Gönül Çatlı

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

The relation of serum nesfatin-1 level with metabolic and clinical parameters in obese and healthy children

Nesfatin‐1, a recently discovered anorexigenic neuropeptide, is expressed in several tissues including pancreatic islet cells and central nervous system. This peptide seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis.

Adipokines in Breast Milk: An Update

Epidemiological surveys indicate that nutrition in infancy is implicated in the long-term tendency to obesity and that a longer duration of breastfeeding is associated with a protective effect against metabolic disorders later in life. However, the precise cause of this association is not well understood. Recent studies on the compounds present in human breast milk have identified various adipokines, including leptin, adiponectin, resistin, obestatin, nesfatin, ghrelin and apelins. Some of these compounds are involved in the regulation of food intake and energy balance. The presence of these adipokines in breast milk suggests that they may be responsible for the regulation of growth in early infancy and that they could influence the energy balance and development of metabolic disorders in childhood and adulthood.

Maturity-onset diabetes of the young (MODY): an update

Abstract Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders characterized by autosomal dominantly inherited non-insulin dependent form of diabetes classically presenting in adolescence or young adults before the age of 25 years. MODY is a rare cause of diabetes (1% of all cases) and is frequently misdiagnosed as Type 1 diabetes (T1DM) or Type 2 diabetes (T2DM). A precise molecular diagnosis is essential because it leads to optimal treatment of the patients and allows early diagnosis for their asymptomatic family members. Mutations in the glucokinase (GCK) (MODY 2) and hepatocyte nuclear factor (HNF)1A/4A (MODY 3 and MODY 1) genes are the most common causes of MODY. GCK mutations cause a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment. However, mutations in the HNF1A and HNF4A cause a progressive pancreatic β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in these patients by acting on adenosine triphosphate (ATP)-sensitive potassium channels, although insulin therapy may be required later in life. Mutations in the HNF1B (MODY 5) is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction. Compared to MODY 1, 2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. In this review, we summarize the main clinical and laboratory characteristics of the common and rarer causes of MODY.

A case of rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor: ROHHADNET syndrome.

OBJECTIVE Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare disorder that mimics both common obesity and genetic obesity syndromes along with several endocrine disorders during early childhood. We aim to present the clinical features, laboratory and imaging results, and treatment outcomes of a patient with ROHHAD syndrome. METHODS In this case report, we describe a 26-month-old boy who was admitted to our emergency department with dyspnea and cyanosis and was suspected to have ROHHAD syndrome due to his rapid-onset obesity and alveolar hypoventilation. RESULTS A thoracal and abdominal magnetic resonance imaging was performed to demonstrate a possible accompanying neural crest tumor and it provided a yet asymptomatic retroperitoneal ganglioneuroblastoma. Based on these findings, the patient was diagnosed as ROHHADNET syndrome. CONCLUSION Because of the high prevalence of cardiorespiratory arrest and probability of accompanying tumors, early recognition of ROHHAD syndrome is important. To prevent presumptive mortality and morbidity, ROHHAD syndrome should be considered in all cases of rapid and early-onset obesity associated with hypothalamic-pituitary endocrine dysfunctions.

Gonadal malignancy risk and prophylactic gonadectomy in disorders of sexual development.

Abstract Disorders of sex development (DSD) are a generic definition including any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads. The most important clinical problems in DSD comprise physical and psychological disturbances and the risk of gonadal tumor development. Germ cell tumor risk is lowest (<5%) in patients with defects in androgene action or synthesis (such as complete androgen insensitivity syndrome, 5α-reductase deficiency), whereas the highest risk (15%–60%) is observed in 46,XY gonadal dysgenesis. The presence of Y chromosomal material in the karyotype increases the risk for the development of gonadal tumors. The reported age of tumor development varies based on the etiology of DSD (gonadal dysgenesis, androgen insensitivity syndrome, androgen synthesis defects, mixed gonadal dysgenesis, etc.). In the past, early gonadectomy was recommended for all cases of 46,XY DSD, however, according to current approaches, gonadal tumor risk is predicted based on the molecular diagnosis and the timing of the gonadectomy depends on the result of molecular analysis. Until now, optimal protocol in the management of DSD is still controversial. In addition to that, safe and well-accepted guidelines are needed. There is limited number of prospective studies on timing of a gonadectomy in childhood and adolescence. Therefore, evidence-based data on timing and indications of gonadectomy in patients with DSD are needed. In this review, recent data regarding gonadal malignancy risk in DSD and recommendations on timing of gonadectomy are presented.

Low Omentin-1 Levels Are Related with Clinical and Metabolic Parameters in Obese Children

This is the first clinical study evaluating the relation of serum omentin 1 levels with anthropometric and metabolic parameters in obese children with a particular interest to identify the possible role of omentin 1 in childhood obesity and related metabolic disturbances.The study included obese children with a body mass index (BMI)>95th percentile and healthy children with a BMI<85th percentile. The healthy and obese subjects had similar age and gender distribution. Glucose, insulin, lipid profile, and omentin 1 levels were measured to evaluate the metabolic parameters.49 obese children who applied to our department with complaint of weight gain and 30 healthy age and sex matched subjects were enrolled. In obese children BMI, body mass index-standard deviation score (BMI-SDS), systolic blood pressure (SBP), diastolic blood pressure (DBP), mid-arm circumference (MAC), triceps skin fold (TSF), waist circumference (WC), homeostasis model assessment-insulin resistance (HOMA-IR), serum insulin, and triglyceride levels were higher whereas omentin-1 levels were lower than control subjects (p<0.05). In the obese group, omentin 1 level was negatively correlated with BMI, insulin, HOMA-IR, and WC, while no significant correlation was observed with other parameters (p>0.05). Additionally, although statistically insignificant, patients with IR (n=31) had lower omentin-1 levels compared to obese children without IR (n=18).Our data indicates that serum omentin 1 levels are i) lower in obese children and ii) negatively correlated with BMI, WC, HOMA-IR and insulin levels suggesting that omentin 1 might be a biomarker for metabolic dysfunction also in childhood and adolescence. Lower omentin 1 levels tended to be associated with insulin resistance however this association failed to reach statistical significance. Further studies in larger populations are needed to better-define the relation of omentin 1 and insulin resistance in obese children.

The relation of leptin and soluble leptin receptor levels with metabolic and clinical parameters in obese and healthy children

We investigated the relation of serum leptin, soluble leptin receptor (sLR) and free leptin index (FLI) with metabolic and anthropometric parameters in obese and healthy children. Height, weight, waist circumference (WC), fasting serum glucose, insulin, lipid profile, leptin and sLR levels of 35 obese children and 36 healthy children were measured and FLI was calculated as the ratio of leptin to sLR. In obese children, serum leptin and FLI were found significantly higher, while sLR level was significantly lower than the healthy children. Comparison of obese children regarding the insulin resistance showed significantly higher serum leptin and FLI in the insulin resistant group; however sLR level was not different between the insulin resistant and non-resistant obese children. In obese children, sLR was not correlated with any of the metabolic parameters except total cholesterol, while FLI was significantly and positively correlated with BMI, WC, TC, fasting insulin, and HOMA-IR. However, regression analysis confirmed that the HOMA-IR was the only independent variable significantly correlated with FLI in obese children. Findings of this study suggest that in obese children and adolescents (i) serum leptin and FLI were found significantly higher, while sLR level was significantly lower than the healthy children, (ii) increased FLI might be a compensatory mechanism for increasing leptin effect in peripheral tissue, (iii) FLI is a more accurate marker to evaluate leptin resistance than leptin or sLR alone, and (iv) increased FLI may contribute toward the development of hyperinsulinemia and insulin resistance.

Acute vitamin D intoxication possibly due to faulty production of a multivitamin preparation.

Vitamin D intoxication usually occurs as a result of inappropriate use of vitamin D preparations and can lead to life-threatening hypercalcemia. It is also known that there are a number of physicians who prescribe vitamin D supplements for various clinical conditions, such as poor appetite and failure to thrive. While inappropriate use of vitamin D supplements may lead to vitamin D intoxication, there are no reports of cases of vitamin D toxicity due to manufacturing errors of vitamin D preparations. Here, we present cases of hypervitaminosis D which developed following the use of a standard dose of a multivitamin preparation. All three cases presented with hypercalcemia symptoms and had characteristic laboratory findings such as hypercalcemia, hypercalciuria, low levels of parathyroid hormone. The very high serum 25(OH) vitamin D levels in these patients indicated vitamin D excess. The vitamin D level of the prescribed multivitamin preparation in the market was studied and was found to contain a very low level of vitamin D (10 IU/5 mL). Although the stated vitamin D content of the preparations ingested by these patients was not high, unproven but possible manufacturing errors were considered to be a possible cause of the hypervitaminosis D diagnosed in these three patients.

Subclinical hypothyroidism in childhood and adolescense.

Abstract Subclinical hypothyroidism (SH) is defined as a serum thyroid-stimulating hormone (TSH) level above the reference range with normal serum free thyroxin (sT4) and free triiodothyronine (sT3) levels. The prevalence of SH in children and adolescents is reported between 1.7% and 9.5%. Hashimoto’s thyroiditis is the most prevalent cause of SH in children. Although it has been suggested that SH is entirely an asymptomatic laboratory diagnosis, typical hypothyroid symptoms as well have been reported in some patients. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); neuromuscular system; and cognitive functions in the long term. The number of studies investigating the effect of childhood SH on growth, bone maturation, lipid parameters, carbohydrate metabolism, neuromuscular system, and cognitive and cardiac function is limited. Knowledge about the natural history of SH is unclear even though there are numerous studies upon this subject. In children and adults, treatment of SH with L-T4 is still a matter of debate, and there is no consensus on this issue yet.