Ayla Güven

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.

Cushing's syndrome and adrenocortical insufficiency caused by topical steroids: misuse or abuse?

BACKGROUND Prolonged application of topical steroids transiently suppresses the hypothalamic-pituitary-adrenal axis (HPA). Infants who are exposed to topical corticosteroids have greater risk for Cushings syndrome or adrenocortical insufficiency caused by suppression of the HPA axis because glucocorticoids are highly absorbed through the diaper area. Here, we report six infants (four girls, two boys) aged between 3 and 8 months who were exposed to potent topical corticosteroids (clobetasol propionate and diflucortolone valerate) by the mothers application without prescription. METHODS We examined the HPA axis and other side effects of the potent glucocorticoid therapy in these infants. After stopping the topical corticosteroid, serum AST, ALT, lipids, morning cortisol and ACTH levels were measured. A low dose ACTH stimulation test was carried out. Hydrocortisone was started for the prevention of glucocorticoid withdrawal syndrome and the dose was gradually decreased. Abdominal ultrasonography was performed to investigate hepatosteatosis. RESULTS The ACTH stimulation test showed suppression of the HPA axis in these infants. Hepatomegaly was found in all infants and three of them had hepatosteatosis. Liver transaminase levels were elevated in five infants. Five patients have been followed for 6-14 months. One infant died due to generalized Cytomegalovirus infection. CONCLUSION We emphasize that physicians should be alert for the dangerous side-effects of topical steroids and they should avoid long-term use. Furthermore, parents should be informed about the side-effects when topical steroid treatment is chosen.

Profile of hypothyroidism in Down's syndrome.

Objective: Although the association between Down’s syndrome (DS) and thyroid dysfunction is well recognized, the cause of this condition is not known. Methods: Hospital records of patients with DS and hypothyroidism referred to our clinic were retrospectively reviewed. Initial thyroid hormone and thyrotropin (TSH) levels, age at admission, initial anthropometric measurements, age at the beginning of therapy, initial L-thyroxine (L-T4) doses, time to normalization of the thyroid function tests, and L-T4 dose at last visit were recorded. Thyroid ultrasound imaging was used to measure the size of the gland. Descriptive data were expressed as mean±SD values. Skewed data were shown as median and interquartile ranges (IQR). Results: There were 62 patients with DS (32 male and 30 female). Median TSH level at the first visit was 10.40 (19.4) µIU/mL and median free T4 level was 1.18 (0.43) ng/dL. There was no statistical difference in terms of age, hormone and antibody levels, thyroid volume and L-T4 doses between boys and girls. Thyroid volumes of 54 patients were measured. Only nine of these patients had a normal-sized thyroid gland. Median total thyroid volume was 0.89 (2.07) mL. Thyroid volume was negatively correlated to L-T4 dose at last visit (p=0.006, r=-0.387). Conclusions: We found a high prevalence of thyroid dysgenesis in patients with DS and hypothyroidism. This association has not been reported before. Further studies investigating the thyroid gland size in these patients need to be performed to confirm the results. Conflict of interest:None declared.

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism.

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared.

Leptin and Soluble Leptin Receptor Levels in Obese Children in Fasting and Satiety States

AIM To investigate the role of soluble leptin receptors in leptin resistance in obese children. METHODS Thirty-one obese children (16 boys and 15 girls) with a median age of 12.1 years and 15 age- and sex-matched controls were included in the study. Leptin and soluble leptin receptor levels were measured in fasting and satiety states. RESULTS Serum leptin levels were significantly higher and soluble leptin receptor levels were significantly lower in obese children compared to controls in fasting and satiety states. In obese children, there was a high and inverse correlation between leptin levels and soluble leptin receptor levels after fasting. Prepubertal obese children had lower leptin and higher soluble leptin, receptor levels compared to pubertal children in both states. CONCLUSION In this study, being the first to consider both fasting and satiety states, obese children were found to have higher leptin, but lower soluble leptin receptor levels, compared to controls. With these findings, it can be postulated that leptin resistance in obese children originates from a defect of soluble leptin receptor production.

Spondyloenchondrodysplasia due to mutations in ACP5: A comprehensive survey.

PurposeSpondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.MethodsWe compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.ResultsWe observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.ConclusionsOur data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

Association Between the Corrected QT Interval and Carotid Artery Intima-Media Thickness in Obese Children

Objective: Sudden death has been reported in asymptomatic obese adults and the mechanism is unclear. In recent years, obesity has shown a dramatic increase in children and this enhances the risk factors for the development of cardiovascular disease. The aim of this study was to investigate whether there is repolarization abnormality and any potential risk factor such as increase in intima-media thickness (IMT) of carotid artery for corrected QT (QTc) prolongation among obese children. Methods: A total of 60 obese children, 30 of which had features of metabolic syndrome (MS), and 23 age-matched controls were included in the study. QTc interval was calculated at rest. The IMT of both common carotid arteries (CCA) was measured. The relationship between QTc, IMT of right and left CCA and insulin sensitivity indices were evaluated in the study group. Results: The QTc interval of the children with simple exogenous obesity (SEO) were longer than in the controls (p=0.024). The IMT of both carotid arteries of the obese girls and boys with and without MS were higher than the controls (p=<0.001). The QTc was significantly affected by the parameters pertaining to the right carotid artery IMT, to chronologic age and HDL-C. Conclusion: Since obesity may cause subclinical atherosclerotic disease regardless of sex, obese children must be followed closely for early cardiovascular problems. Conflict of interest:None declared.

Developmental defects of the thyroid gland: relationship with advanced maternal age.

Objective: Developmental defects of the thyroid gland are the most frequent causes of permanent congenital hypothyroidism. This study aimed to investigate the epidemiological features of patients with thyroid dysgenesis (TD). Methods: Medical records of 234 patients with TD followed between the years 2008 and 2010 were evaluated retrospectively. Diagnosis was made by ultrasonography. Results: Of 234 patients, 120 (51.3%) were male and 114 (48.7%) were female. Male to female ratio was 1.08 and there were no significant differences in epidemiologic and clinical findings between girls and boys. One hundred eighty-three patients (78.2%) were diagnosed as hypoplasia, 35 (14.9%) as thyroid agenesis, 4 as ectopic thyroid gland and 12 as hemiagenesis. The mean maternal age of the group was 28.9±0.4 years (range 18 to 45 years), which is significantly higher than the recently reported mean maternal ages for Turkish women. Conclusions: Advanced maternal age was more prevalent in patients with TD. Our clinical and epidemiologic findings suggested no evidence of sexual dimorphism. Conflict of interest:None declared.

Are growth factors and leptin involved in the pathogenesis of premature adrenarche in girls

A transient increase in height and bone age as well as hyperinsulinism is seen in patients with premature adrenarche (PA). In addition, the weights of these patients are more than those of healthy peers. The aim of this study was to evaluate the role of leptin, IGF-I and IGFBPs in hyperandrogenemia and increased body weight observed in girls with PA. In this study, IGF-I, IGFBP-3, IGFBP-1 and leptin levels were investigated in 27 children with PA aged 5.4-8.6 years and 13 healthy children aged 5.7-8.58 years. Twenty patients were lean. The bone ages and BMIs of the children with PA were significantly higher than those of the healthy controls (p < 0.05). IGF-I (p < 0.005), IGFBP-3 (p < 0.05) and leptin (p < 0.0001) levels of lean PA girls were higher than controls. The leptin level of the obese PA girls was higher than that of the lean PA girls (p < 0.05) and controls (p < 0.0001). The IGFBP-1 level of the PA girls with and without obesity was lower than controls (p < 0.05). A negative correlation was observed between IGFBP-1 and leptin levels of the girls with PA (r = -0.64, p < 0.05). Serum leptin levels were influenced by BMI (p = 0.001), basal 17-OHP (p = 0.002) and stimulated 17-OHP (p = 0.019) in patients with PA. In conclusion, we suggest that elevated IGF-I and insulin give rise to increased adrenal androgens and leptin levels. On the other hand, both insulin and leptin cause decreased levels of IGFBP-1 in girls with PA, even if they are lean.

Gonadotropin releasing hormone analog treatment in children with congenital adrenal hyperplasia complicated by central precocious puberty

OBJECTIVECongenital adrenal hyperplasia (CAH) can be complicated by central precocious puberty (CPP) in children, which may compromise final height. We aimed to evaluate the effect of gonadotropin-releasing hormone analog (GnRHa) therapy on growth in children with CAH.DESIGNTwelve children with CAH were enrolled in a follow-up study. Eight patients underwent the GnRH stimulation test. GnRHa-treatment was administered at 3.75 mg every 4 weeks; the dose had to be increased to 7.5 mg in three patients. Bone age, growth velocities and body mass index of the patients were monitored during treatment.RESULTSMedian chronologic age and bone age at diagnosis were 6.8 (3.5) years and 11 (1.2) years, respectively. Median follow-up was 4.4 (4.9) years. A significant difference was found in the median ratio of bone age to chronological age between diagnosis and last visit (p=0.005) and between the beginning of GnRHa treatment and last visit (p=0.004). Median growth velocity was 4 (2.5) cm, 3.4 (5.2) cm and 5.5 (5.5) cm at the end of the first, second and third years of the therapy, respectively. Second-year growth velocity was inversely correlated with median bone age at diagnosis (rho:−0.758, p=0.004) and at the initiation of therapy (rho:−0.876, p<0.001).CONCLUSIONGnRHa therapy should be considered for augmentation of linear growth and diminishment of bone age advancement in children with CAH complicated by CPP, particularly in children who do not have extremely advanced bone age for chronological age.