Biallelic PROKR2 variants and congenital hypogonadotropic hypogonadism: a case report and a literature review.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that causes gonadotropin-releasing hormone (GnRH) deficiency and sexual immaturity. CHH may accompany an abnormal sense of smell (Kallmann syndrome, KS) or no such manifestation (normosmic-CHH). This unusual combination of manifestations is explained by the fact that GnRH neurons originate in the olfactory placode and migrate to the forebrain during embryogenesis. We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. He was noticed to have sexual immaturity (small testes with no pubic hair) at age 20 years, when diabetic ketoacidosis developed. Basal and GnRH-stimulated levels of LH (1.0→12.0 IU/L) and FSH (1.9→6.1 IU/L) were detectable but low. The results of the T&T olfactometer and the Alinamin test were definitely normal, with an anatomically normal olfactory system on MRI. Sequencing of 22 CHH-related genes was performed, and compound heterozygous PROKR2 variants were identified: one was a previously known loss-of-function variant (p.Trp178Ser) and the other was a nonsense variant (p.Trp212*). Through a literature review, we found 22 patients (including our patient) with CHH due to biallelic PROKR2 variants, which led us to recognize that most of the patients (86%) were diagnosed with KS. Clinical observations in this study indicate that, even though they have CHH, biallelic PROKR2 variant carriers may have a normal olfactory system as well as presumably normal migration of GnRH neurons. This suggests that the PROK2-PROKR2 pathway affects the function of GnRH neurons after their migration.

Very rare case of Graves' disease with resistance to methimazole: a case report and literature review.

BACKGROUND: Methimazole (MMI) is used to treat hyperthyroidism in Graves' disease. It is rare to encounter patients in whom hyperthyroidism cannot be controlled using high doses of MMI.Case presentation: A 21-year-old woman was referred to our hospital because of MMI-resistant Graves' disease. Although her MMI dose had been increased to 120 mg/day, her serum thyroid hormone concentration was too high to be measured. Additional therapy with lithium carbonate, and then with dexamethasone and inorganic iodine, was initiated. After 14 days, the patient's serum thyroid hormone concentration normalized, while she was taking 150 mg/day MMI, 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, and total thyroidectomy was then performed. The patient was discharged 8 days after the thyroidectomy and experienced no major complications. CONCLUSIONS: We have presented a rare case of Graves' disease that was resistant to high-dose MMI. Combination therapy of MMI with lithium carbonate, dexamethasone and inorganic iodine may represent a therapeutic option for the preoperative preparation of patients with MMI-resistant Graves' disease.

Glucose Variability is Independently Correlated with Serum Level of Pigment Epithelium-Derived Factor in Type 2 Diabetes.

INTRODUCTION: Pigment epithelium-derived factor (PEDF) may play a role in cardiometabolic disorders. The aim of this study was to investigate which biochemical and clinical parameters are independently associated with serum PEDF levels in patients with type 2 diabetes mellitus (T2DM). METHODS: We performed a cross-sectional analysis of 124 patients with T2DM who underwent continuous glucose monitoring (CGM) and blood chemistry analysis, including the diacron-reactive oxygen metabolites (d-ROMs) test and serum PEDF measurement (study 1). Then we investigated whether the changes in the studied biochemical and clinical parameters after 24 weeks of treatment (Δparameters) with anti-hyperglycemic agents, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and/or insulin and anti-hypertensive drugs and statins, were independently correlated with change in PEDF (ΔPEDF) in 52 of the patients with T2DM for whom there was sufficient serum samples to perform the post-treatment analysis (study 2). Serum levels of PEDF were measured with an enzyme-linked immunosorbent assay. CGM metrics were calculated on days 2 and 3. Oxidative stress was evaluated using the d-ROMs test. RESULTS: Body mass index (BMI), triglycerides, fasting C-peptide, mean amplitude of glycemic excursions (MAGE), urinary albumin-to-creatinine ratio (UACR), and d-ROMs were positively associated with serum PEDF level, and high-density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR) were inversely associated with serum PEDF level. Because these parameters were correlated with each other, multivariate stepwise analysis was performed: eGFR, HDL-C, BMI, MAGE, and UACR remained significant (R2 = 0.452). Furthermore, ΔMAGE and Δd-ROMs were positively correlated with ΔPEDF in study 2. CONCLUSIONS: The results of this study suggest that MAGE may be independently correlated with elevations in serum PEDF level in patients with T2DM.

[Bone fragility in type 1 diabetes and type 2 diabetes.]

Diabetes mellitus causes hyperglycemia due to resistance to insulin action in peripheral organs in addition to progressive loss of ß-cell function, thus it is involved in the development and progression of diabetic microangiopathy(retinopathy, nephropathy, and neuropathy). In addition, abnormalities of bone metabolism is regarded as a chronic complication related to both type 1 diabetes and type 2 diabetes. Accumulating evidence suggests that type 1 diabetes patients had decreased bone mineral density(BMD)and the fracture risk in the femoral neck is markedly higher, when compared to non-diabetic patients. A lack of insulin level in the portal vein is associated with systemic deficiencies of Insulin-like growth factor-1(IGF-1), known as growth-promoting polypeptide essential for promoting growth and bone formation. Thus, loss of IGF-1 play a crucial role for the pathogenesis of reduced BMD in type 1 diabetes. In type 2 diabetes, despite high bone mineral density with obesity, several studies have shown that men and women with type 2 diabetes mellitus are at increased risk for bone fracture. In other words, unlike type 1 diabetes patients, an increase in the risk of fracture in type 2 diabetes is significantly related to compromised bone quality, the other factor of impaired bone strength.

A case of painless thyroiditis in a very early stage of pregnancy.

We report a case of painless thyroiditis detected during the first trimester of pregnancy. A 29-year-old Japanese woman was hospitalized because of thyrotoxicosis and she was confirmed to be pregnant. The gestational age was 4 weeks. Blood examinations revealed negative TSH receptor antibodies, however, we started potassium iodide because we were unable to rule out Graves' disease. Thyroid hormone levels were normalized in 3 weeks and remained low even after discontinuation of medication. She received replacement therapy with levothyroxine sodium hydrate till 3 months after delivery. Painless thyroiditis can be one of the differential diagnoses of thyrotoxicosis in a very early stage of pregnancy.