Differentiated Thyroid Cancer in Children and Adolescents: Clinicopathological Characteristics of 32 Patients Followed up in our Pediatric Endocrinology Unit.

Objectives: This study aims to investigate the clinical and pathological features of patients with differentiated thyroid cancer (DTC) treated at our tertiary care institution. Methods: Thirty-two children and adolescents followed up with the diagnosis of DTC between 2001 and 2017 were enrolled. We classified patients with DTC into two groups as below and above 10 years of age, and compared their clinical and pathological features. Results: The mean age at presentation was 11.2±4 years. The female/male ratio was 7 (28:4). The diagnosis was papillary thyroid cancer (PTC) in 90.6% (n=29). The frequencies of lymph node and pulmonary metastases were 53.1% and 21.8%, respectively. The groups were comparable in terms of gender, initial clinical signs and tumor histopathology. The mean tumor size was greater in the younger age group (p=0.008). However, there was no difference between the two groups in terms of lymph node and pulmonary metastases. The pathological parameters associated with tumor aggressiveness were also similar between the groups, except lymphovascular invasion. Lymphovascular invasion was more frequent in the younger age group (p=0.01). Patients with lymph node and pulmonary metastases were more likely to have extrathyroidal extension and lymphovascular invasion. Conclusion: PTC was the most common type of DTC and presented with considerable rates of lymph node and pulmonary metastases. Tumor size was greater and lymphovascular invasion was more common in younger patients. Overall prognosis was favorable despite high rates of lymph node and pulmonary metastases.

A New Variant of the IER3IP1 Gene: The First Case of Microcephaly, Epilepsy, and Diabetes Syndrome 1 from Turkey.

Microcephaly, Epilepsy, and Diabetes Syndrome 1 (MEDS1) is a rare autosomal recessive disorder and caused by defects in the IER3IP1 (Immediate Early Response 3 Interacting Protein 1) gene. Only 9 cases have been described in the literature. MEDS1 manifests as microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes. A simplified gyral pattern has been described in all cases reported to the date. Diagnosis is made by demonstration of specific mutations in the IER3IP1 gene. In this study, we present an additional case of a patient with MEDS1 who is homozygous for the c.53C >T p.(Ala18Val) variant. The case, the first to be reported from Turkey, differs from other cases due to the absence of a typical simplified gyral pattern on early brain MRI, the late onset of diabetes, and the presence of a new genetic variant. The triad of microcephaly, generalized seizures and permanent neonatal diabetes should prompt screening for mutations in IER3IP1.

Is Waist-height Ratio Associated with Thyroid Antibody Levels in Children with Obesity?

Objective: Obesity is known to affect thyroid function. Recently, waist-height ratio (WHtR) has been considered as a useful marker of subclinical hypothyroidism in obese cases, but its relation with thyroid autoimmunity still remains unclear. We evaluated the effect of body fat mass, WHtR, and metabolic parameters on thyroid autoantibody levels in children with obesity. Methods: This was a cross-sectional study carried out with an obese [n=56, male/female (M/F): 29/26] and a healthy group (n=38, M/F: 19/19). All subjects underwent anthropometric measurements, laboratory investigations for thyroid function tests, thyroid peroxidase (TPO-ab) and thyroglobulin-antibodies (Tg-ab), transaminases, blood glucose, insulin levels, and lipids after overnight fasting; homeostatic model assessment for insulin resistance (HOMA-IR) was calculated for assessment of insulin resistance. Fat mass was estimated by multiple frequency bioimpedance analysis in the obese group, which was further divided into two subgroups according to the median of WHtR. All parameters were compared between the groups/subgroups. Results: In the obese group, weight, height, body mass index (BMI), free triiodothyronine, thyrotropin, TPO-ab, insulin, low density lipoprotein-cholesterol, total cholesterol, alanine aminotransferase levels, and HOMA-IR were significantly higher than the controls group (p<0.05 for all). Median of WHtR was 0.6 in the obese group. In the "WHtR >0.6" subgroup (n=28), weight, BMI, fat mass, TPO-ab, Tg-ab, insulin and triglyceride levels were higher than WHtR ≤0.6 subgroup (p<0.05). A positive correlation was obtained between Tg-ab and WHtR (rho=0.28, p=0.041). Conclusion: Euthyroid children with obesity and a WHtR >0.6 are likely to have higher thyroid antibody levels, and Tg-ab levels have a positive correlation with WHtR, which reveals an association of central adiposity with thyroid autoantibody levels in these cases.

A Case of Vitamin D-Dependent Rickets Type 1A with a Novel Mutation in the Uzbek Population.

Vitamin D-dependent rickets type 1A (VDDR-1A) (Online Mendelian Inheritance in Man #264700) is a rare, autosomal recessively inherited disorder due to inactivating mutations in CYP27B1. It is characterized by early onset of rickets with hypocalcemia. We aimed to describe the clinical and laboratory findings in a VDDR-1A case and to report a novel homozygote truncating mutation NM_000785.3 c.403C>T (p.Q135*) in CYP27B1 which to our knowledge is the first described mutation in the Uzbek population. The patient was admitted with tetany at the age of 12 months. He was a healthy Uzbek boy until 9 months of age when he had a seizure due to hypocalcemia. Vitamin D treatment was given orally in Turkmenistan (no data available for dose and duration). The patient was the product of a consanguineous marriage. His brother had died with hypocalcemia and pneumonia. At physical examination, anthropometric measurements were within normal limits; he had caput quadratum, enlarged wrists, and carpopedal spasm. Blood calcium, phosphorus, alkaline phosphatase, and parathormone (PTH) levels were 5.9 mg/dL, 3.5 mg/dL, 987 IU/L, and 182.8 pg/mL (12-72), respectively. Radiological findings included cupping and fraying of the radial and ulnar metaphyses. Renal ultrasound revealed nephrocalcinosis (grade 1). Despite high serum PTH and 25-hydroxyvitamin D3 levels, 1,25-dihydroxyvitamin D3 level was low, suggesting a diagnosis of VDDR-1A. The patient was treated with calcium carbonate and calcitriol. DNA sequencing revealed a novel homozygous mutation of NM_000785.3 c.403C>T (p.Q135*) in CYP27B1. VDDR-1A is a rare disorder which needs to be considered even in countries where nutritional vitamin D deficiency is still common.

Vitamin D Deficiency and Hashimoto's Thyroiditis in Children and Adolescents: a Critical Vitamin D Level for This Association?

OBJECTIVE: Vitamin D has been suggested to be active as an immunomodulator in autoimmune diseases such as Hashimoto's thyroiditis (HT). The goal of the present study was to investigate the vitamin D status in HT patients. METHODS: This prevalence case-control study was conducted on 90 patients with HT (of ages 12.32 ± 2.87 years) and 79 age-matched healthy controls (11.85 ± 2.28 years). Serum 25-hydroxyvitamin D3 [25(OH)D3] levels were measured in all 169 subjects. RESULTS: The prevalence of vitamin D deficiency in HT patients (64 of 90; 71.1%) was significantly higher than that in the control group (41 of 79; 51.9%) (p=0.025). Mean serum 25(OH)D3 level in the HT group was significantly lower compared to the control group (16.67 ± 11.65 vs. 20.99 ± 9.86 ng/mL, p=0.001). HT was observed 2.28 times more frequently in individuals with 25(OH)D3 levels <20 ng/mL (OR: 2.28, CI: 1.21-4.3). CONCLUSION: Vitamin D deficiency is associated with HT in children and adolescents. Levels lower than 20 ng/mL seem to be critical. The mechanism for this association is not clear.

Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene.

Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic cases also may occur. Due to activating mutation in luteinizing hormone (LH))/choriogonadotropin receptor (LHCGR) gene, early virilization and advancement in bone age are common with increased serum testosterone levels above adult ranges, despite low LH and follicular-stimulating hormone (FSH) levels. There are different treatment regimens, such as combination of bicalutamide (antiandrogen agent) and a third-generation aromatase inhibitor, that are reported to be well-tolerated and successful in slowing bone age advancement and preventing progression of virilization. We report here two patients who presented with peripheral precocious puberty and an activating mutation in the LHCGR gene: one with a family history and previously determined mutation and the other without family history and with a novel mutation (c.830G>T). Combination of bicalutamide+anastrozole was ineffective in slowing pubertal progression and bone age. Short-term results were better with ketoconazole.

Primary adrenal insufficiency caused by a novel mutation in DAX1 gene.

Adrenal hypoplasia congenita (AHC) is a rare disorder. The X-linked form is related to mutations in the DAX1 (NROB1) gene. Here, we report a newborn who had a novel hemizygous frameshift mutation in DAX1(c.543delA) and presented with primary adrenal failure that was initially misdiagnosed as congenital adrenal hyperplasia. This report highlights the value of genetic testing for definite diagnosis in children with primary adrenal failure due to abnormal adrenal gland development, providing the possibility both for presymptomatic, and in cases with a sibling with this condition, for prenatal diagnosis.