Quality of Life in Patients with Phenylketonuria: A Systematic Review.

The impact of phenylketonuria (PKU) on Quality of life (QoL) has been a topic of interest in recent research. This article reviews current researches on the impact of PKU on QoL. The review examines factors that may influence QoL, such as age, metabolic control, and treatment adherence. In this systematic review study, relevant articles were identified using a search strategy built with the keywords phenylketonuria, PKU, or hyperphenylalaninemia (or their synonyms) and QoL in Web of Science, Scopus, and PubMed databases. After identifying the articles, duplicates, reviews, scientific abstracts, articles published in languages other than English, and non relevant studies were excluded. The search strategy identified 951 records from databases, and after excluding duplicates, irrelevant studies, and those published in non English languages, 26 records were left that contained data on 1816 patients with PKU/hyperphenylalaninemia. The studies included both children/adolescents and adults. Overall, the studies found that the QoL of PKU patients was comparable to normative data, but some aspects such as emotional health and school functioning were lower. Metabolic control was found to significantly correlate with QoL. Younger patients and men had better QoL in several studies, while late treated patients and those with lower education had worse outcomes. It is concluded that QOL in patients with PKU is similar to the general population. However, given the chronic nature of the condition, it is important to pay special attention to their QoL. Poor QOL is associated with female gender, lower education, older age, and poor metabolic control.

Evaluation of cardiac findings in mucopolysaccharidosis.

PURPOSE: Mucopolysaccharidoses (MPS) are a group of rare genetic diseases and heart involvement is one of the important conflicts in most types, which may cause serious complications. We used M-Mode and two-dimensional speckle tracking echocardiography (2D-STE) to explore cardiovascular involvements in MPS patients. METHOD: The present cross-sectional study investigated the frequency of cardiac involvements in MPS patients. Included participants were MPS types I, II, III, IV, and VI who underwent specialized echocardiography exams to assess valvular function, systolic and diastolic function, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: 35 patients were enrolled in this study. The total mean age of patients was 9.58 ± 5.11 years and 71.4% were male. Type IV (40%) and type III (31.4%) were the most frequent MPS. Although LVEF did not differ notably among MPS types, GLS was significantly different (p = 0.029). Mitral regurgitation was observed remarkably more in MPS type III (p = 0.001) while mitral stenosis was more common in type III (p = 0.007). There was a significant association between LVEF and GLS (ß= -0.662; p = 0.025) and between LVEF and MPS type (ß = 1.82; p = 0.025) when adjusted for GLS. CONCLUSION: Cardiac complications are very common and are one of the most important causes of death in MPS patients. 2D-STE seems to be superior to M-Mode for detection of early and subclinical cardiac dysfunction in MPS patients.

Childhood Obesity Is Associated With Subclinical Left Ventricular Dysfunction Detected by Speckle Tracking Echocardiography.

Childhood obesity is related to cardiac structural and functional changes, increasing the risk of heart disease. Sixty normotensive children were assigned based on body mass index (BMI) into normal weight, overweight, and obese groups and examined by two-dimensional speckle tracking echocardiography (2D-STE). Weight (P = .001) and BMI (P = .001) differed significantly among the 3 groups. Left ventricular (LV) strain (P = .001) and strain rate (P = .002) in overweight and obese children (P = .001) were significantly lower compared to normal weight group. LV mass in obese children was notably larger compared to overweight children (P = .047). LV strain was associated with age (P = .031), weight (P = .001), and height (P = .022). There was an association between LV strain rate with weight (P = .001) and between left atrial area and height of children (P = .007). Obesity in normotensive obese children is associated with subclinical alteration of LV dimension and myocardial longitudinal strain recognized by 2D-STE.

New molecular insights into the A218V variant impact on the steroidogenic acute regulatory protein (STAR) associated with 46, XY disorders of sexual development.

Disorders of sexual development (DSD) are an abnormal congenital conditions associated with atypical development of the urogenital tract and external genital structures. The steroidogenic acute regulatory (STAR) gene, associated with congenital lipoid adrenal hyperplasia (CLAH), is included in the targeted gene panel for the DSD diagnosis. Therefore, the genetic alterations of the STAR gene and their molecular effect were examined in the CLAH patients affected with DSD. Ten different Iranian families including twelve male pseudo-hermaphroditism patients with CLAH phenotype were studied using genetic linkage screening and STAR gene sequencing in the linked families to the STAR locus. Furthermore, the structural, dynamical, and functional impacts of the variants on the STAR in silico were analyzed. Sanger sequencing showed the pathogenic variant p.A218V in STAR gene, as the first report in Iranian population. Moreover, modeling and simulation analysis were performed using tools such as radius of gyration, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and molecular docking showed that p.A218V variant affects the residues interaction in cholesterol-binding site and the proper folding of STAR through increasing H-bound and the amount of α-Helix, deceasing total flexibility and changing fluctuations in some residues, resulting in reduced steroidogenic activity of the STAR protein. The study characterized the structural and functional changes of STAR caused by pathogenic variant p.A218V. It leads to limited cholesterol-binding activity of STAR, ultimately leading to the CLAH disease. Molecular dynamics simulation of STAR variants could help explain different clinical manifestations of CLAH disease.

The Relationship Between Body Mass Index and Depression, Anxiety, Body Image, and Eating Attitudes in Adolescents in Iran.

Background: The aim of this study was to investigate the relationship between body mass index (BMI) and depression, anxiety, body image, and eating attitudes in 12- to 16-year-old adolescents. Materials and Methods: In this descriptive-analytical study on 437 students in Shahrekord, Iran, selected by two-step random sampling (selection of schools and students), participants were divided into normal weight (BMI: 5-85th), overweight (BMI: 85-95th), and obese (BMI >95th) groups and completed the questionnaires and data were analyzed by SPSS version 23. Results: BMI had a positive correlation with anxiety, depression, and dysfunctional eating attitudes, and negative correlation with body image in adolescents. Mean scores of depression and anxiety in both overweight and obese groups were significantly higher than those in normal weight adolescents but scores of body image and eating attitudes were not different between overweight and normal weight groups. Conclusion: Obesity and overweight may have adverse effects on mental health of adolescents and more attention to psychological aspect of obesity can help us to provide better health services to overweight and obese adolescents.

Cognitive function in untreated subjects with mild hyperphenylalaninemia: a systematic review.

BACKGROUND: This systematic review study aims to evaluate the cognitive function of patients with mild hyperphenylalaninemia (mHPA) without treatment. METHODS: A systematic literature search was done from the 1st of May to the 30th of July in 2021 on published studies. The search strategy was ((hyperphenylalaninemia) OR (phenylketonuria) AND (cognition)). We use PubMed, Scopus, and the Web of Science databases. Studies which reported their findings regarding the cognitive function of patients with mHPA (screening serum phenylalanine > 120 and < 600 µmol/L) were included and reviewed. RESULTS: From initially retrieved 2805 studies, finally, 15 studies (10 on untreated patients with Phe levels below 360 µmol/L, 7 on untreated patients with Phe levels between 360 and 600 µmol/L, four 120-600 µmol/L) were selected. Most of the studies used the Wechsler Intelligence Scale for IQ evaluation, two (2/15) of them used the Stanford-Binet test and two used both tests. Four studies have reported a worse cognitive outcome compared to the control group, and in one study, relative defects in attention and working memory were reported. Other studies have reported normal IQ levels and no significant cognitive defects. CONCLUSION: It is suggested that Phe levels between 120 and 360 µmol/L are generally safe. Some studies showed that untreated patients with higher levels might show some degrees of cognitive impairment. In conclusion, current knowledge is insufficient to state that treatment is not required for HPA patients to preserve their cognitive status, especially in patients with Phe levels of 360-600 µmol/L. Further studies with a larger sample size and standardized cognitive function evaluation tools are needed.

Prevalence of Nonalcoholic Fatty Liver Disease in Children with Renal Failure Underwent Treatment with Dialysis.

Background: In this study, we aimed to investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with renal failure under treatment with dialysis and its association with biochemical measurements. Methods: In this cross-sectional study, children aged less than 18 years with chronic kidney disease (CKD) who were under treatment with dialysis at least 3 months ago were enrolled. To evaluate fatty liver in those patients who had no recent liver ultrasonography (last 6 months), liver ultrasonography was performed. The characteristics of patients with renal failure with and without NAFLD based on the ultrasonographic evaluation were compared. The association between NAFLD and the studied variables was evaluated. Results: In this study, 39 children (31 males and 8 females) with renal failure who underwent treatment with dialysis were included. From the studied population, six (19.4%) had NAFLD based on ultrasonographic evaluation. There were no differences between renal failure patients with and without NAFLD regarding the biochemical and anthropometric characteristics (P > 0.0). Conclusions: The prevalence of NAFLD in our studied children with renal failure who underwent treatment with dialysis was like the general population and it was not associated with the biochemical and anthropometric characteristics of the patients. Given the importance of NAFLD in renal failure patients as well as its subtle nature, it is recommended to screen patients with CKD for NAFLD.

Prevalence of nephrocalcinosis in children with congenital adrenal hyperplasia.

Background: We aimed to investigate the prevalence of nephrocalcinosis (NC) among children with diagnosed congenital adrenal hyperplasia (CAH). Our findings would be helpful for earlier diagnosis, management, and prevention of NC-related complications. Materials and Methods: In this cross-sectional study, children with CAH, aged <18 years old who were regularly referred for follow-up, were included. The information of the patients was extracted from their medical files, and they underwent renal ultrasonography for evaluation of the presence of NC. Results: From 120 studied patients with CAH, four patients (3.3%) had NC. The prevalence of NC was higher in males than females (P = 0.05). Mean age and age of CAH diagnosis had a trend to be lower in CAH patients with NC than those without. Regression analysis indicated significant association between NC and sex (P = 0.027, r = 2.24). Conclusion: The results of this study indicated a 3.3% prevalence rate of NC for children with CAH. NC had a trend to be more prevalent in male children with CAH. Though it was not significantly different but given that the mean age and age at diagnosis of CAH in children with CAH and NC was lower that CAH patients without NC, it is suggested that in patients with CAH and NC other factors such as genetic background or unknown disease related factors are associated with hypercalcemia and NC.

Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants.

BACKGROUND: Leukodystrophies are the main subgroup of inherited CNS white matter disorders which cause significant mortality and morbidity in early years of life. Diagnosis is mostly based on clinical context and neuroimaging findings; however, genetic tools, particularly whole-exome sequencing (WES), have led to comprehending the causative gene and molecular events contributing to these disorders. Mutation in Alkaline Ceramidase 3 (ACER3) gene which encodes alkaline ceramidase enzyme that plays a crucial role in cellular growth and viability has been stated as an uncommon reason for inherited leukoencephalopathies. Merely only two ACER3 mutations in cases of progressive leukodystrophies have been reported thus far. RESULTS: In the current study, we have identified three novel variants in ACER3 gene in cases with new neurological manifestations including developmental regression, dystonia, and spasticity. The detected variants were segregated into family members. CONCLUSION: Our study expands the clinical, neuroimaging, electroencephalographic, and genetic spectrum of ACER3 mutations. Furthermore, we reviewed and compared the findings of all the previously reported cases and the cases identified here in order to facilitate their diagnosis and management.

Assessing the Phenylketonuria Screening Program in Newborns, Iran 2015-2016.

Phenylketonuria is one of the most important congenital disorders and an autosomal recessive metabolic disease that can cause irreversible brain damages, mental retardation, and cognitive disorders if left untreated. In order to reduce the genetic abnormalities caused by this metabolic disease, screening programs are implemented. The quality of the program must be properly assessed to achieve the objectives of this program if promoting children's health is of concern. The descriptive-analytic method is adopted here to assess the phenylketonuria screening program in practice in Chaharmahal and Bakhtiari province since 2012 and analyze the incidence and program coverage. The quality of the screening program is assessed through analyzing the time of diagnosis, beginning of the treatment and the healthcare centers' facilities with checklists. The parental and the staff awareness is assessed through knowledge measuring questionnaires. Cumulative incidence of phenylketonuria in Chaharmahal and Bakhtiari province from 2012 to 2015, is 1 in every 6662 live births. The program coverage across the region is 100%. The recorded on-time sampling index before 5 days of age, indicate 84.6 % in 2015 from 80% in 2012. The treatment begun before the newborn 4 weeks was over in all cases. Program sensitivity was 100 %, and its specificity was 99.9%. Staff awareness is fair with no impact on parental awareness. General quality of the screening program is appropriate, and as to sensitivity and on-time curing specificity, higher staff and parental awareness supervision are recommended as well.

Vitamin D ameliorates systolic but not diastolic blood pressure in patients with type 2 diabetes: Results from a meta-analysis of randomized controlled trials.

Inconsistent findings have been reported regarding the effects of vitamin D on blood pressure in patients with type 2 diabetes (T2D). This study aimed to evaluate the subject through a meta-analysis. A computerized literature search on five databases was performed and randomized controlled trials (RCTs) published until March 2016 were identified. The eligibility criteria for articles to be selected were parallel-group RCTs in which consumption of a kind of vitamin D was compared with placebo in patients with T2D. Un-standardized mean difference and its corresponding 95 % confidence interval (CI) was calculated from the effect sizes by using random effects model. Studies comparing intervention group (received vitamin D) with control group (received placebo) were enrolled in meta-analysis. Meta-analysis on 26 studies with 1789 type 2 diabetic subjects showed that vitamin D significantly reduced systolic blood pressure (SBP; -0.97 mmHg, 95 % CI: -1.94, -0.001, P = 0.050), but not diastolic blood pressure (DBP; -0.10 mmHg, 95 % CI: -0.22, 0.02, P = 0.087). Subgroup analyses showed that administration of vitamin D in patients with baseline serum 25-hydroxy vitamin D < 50 nmol/l and baseline SBP < 140 mmHg significantly reduced SBP. Moreover, the patients who received vitamin D without Ca co-supplementation showed significant reduction in SBP. Vitamin D doses (≤ 2000 or > 2000 IU/day) and method of vitamin D application (Supplementation or food fortification) did not affect the blood pressure. This study demonstrated that vitamin D improved SBP in type 2 diabetic patients. Therefore, this vitamin can be considered as an adjuvant therapy in these patients.

Association between Vascular Endothelial Markers and Carotid Intima-Media Thickness in Children and Adolescents with Type 1 Diabetes Mellitus.

INTRODUCTION: Type 1 Diabetes Mellitus (T1DM) is one of the important risk factor for cardiovascular disease. Endothelial dysfunction and increased Carotid Intima-Media Thickness (CIMT) result in cardiovascular complications. Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1) are two adhesion molecules that are markers of early atherosclerosis and play a significant role in developing atherosclerosis. AIM: To evaluate CIMT and its association with the levels of ICAM-1 and VCAM-1 in children and adolescents with T1DM. MATERIALS AND METHODS: In this descriptive, cross-sectional study conducted between April 2013 and September 2014, 29 children aged 7-20 years with T1DM for at least two years and 29 age and sex-matched, healthy individuals were evaluated. Plasma level of ICAM-1 and VCAM-1 was measured by ELISA, and CIMT via Doppler ultrasound was also assessed. The data were analysed by t-test and Pearson's correlation coefficient in SPSS 16.0 (p≤0.05). RESULTS: Independent t-test indicated that there is a significant difference in ICAM-1 level between the patients and controls (p<0.001). Further, CIMT was significantly higher in diabetic subject (p<0.001). CIMT was not significantly associated with the level of VCAM-1 and ICAM-1 in the patients (p>0.5). CONCLUSION: ICAM-1 and VCAM-1 were not associated with CIMT but, CIMT and level of ICAM-1 were significantly, higher in diabetic patients, and therefore could be used as useful tools for identification of early atherosclerosis in children and adolescents with T1DM.

The association between mercury levels and autism spectrum disorders: A systematic review and meta-analysis.

BACKGROUND & AIMS: The relationship between mercury and autism spectrum disorders (ASD) has always been a topic of controversy among researchers. This study aimed to assess the relationship between ASD and mercury levels in hair, urine, blood, red blood cells (RBC), and brain through a meta-analysis. METHODS: A systematic search was performed in several databases including PubMed, ISI Web of Science, Cochrane register of controlled trials, Google Scholar, Scopus, and MagIran until June 2017. Case-control studies evaluating concentration of total mercury in different tissues of ASD patients and comparing them to the healthy subjects (control group) were identified. Necessary data were extracted and random effects model was used to calculate overall effect and its 95% corresponding confidence interval (CI) from the effect sizes. RESULTS: A total of 44 studies were identified that met the necessary criteria for meta-analysis. The mercury level in whole blood (Hedges=0.43, 95% CI: 0.12, 0.74, P=0.007), RBC (Hedges=1.61, 95% CI: 0.83, 2.38, P<0.001), and brain (0.61ng/g, 95% CI, 0.02, 1.19, P=0.043) was significantly higher in ASD patients than healthy subjects, whereas mercury level in hair (-0.14mg/g, 95% CI: -0.28, -0.01, P=0.039) was significantly lower in ASD patients than healthy subjects. The mercury level in urine was not significantly different between ASD patients and healthy subjects (0.51mg/g creatinine, 95% CI: -0.14, 1.16, P=0.121). CONCLUSIONS: Results of the current meta-analysis revealed that mercury is an important causal factor in the etiology of ASD. It seems that the detoxification and excretory mechanisms are impaired in ASD patients which lead to accumulation of mercury in the body. Future additional studies on mercury levels in different tissues of ASD patients should be undertaken.

Case Presentation of a 23-Month-old Herpes Simplex Virus-infected Girl with Brain and Oesophageal Involvement.

Herpes simplex virus (HSV) is the most common identifiable cause of serious or life threatening sporadic, endemic encephalitis. Typical HSV encephalitis in patients outside neonatal age is caused by HSV-1. A 23-month-old girl was referred to our hospital with a three-day history of fever, listlessness, slurred speech, and suspicious oesophageal foreign body impaction. Laboratory evaluations showed white blood cell count of 10900 /mm3 with 65% neutrophils. Upper endoscopy revealed diffuse severe ulceration in middle to distal third of oesophagus and no foreign body was found in oesophagus or stomach. Parenteral acyclovir was prescribed for herpes encephalitis in addition to antibiotics for central nervous system infection. Chest X-ray and brain MRI was unremarkable. Lumbar puncture revealed normal protein and glucose with 10 white cell count. She developed a raising liver enzyme tests. Total and direct bilirubin was 1.2 mg/dc and 0.2 mg/dc respectively. Because of neurological symptoms, acyclovir was adopted for our patient from the beginning. The girl did not respond to medication and died after 28 days. Progression of her disease prior to referral appears to contribute to the administered treatment inefficacy. Severe rapid progression of disease prior to referral and potential resistance to acyclovir could cause treatment failure.

Relationship between Serum Visfatin and Vascular Inflammation Markers Level in Beta Thalassemia Major Patients.

BACKGROUND: Understanding the possible role of visfatin in the pathogenesis of beta-thalassemia major (BTM) and its relationship with markers of endothelial function could help us to provide more effective therapeutic approaches for treatment of patients with BTM and its related complications. The aim of current study was to compare serum level of visfatin between patients with BTM and control group and determine its correlation with markers of endothelial function, intracellular adhesion molecule (ICAM) and vascular adhesion molecule (VCAM). METHODS: In this case-control study, patients with BTM receiving regular blood transfusion aged 10-20 years and a group of healthy subjects were enrolled. Selected subjects examined clinically and venous blood samples obtained for visfatin, ICAM, VCAM, cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol and ferritin measurements. Mean (standard deviation) of studied laboratory measurements compared in two studied groups and the relation between visfatin and ICAM, VCAM, ferrittin, body mass index determined. RESULTS: In this study 31 patients with BTM and 30 healthy controls studied. Mean of visfatin was significantly higher in patients with BTM than control group (133.9 ± 60.1 vs. 43.3 ± 27.9, P < 0.001). CONCLUSIONS: The higher level of visfatin among patients with BTM indicated the possible inflammatory role of this adipocytokine in BTM. It seems that for understanding the underlying mechanisms and its relation with vascular inflammatory markers and endothelial function further studies with larger sample size is needed.

The role of ultrasonography in primary congenital hypothyroidism.

BACKGROUND: The aim of this study was to compare the usefulness of ultrasonography and scintigraphy in diagnosing the etiology of primary congenital hypothyroidism (CH). METHODS: The newborns that were examined by both thyroid scintigraphy and ultrasonography during CH screening program in Isfahan were included in this study. The ultrasonographic findings were compared with the scintigraphic findings and the sensitivity and specificity of the ultrasonography was determined. RESULTS: During this study, 102 CH newborns were studied. According to the ultrasonographic results, 61.8%, 26.5%, 2.9% and 8.8% of them had normal thyroid gland, agenesia, ectopia and hypoplasia, respectively, and according to scintigraphic results, 55.9%, 35.3% and 8.8% of them had normal thyroid gland, agenesia and ectopia, respectively. Ultrasound detected sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratio were 77%, 92%, 89%, 84%, 9.6 and 0.25, respectively. The sensitivity and specificity of ultrasonography compared with thyroid scintigraphy in diagnosis of thyroid gland ectopia was 33% and 100%, respectively. CONCLUSIONS: Though thyroid ultrasonography failed to diagnose 67% of ectopic cases and nonfunctioning thyroid gland, it had the ability to determine the anatomy of thyroid gland. So, considering some limitations of scintigraphy, we concluded that ultrasonography is a relatively appropriate imaging tool for diagnosing CH etiologies, especially in the initial phase of CH screening.

A Case of Atypical McCune-Albright Syndrome with Vaginal Bleeding.

BACKGROUND: McCune-Albright syndrome (MAS) is a rare non-inherited disorder characterized by the clinical triad of precocious puberty, cafe-au-lait skin lesions, and fibrous dysplasia of bone. CASE PRESENTATION: We report a girl with MAS, presenting initially with vaginal bleeding at the age of 17 months. Ultrasonography revealed unilateral ovarian cysts and ureteral and ovarian enlargement. Considering the clinical and paraclinical findings, the patient diagnosed as a case of gonadotropin-independent precocious puberty was treated with medroxy-progestrone acetate (MPA) for three months. During the follow up, recurrent episodes of bleeding, ovarian activation and cyst formation, as well as breast size development were reported. At the age of 5.5 years, fibrous dysplasia was detected, which in coexistence with precocious puberty confirmed the diagnosis of MAS. The patient had no cafe-au-lait skin macles during follow up. CONCLUSION: Considering that clinical manifestations of MAS appear later in the course of recurrent periods of ovarian activation and cyst formation, a careful clinical observation and follow up of patients is necessary and the diagnosis of MAS must be kept in mind in cases with gonadotropin-independent precocious puberty.