The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

The exon 3-deleted/full-length growth hormone receptor polymorphism and response to growth hormone therapy in growth hormone deficiency and Turner syndrome: a multicenter study.

BACKGROUND/AIM: The exon 3-deleted/full-length (d3/fl) growth hormone (GH) receptor (GHR) polymorphism has been associated with responsiveness to GH therapy in some diagnostic groups. However, there are still controversies on this issue. To evaluate the effect of the GHR exon 3 polymorphism on growth after 1 and 2 years of GH therapy in Turkish patients with GH deficiency (GHD) and Turner's syndrome (TS) and the distribution of GHR exon 3 isoforms. MATERIALS AND METHODS: 218 patients with GHD (125 males/93 females) and 43 patients with TS were included in the study. The control group included 477 healthy adults aged from 18 to 57 years (54 females/423 males). Anthropometric parameters and insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 were evaluated annually. GHR isoforms were studied using simple multiplex PCR. Height and body mass index were expressed as standard deviation score (SDS). RESULTS: There were no differences among TS, GHD and healthy adults regarding the distribution of GHR exon 3 isoforms (fl/fl, fl/d3 and d3/d3). There was a significant increase in height SDS in both diagnostic groups on GH therapy; however, there were neither differences in height SDS and Δheight velocity between fl/fl, fl/d3 and d3/d3 groups nor a correlation between the distribution of GHR exon 3 isoforms and change in IGF-1 SDS and IGFBP-3 SDS levels on GH therapy in either of the diagnostic groups. There was also no gender difference in GHR isoforms in healthy adults. CONCLUSION: The results suggest that responsiveness to GH therapy does not depend on the exon 3 GHR genotypes in GHD and TS patients.

Proton magnetic resonance spectroscopy findings and clinical effects of montelukast sodium in a case with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome is a rare hereditary metabolic disorder characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. This genetic disease is caused by fatty acid aldehyde dehydrogenase deficiency, leading to an accumulation of long-chain alcohols. The role of enzyme in the degradation of leukotrienes paved the way to the development of a new therapeutic strategy for Sjögren-Larsson syndrome, leukotriene antagonists. We describe a 3-year-old boy with Sjögren-Larsson syndrome who had a lipid peak on proton magnetic resonance spectroscopy despite normal findings on cerebral magnetic resonance imaging. He benefited from treatment with montelukast sodium, especially with respect to the agonizing pruritus.

Protein oxidation in obesity and insulin resistance.

INTRODUCTION: Advanced oxidation protein products (AOPP) are considered reliable markers to estimate the degree of oxidant-mediated protein damage. Data on oxidative stress in childhood obesity and insulin resistance are limited. OBJECTIVE: The aim of this study was to investigate the AOPP level as an oxidative stress marker in obesity and insulin resistance. The study included 57 pubertal obese children and adolescents (30 girls and 27 boys) and 20 healthy pubertal children and adolescents (11 girls and 9 boys). MATERIALS AND METHODS: All participants in the obesity group underwent an oral glucose tolerance test (OGTT) and two separate groups were formed according to the existence of insulin resistance. RESULTS: AOPP levels were measured in the obesity and control groups spectrophotometrically. The obesity group consisted of 25 children and adolescents with insulin resistance and 32 subjects without insulin resistance. AOPP levels in the obesity group were found to be significantly higher than those in the control group. Although AOPP levels in the subjects with insulin resistance were higher than the subjects without insulin resistance, there was no significant difference between AOPP levels of subgroups with insulin resistance and without insulin resistance. CONCLUSION: This study showed protein oxidation in obesity with a novel oxidative stress marker and it also suggests that insulin resistance may play an important role as a source of oxidative stress in the development of other diseases after pubertal years.

Effects of 3 years of intravenous pamidronate treatment on bone markers and bone mineral density in a patient with osteoporosis-pseudoglioma syndrome (OPPG).

We present a 21 year-old woman with osteoporosis-pseudoglioma syndrome (OPPG) suffering from bone pain and frequent long bone fractures (approximately 1 or 2 fractures/year) who was treated with i.v. pamidronate for 3 years. OPPG is a rare autosomal recessive disorder characterized by severe widespread osteoporosis leading to pathological fractures and congenital or early onset blindness. Bone mineral density (BMD) (g/cm2) was determined at lumbar spine and femur neck by dual energy X-ray absorptiometry. BMD studies were also performed in her parents and 18 year-old brother who were phenotypically normal. Within 2 months of the first pamidronate treatment the patient reported considerable decrease in bone pain and improved mobility. During the treatment period no important side effects and no recurrent bone fracture were reported. There were substantial increases in BMD, T score and z-score at both lumbar spine and femoral neck during therapy. Baseline lumbar spine BMD increased from 0.416 to 0.489 g/cm2 and femoral neck BMD increased from 0.455 to 0.532 g/cm2 after 3 years. Although her parents and brother did not have any history of fracture, BMD measurements revealed that her parents were osteopenic and her brother was osteoporotic. We demonstrated that pamidronate therapy seems to be safe and beneficial in both spinal and peripheral skeleton osteoporosis in patients with OPPG. Moreover, the present study clearly indicates that bone density studies and LRPS gene screening for mutations should be performed in phenotypically normal family members of patients with OPPG.

Acanthosis nigricans in association with congenital adrenal hyperplasia: resolution after treatment. Case report.

A case is described of a three-day-old female with salt wasting type of 21-hydroxylase deficient congenital adrenal hyperplasia who presented with acanthosis nigricans of both axillae. Following corticosteroid and mineralocorticoid therapy for disease, the acanthosis nigricans resolved. It is believed that this is the first reported case of acanthosis nigricans occurring in association with congenital adrenal hyperplasia, a phenomenon that resolved after treatment. We speculate that the acanthosis nigricans resulted from hyperandrogenemia or other unknown factors in our patient.

Female pseudohermaphroditism due to classical 21-hydroxylase deficiency and insulin resistance in a girl with Turner syndrome.

We report five-year-old girl with female pseudohermaphroditism due to classical form of 21-hydroxylase deficiency associated with Turner's syndrome (45,X/46,XX) and insulin resistance. She had clitoromegaly since birth, but Turner's syndrome and 21-hydroxylase deficiency were diagnosed incidentally at one and five years of age, respectively. Moreover, we determined insulin resistance, which resolved following corticosteroid therapy for disease. We regard the rare combination as a coincidental occurrence. We stress that adrenal function should be assessed, at least in the presence of clitoral enlargement, in patients with Turner's syndrome, particularly if their karyotype does not contain a Y chromosome. We conclude that chronic hypersecretion of androgen precursors due to an inborn error of metabolism can induce a reduction in insulin sensitivity. Improvement in insulin resistance after treatment of hyperandrogenism has not been previously reported.

Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents.

OBJECTIVE: Simple fasting methods to measure insulin resistance, such as the homeostasis model assessment (HOMA), fasting glucose/insulin ratio (FGIR), and quantitative insulin sensitivity check index (QUICKI) methods, have been widely promoted for adult studies but have not been evaluated formally among children and adolescents. The aim of this study was to compare the HOMA, FGIR, and QUICKI methods for measuring insulin resistance, expressed by oral glucose tolerance test (OGTT) results, among obese children and adolescents. METHODS: Fifty-seven pubertal obese children and adolescents (30 girls and 27 boys; mean age, 12.04 +/- 2.90 years; mean BMI: 29.57 +/- 5.53) participated in the study. All participants underwent an OGTT. Blood samples were obtained 0, 30, 60, 90, and 120 minutes after oral glucose administration for glucose and insulin measurements, and 2 separate groups were studied, according to the presence or absence of insulin resistance. HOMA, FGIR, and QUICKI methods were studied for validation of insulin resistance determined with the OGTT for these groups. RESULTS: The groups consisted of 25 obese children and adolescents with insulin resistance (14 girls and 11 boys; mean age: 12.88 +/- 2.88 years; mean BMI: 31.29 +/- 5.86) and 32 subjects without insulin resistance (16 girls and 16 boys; mean age: 11.38 +/- 2.79 years; mean BMI: 28.23 +/- 4.94). There were significant differences in the mean HOMA (6.06 +/- 4.98 and 3.42 +/- 3.14, respectively) and QUICKI (0.313 +/- 0.004 and 0.339 +/- 0.004, respectively) values between the 2 groups. Sensitivity and specificity calculations based on insulin resistance with receiver operating characteristic curve analysis indicated that HOMA had high sensitivity and specificity for measuring insulin resistance. CONCLUSIONS: As a measure of insulin resistance among children and adolescents, HOMA is more reliable than FGIR and QUICKI. The present HOMA cutoff point for diagnosis of insulin resistance is 3.16. The HOMA cutoff point of >2.5 is valid for adults but not for adolescents.

Bardet-Biedl syndrome with syndrome X: a patient report.

Bardet-Biedl syndrome (BBS) is an autosomal recessive condition with a wide spectrum of clinical features. The principal manifestations are rod-cone dystrophy (sometimes called atypical retinitis pigmentosa), postaxial polydactyly, central obesity, mental retardation, hypogonadism, and renal dysfunction. The clinical diagnosis of syndrome X defines a patient with abnormal glucose metabolism, hypertension, hyperlipidemia and obesity. We report here a 15 year-old girl with BBS presenting with syndrome X.

Relationship between cord blood levels of IGF-I and ferritin in healthy term neonates.

OBJECTIVE: We hypothesize that the balance of maternal and fetal insulin-like growth factor-I (IGF-I) concentrations contributes to the regulation of substrate distribution between mother and fetus, and may thus mediate the maintenance of blood ferritin concentration in the fetus. Therefore, the relationship between cord blood IGF-I to ferritin concentration was investigated. INFANTS AND METHODS: Twenty-six term neonates were recruited. Anthropometric measures were recorded and umbilical cord blood samples were collected at birth. We studied serum concentrations of IGF-I in relation to blood ferritin and anthropometric data in term neonates. To assess the importance of the correlation of ferritin with both IGF-I and all other parameters, multiple linear regression analysis was carried out, with ferritin as the dependent variable and IGF-I and anthropometric parameters as independent variables. RESULTS: The mean concentrations of cord blood IGF-I and ferritin levels were 45.2 +/- 36.8 ng/ml and 225.5 +/- 124.2 ng/ml, respectively, at birth. A positive correlation was observed between IGF-I and ferritin concentrations of term neonates (r = 0.53, p = 0.005). IGF-I emerged as a significant predictor of ferritin concentration (beta = 1.79, p = 0.005) contributing to 28% of its variability. CONCLUSIONS: We showed a relationship between cord blood IGF-I and ferritin levels in term neonates, suggesting that even within an unremarkable population, fetal ferritin level may be influenced by IGF-I. Moreover, we speculated that IGF-I might also be important in the regulation of placental transport of ferritin.

Prevalence of anti-HAV and anti-HEV antibodies in Konya, Turkey.

OBJECTIVE: To determine the prevalence of antibodies to hepatitis A (HAV) and E (HEV) viruses in the different areas of Konya. METHODS: Anti-HAV and anti-HEV antibodies were investigated in 210 healthy children randomly selected (100 from rural areas and 110 from urban areas of Konya). None gave a history of previous icterus nor other signs of hepatitis, had received blood transfusion and HAV vaccine, or had been on hemodialysis. RESULTS: Evidence of HAV infection occurred in children under the age of 6 years. The seroprevalence rate was 67.8% in rural areas and 25.8% in urban areas. This increased rapidly with age and became universal after 11 years of age in both areas. In contrast, HEV infections were not detected until children were 6-11 year olds, and the 5.2% seroprevalence rate in urban areas and 8.5% seroprevalence rate in rural areas in this age group did not significantly increase in older age group. The prevalence of anti-HAV as well as anti-HEV was significantly higher in children with poor socio-economic conditions in both areas. CONCLUSIONS: These results suggest that HAV infection in rural areas of Konya is widespread and that environmental and socio-economic factors play a major role in its transmission. In contrast, hepatitis E is not a public health problem in Konya.

Triple-x syndrome accompanied by congenital adrenal hyperplasia: case report.

The 47,XXX karyotype is a rare sex chromosome anomaly. This karyotype is usually not associated with a characteristic physical phenotype. In the presented case, a triple-X girl patient associated with 11beta-hydroxylase deficiency is identified. The case was referred to the Endocrinology Unit at six days of age because of ambiguous genitalia. The karyotype in this case was 47,XXX, an unexpected finding. Diagnosis of 47,XXX individuals remains difficult because specific clinical criteria used to identify this condition are not available. Congenital adrenal hyperplasia has not been previously reported in patients with triple-X syndrome.

Growth hormone deficiency, situs inversus, hypertrichosis and brachydactyly.

A 6 year-old female showed growth hormone deficiency, situs inversus totalis, short stature, blue sclerae, facial dismorphism, brachydactyly, developmental delay and hypertrichosis. The described phenotype represents a new syndromic situs inversus with a characteristic phenotype. Here, we present the first patient with this association in the literature.

Plasma homocysteine concentrations in adolescents with subclinical hypothyroidism.

OBJECTIVE: Hyperhomocysteinemia is a risk factor for premature atherosclerotic vascular disease and venous thrombosis. The aim of the present study was to assess plasma total homocysteine (tHCys) concentrations in adolescent patients with subclinical hypothyroidism. PATIENTS AND METHODS: Nineteen patients with subclinical hypothyroidism and 19 healthy children were studied. Fasting plasma concentrations of tHCys and its putative determinants (plasma concentrations of free thyroxine [FT4], folate, vitamin B12 and renal function) were measured. RESULTS: tHCys concentrations showed no statistical difference between patients and controls (p > 0.05). Moreover, the difference in tHCys and total cholesterol concentrations was not significant between patients with mild TSH elevations (< or = 10 mIU/l) and patients with prominent TSH elevations (> 10 mIU/l). No correlation was found between tHCys concentrations and its putative determinants. CONCLUSIONS: We concluded that plasma tHCys concentrations were not increased in adolescent patients with subclinical hypothyroidism.

Adrenocortical adenoma associated with inadequately treated congenital adrenal hyperplasia.

We report a 6 year-old boy with the simple virilizing form of 21-hydroxylase deficiency in whom an adrenal adenoma developed following 5 years of steroid treatment. Extremely high levels of basal serum 17alpha-hydroxyprogesterone as well as an exaggerated response of 17alpha-hydroxyprogesterone to adrenocorticotropic hormone confirmed congenital adrenal hyperplasia at 7 years of age. Initially elevated serum steroid levels were restrained by high dose hydrocortisone therapy, but he chronically tended to take inadequate doses of glucocorticoid. At 12 years of age an adenoma was found in the cortex of the hyperplastic right adrenal gland. The importance of early diagnosis and compliance with medication in the simple virilizing form of 21-hydroxylase deficiency is stressed.