rates of about 3 months. In this paper, we report on a patient with advanced chronic lymphocytic leukemia and non-small cell lung carcinoma who developed severe hypercalcemia and discuss the diagnosis and treatment of this metabolic complication. PATIENT CONCERNS: A 56-year old male with a 2-year history of Rai stage IV chronic lymphocytic leukemia presented with life-threatening hypercalcemia. Positron emission tomography/computed tomography revealed a suspicious lung lesion. A transbronchial biopsy was performed from the upper left lobe. Due to the small size of the specimen, immunohistochemical markers were performed and revealed positive staining for cytokeratin 7 and negative for TTF-1, napsin A and p 40, which were consistent with non-small cell lung carcinoma. DIAGNOSIS: Humoral hypercalcemia of malignancy was diagnosed. INTERVENTION: The patient was treated with saline infusion, calcitonin, intravenous pamidronate, followed with denosumab. OUTCOMES: The hypercalcemia was successfully treated and the patient's calcium levels returned to normal. Further evaluation revealed a non-small cell lung carcinoma as a second primary malignancy. The patient was treated with venetoclax for his refractory CLL and received chemotherapy and immunotherapy for lung adenocarcinoma. Several days after starting venetoclax, he developed Legionella pneumonia and short time after the second course of chemotherapy, a severe sepsis occurred and he passed away. LESSONS: Coexistence of 2 unrelated malignancies, whichever could be a reason for hypercalcemia of malignancy is a rare event. Severe hypercalcemia, which is possible but rare feature of CLL should be a reason for further prompt evaluation.

Effects of Recommendations for Diabetes Management at Hospital Discharge on Long-Term Diabetes Control.

OBJECTIVE: To determine the impact of diabetes-specific recommendations at 1 year after hospital discharge on glycemic control and diabetes care in an outpatient setting. METHODS: A total of 139 patients with type 2 diabetes on a basal-bolus insulin regimen during hospitalization were included in the statistical analysis. We gathered data on treatment regimens after 12 to 16, 26 to 30, and 52 to 56 weeks following discharge as well as glycosylated hemoglobin (HbA1c) levels for all patients. Prescriptions for diabetes therapy were retrieved. All changes in insulin or oral/noninsulin injectable drug regimens were recorded. RESULTS: Half of the patients (n = 69) were discharged on their preadmission regimen (no change), and a change in the home treatment was recommended in the other half (n = 70). In the group of patients whose preadmission therapy was adjusted, HbA1c decreased from 9.6% (80 mmol/mol) to 8.5% (69 mmol/mol) (P = .0004) 1 year after discharge. In the group of patients discharged on their preadmission regimen, no significant changes in HbA1c levels during the study were observed. At follow-ups occurring 12 to 16 weeks after discharge, 52% (95% CI: 37.4%-66.3%) of patients in the change group had their treatment modified, compared with 18.6% (95% CI: 9.7%-30.9%) in the no-change group. In the group of patients discharged on their preadmission regimen, no significant change was observed. At the beginning of the study, patients in the change treatment group had higher HbA1c levels than patients in the no-change group (9.6 ± 2.0 vs 8.6 ± 1.7, P < .001). At the end of the study, no significant changes in terms of HbA1c levels were found between the groups (8.8 ± 1.9 vs 8.5 ± 1.9, P = .2). CONCLUSIONS: Significant improvement in diabetes control occurred 1 year after hospital discharge in patients who underwent modifications in their treatment. This supports the relevance of providing and implementing proper care recommendations at transition.

Testosterone Management in Aging Males: Surveying Clinical Practices of Urologists and Endocrinologists in Israel.

INTRODUCTION: Although there is increased public concern about low testosterone levels in aging men, the diagnosis and treatment of hypogonadism in this growing population is controversial. AIM: To document the current practices of endocrinologists and urologists in the management of older men with low testosterone in Israel. METHODS: A 20-question survey of the management of hypogonadism was sent to members of the Israel Endocrine Society and the Israeli Urology Association MAIN OUTCOME MEASURES: Participants were interviewed about their practice in diagnostic workup, prescription habits and monitoring of testosterone therapy. RESULTS: The response rate was low (range 8-12%). Significant differences were found between members of the 2 professional associations. Overall, endocrinologists take a more conservative approach to the diagnosis and initial workup, modes of treatment, and to concerns about the safety of testosterone therapy. A divergence from the published clinical guidelines was also noted in some aspects of the clinical practices in both groups. CLINICAL IMPLICATIONS: Significant variances in the diagnosis and treatment approach of hypogonadism between endocrinologists and urologists, as well as divergences from clinical guidelines, may lead to misuse of testosterone therapy. STRENGTHS & LIMITATIONS: This is the first study undertaken in Israel among urologists and endocrinologists of this increasingly recognized health issue. In our country, these 2 groups of physicians comprise nearly all of the testosterone treatment providers. The limitation of this study is linked to bias of all surveys based on subjective reporting, the fact that it was performed in only 1 country, and that we did not control for the specific assay used to measure testosterone levels. CONCLUSIONS: These findings highlight the need for the implementation of coordinated guidelines to facilitate the appropriate diagnosis and treatment of men who can benefit from testosterone therapy and to minimize the risks of this therapy. Ishay A, Tzemah S, Nitzan R, et al. Testosterone Management in Aging Males: Surveying Clinical Practices of Urologists and Endocrinologists in Israel. Sex Med 2019;7:409-417.

Hyperprolactinemia diagnosis in elderly men: a cohort of 28 patients over 65 years.

PURPOSE: To characterize a cohort of elderly men with prolactinomas and their response to treatment. METHODS: We have identified 28 elderly men diagnosed after the age of 65 with prolactinomas at seven different endocrine clinics in Israel. A retrospective electronic chart review identified a control group of 76 younger men with macroprolactinomas treated in one of the centers. RESULTS: Mean age at diagnosis was 71.3 ± 5.6 (range 65-86) years, and current age 76.6 ± 7.5 years. Initial complaints leading to diagnosis included sexual dysfunction in 17 males (61%), headaches in two patients (7%), and visual abnormalities in two (7%). Three men presented with osteoporosis. Ten patients (36%) were diagnosed incidentally following brain imaging for unrelated reasons. Seventeen patients (61%) had macroadenoma, while eleven (39%) presented with a microadenoma or no visible adenoma. Mean prolactin (PRL) at presentation was 1594 (median 382; range 50-18,329) ng/ml. Testosterone was low in 21 men. Patients were treated with cabergoline (max dose, 1.1 ± 0.5 mg/week), except for one given bromocriptine; none required pituitary surgery or radiotherapy. Treatment normalized PRL in 24 patients, and in three men PRL suppressed to <2 ULN. Fifteen men normalized testosterone, three improved without normalization, and in three the normal baseline level increased. After a mean follow-up of 5.3 years, 14/15 patients harboring a macroadenoma showed significant adenoma shrinkage. Most patients reported improvement of low libido/erectile dysfunction. In the control group 60 men (79%) achieved PRL normalization. CONCLUSIONS: Elderly men with prolactinomas are diagnosed incidentally in 36% of cases. Long-term medical therapy is successful, achieving biochemical remission, adenoma shrinkage, and clinical improvement in almost all patients.

Good glycemic control of gestational diabetes mellitus is associated with the attenuation of future maternal cardiovascular risk: a retrospective cohort study.

BACKGROUND: To examine whether glycemic control of gestational diabetes mellitus (GDM) could modify the risk for future maternal metabolic and cardiovascular morbidities. METHODS: A retrospective cohort study of women with a first diagnosis of GDM who delivered between 1991 and 2011. Women were divided into groups of good and poor glycemic control, defined as a mean daily glucose of up to 95 mg/dL (N = 230) and more than 95 mg/dL (N = 216), respectively. In addition, a control group of women without GDM (N = 352) was also analyzed. The primary outcomes were the development of type 2 diabetes mellitus (T2DM), obesity, hypertension, or dyslipidemia. RESULTS: Mean follow-up time was 15.8 ± 5.1 years. Assessment was performed at a maternal age of 45 ± 7 years. The rates of the study outcomes in the control, GDM with good glycemic control and GDM with poor glycemic control were as follows: T2DM [19 (5.4%), 87 (38%), 127 (57%)]; hypertension [44 (13%), 42 (18%), 44 (20%)]; obesity [111 (32%), 112 (48%), 129 (58%)]; and dyslipidemia [49 (14%), 67 (29%), 106 (48%)]. Glycemic control was an independent risk factor for T2DM in multivariate Cox regression analysis (hazard ratio (HR) for poor glycemic control vs. controls 10.7 95% CI [6.0-19.0], good glycemic control vs. control HR 6.0 [3.3-10.8], and poor glycemic control vs. good glycemic control HR 1.8 [1.3-2.4]). Glycemic control was also an independent risk factor for dyslipidemia (poor glycemic control vs. controls HR 3.7 [2.3-5.8], good glycemic control vs. controls HR 2.0 [1.2-3.2], and poor glycemic control vs. good glycemic control HR 1.8 1.8 [1.3-2.6]). The fasting glucose level during oral glucose tolerance test (OGTT) was also an independent risk factor for these complications. The interaction term between glycemic control and the fasting value of the OGTT was not statistically significant, suggesting that the effect of glycemic control on the rate of future T2DM and dyslipidemia was not modified by the baseline severity of GDM. CONCLUSION: GDM and especially poor glycemic control are associated with T2DM and dyslipidemia. Strict glycemic control for reducing that risk should be evaluated in prospective trials.

Glycemic control with a basal-bolus insulin protocol in hospitalized diabetic patients treated with glucocorticoids: a retrospective cohort study.

BACKGROUND: Improved glycemic control is the desired outcome after the discharge of patients with diabetes. We aimed to determine the efficacy of a basal-bolus insulin protocol in hospitalized patients with diabetes treated with glucocorticoids. METHODS: A retrospective cohort study compared the glycemic control of 150 hospitalized patients with diabetes and elevated inflammatory markers who were either treated with (n = 61) or without glucocorticoids (n = 89). All patients were treated with a basal-bolus regimen. RESULTS: Glycosylated hemoglobin A1C (HbA1C) levels, mode of diabetes treatment before admission, length of hospitalization and inflammatory markers were similar in both groups of patients (treated and untreated with glucocorticoid). There was a trend toward female predominance in the glucocorticoid-treated group. Mean daily glucose levels were higher in patients taking glucocorticoids when compared with untreated patients (12.5 ± 2.7 mmol/l vs. 10.9 ± 2.4 mmol/l, p < .0001), and significantly higher at 5:00 PM (13.1 ± 3.4 vs. 10.2 ± 3 mmol/l, p < .0001), and 8:00 P.M. (13.9 ± 4.1 mmol/l vs. 11 ± 3.1 mmol/l, p < 0.001) . No difference was detected between the two groups in prandial and basal insulin doses during hospitalization. Overall, 64% of patients in the glucocorticoid-treated group versus 39% in the untreated group had inadequate glycemic control during hospitalization (p = 0.003). CONCLUSION: A significantly higher percentage of patients with diabetes who were treated with glucocorticoids during hospitalization did not achieve glycemic control with a basal-bolus insulin protocol. These patients had significantly higher mean blood glucose levels due to elevated levels in the afternoon and evening. New basal-bolus protocols with appropriate adjustments of short acting insulin are needed to treat patients with diabetes on glucocorticoid therapy.

[Historical aspects and new formulations of levothyroxine sodium for hypothyroidism treatment].

At the end of the 19th century symptoms and signs of hypothyroidism were described in the medical literature. At that time myxedema was a main clinical presentation of the hypothyroid patient. Today, the diagnosis of hypothyroidism is determined mainly by laboratory evaluation with most patients exhibiting only a few clinical signs of thyroid dysfunction. The treatment of hypothyroidism has progressed from partially purified extracts of bovine thyroid gland to an oral administration of synthetic hormone. Since 1981 the only thyroid hormone replacement drug approved by the Israeli Ministry of Health was the Eltroxin brand, made by GlaxoSmithKline. Levothyroxine has a narrow therapeutic range, thus a potential variance exists in the therapeutic efficacy among different levothyroxine preparations. In 2007 the Food and Drugs Administration (FDA) announced that the difference in potency of various levothyroxine brands should not exceed ten percent. In 2007 the GSK Company moved the manufacturing of Eltroxin from Canada to Germany. This resulted in a change of the inert ingredients of the drug. It is of interest to know that since the arrival of the new thyroxine formulation in the Israeli pharmaceutical market there has been a dramatic increase in reports of adverse reactions. The media coverage of adverse effects associated with Eltroxin became widespread in television, newspapers and internet sites. This led to a burden on the healthcare system, manifesting itself by an increase in thyroid blood tests, physician follow-up visits, as well as the importing and distribution of a new brand of thyroxine.

Hypothalamic-pituitary-adrenal axis function following intravitreal triamcinolone acetonide injection.

To evaluate the pituitary-adrenal axis function by means of the adrenocorticotropic hormone (ACTH) stimulation test following a single intravitreal injection of triamcinolone acetonide (IVTA). Prospective comparative clinical interventional study. Twenty-eight patients (28 eyes) received a single IVTA (4 mg in 0.1 ml) for macular edema. The basal cortisol level and the response to 1 µg adrenocorticotropic hormone stimulation were determined on the morning before IVTA injection and at 1 day and 1, 2, and 4 weeks after IVTA injection. Results were compared with those obtained from a control group of 50 healthy subjects. All patients in the study had normal basal cortisol and normal response to ACTH challenge before receiving IVTA. 1 day following IVTA, basal cortisol was suppressed in one patient in the study group. Fasting serum cortisol levels at 1, 2, and 4 weeks after IVTA injection were normal in all patients in the study group. 1 day following IVTA, the peak response to ACTH at 30 min was blunted in four patients (14.3 % of the study group, p = 0.05) and the cortisol response at 60 min was suppressed (p = 0.009). 1 week following IVTA, the response to ACTH challenge was blunted in only one patient. A single IVTA injection may be associated with impaired hypothalamic-pituitary-adrenal function in some patients during the first 24 h following IVTA.

Minimally invasive follicular thyroid carcinoma developed in dyshormonogenetic multinodular goiter due to thyroid peroxidase gene mutation.

BACKGROUND: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has only been reported in one patient harboring mutations in the thyroid peroxidase (TPO) gene. PATIENT FINDINGS: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of levothyroxine treatment and consequently normal thyrotropin (TSH) levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland. SUMMARY: Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG. CONCLUSIONS: Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma.

Minimal Invasive Follicular Thyroid Carcinoma Developed in Dyshormonogenetic Multinodular Goiter Due to Thyroid Peroxidase Gene Mutation.

Background: The occurrence of thyroid carcinoma in patients with congenital hypothyroidism (CH) caused by dyshormonogenesis is very rare, and has been reported in only one patient harboring mutations in the thyroid peroxidase (TPO) gene. Patient findings: We report on a 29-year follow-up of two consanguineous siblings with CH due to total iodide organification defect who also had sensorineural hearing loss. Molecular analysis revealed a novel biallelic mutation of the TPO gene in which phenylalanine substitutes serine at codon 292 (c.875C>T, p.S292F) in exon 8. Despite early initiation, adequate doses of L-thyroxine treatment and consequently normal TSH levels, the proposita developed a huge multinodular goiter (MNG) and underwent total thyroidectomy due to tracheal compression. Pathological examination revealed a unifocal follicular thyroid carcinoma without vascular invasion in the left lobe of the thyroid gland. Summary: Our finding of follicular thyroid carcinoma arising from dyshormonogenetic MNG in a patient without elevated serum TSH levels indicates that genetic and environmental factors other than TSH level might be involved in the development of thyroid carcinoma in dyshormonogenetic MNG. Conclusions: Despite the rare occurrence of thyroid carcinoma in dyshormonogenetic MNG, we recommend long-term follow-up and regular neck ultrasound imaging to prevent delayed diagnosis of thyroid carcinoma.