Saygin Abali

Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis

CONTEXT Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. OBJECTIVES Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. PATIENTS AND METHODS In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. RESULTS By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. CONCLUSION We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

Diabetes care, glycemic control, complications, and concomitant autoimmune diseases in children with type 1 diabetes in Turkey: a multicenter study.

Objective: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries. The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control. The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence. The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey. Methods: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood. Epidemiological and clinical characteristics of the patients were recorded. Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated. Results: Mean age, diabetes duration, and hemoglobin A1c level were 12.5±4.1 years, 4.7±3.2 years, and 8.5±1.6%, respectively. Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%. Chronic lymphocytic thyroiditis was noted in 12%, Graves’ disease in 0.1%, and celiac disease in 4.3% of the patients. Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively. Diabetic nephropathy was not present in any of the patients. Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01). A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively). Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese. Conclusions: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered. Conflict of interest:None declared.

Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS

CONTEXT Loss-of-function GNAS mutations lead to hormone resistance and Albrights hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP). OBJECTIVE We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance. CASE The patient is a female who presented at the age of 13.5years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gsα activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the fathers DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gsα transcripts from the patients peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gsα amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal. CONCLUSION These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP.

Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.

BACKGROUND NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. OBJECTIVE To describe a case of NSHPT unresponsive to cinacalcet. PATIENT AND RESULTS A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. CONCLUSION The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Higher insulin detemir doses are required for the similar glycemic control: comparison of insulin detemir and glargine in children with type 1 diabetes mellitus

We aimed to compare hemoglobin A1c (HbA1c), total and basal insulin doses, basal insulin injection frequencies, and body mass index (BMI) in children with type 1 diabetes mellitus (T1DM) who are receiving detemir and glargine as basal insulin in a basal‐bolus therapy.

Premature pubarche, hyperinsulinemia and hypothyroxinemia: Novel manifestations of congenital portosystemic shunts (Abernethy Malformation) in children

Congenital portosystemic shunt (CPSS) is persistence of an anomalous embryological connection of the portal vein with a large vein of the vena cava system. Clinical presentations include neonatal cholestasis, liver tumors, and encephalopathy, but can be variable in timing and symptomatology. We report 2 girls who presented 10 years apart with the same complaint of early pubarche at age 7 years, with inappropriately low DHEAS levels. In addition to hyperandrogenemia (elevated testosterone and androstenedione) and advanced bone age, both had hyperinsulinemia, and hypothyroxinemia. The 2nd case also had symptomatic hypoglycemia. Presentation of CPSS with this combination of findings in prepubertal children has not been reported previously. With further investigations, we proposed novel mechanisms explaining these manifestations. Hyperandrogenemia is caused by decreased hepatic sulfation of DHEA to less active DHEAS due to shunting of DHEA to systemic circulation. Elevated DHEA is then used for synthesis of more potent androgens. Shunting of postabsorbtive glucose from portal to systemic circulation causes early hyperglycemia leading to exaggerated insulin secretion. Insulin bypasses the hepatic metabolism directly entering into the systemic circulation, which results in hyperinsulinemia, then in turn causes late hypoglycemia. Finally, hypothyroxinemia was linked to thyroxin-binding globulin deficiency, which has not been reported in CPSS.

Hypoglycemia is common in children with cystic fibrosis and seen predominantly in females

To determine the prevalence of hypoglycemia in children and adolescents with cystic fibrosis (CF) in 2‐hour oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) under free‐living conditions.

Risk factors for mortality caused by hypothalamic obesity in children with hypothalamic tumours

Hypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation.

Turner syndrome and associated problems in turkish children: A multicenter study

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto’s thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.

GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey

Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.