The implications of varicose vein surgery on sleep evaluation scales.

Background: Varicose veins commonly occur on the legs and cause discomfort, pain, and aesthetic issues. Varicose vein surgery has an significant impact on sleep disorders such as Restless Leg Syndrome (RLS), daytime sleepiness (DS), and sleep quality (SQ). We intended to determine if preoperative and postoperative sleep quality, excessive daytime sleepiness, and RLS severity impacted in those who had varicose vein surgery. Materials and methods: The research included 160 patients who presented to the Cardiovascular Surgery outpatient clinic with symptoms of leg pain and cramping and were diagnosed with venous insufficiency. The Restless Legs Syndrome Study Group Rating Scale (RLSS), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI) tests were performed on patients. The patients' scores on the scales were compared preoperatively and postoperatively. Results: The mean age of the 160 patients was calculated to be 48.7 ± 10.6 years. There were 109 female (68.1%) and 51 male (31.9%). The mean ferritin level of the patients was calculated as 61.4 mL/ng (4.3-421 mL/ng). After varicose vein surgery 63% reported improved sleep quality. Individuals with increased DS had lower postoperative RLSS scores and higher SQ. There was a decrease in postoperative RLSS scores and an increase in postoperative SQ in patients with normal DS (p < 0.001). Postoperative RLSS and DS scores were lower in patients with good SQ (p < 0.001). Conclusion: Patients had a lower RLSS score, a lower DS score, and a higher SQ after varicose vein surgery. Surgical treatment is critical to improving the quality of life and sleep comfort of patients with varicose veins and sleep disorders.

Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience.

OBJECTIVES: To evaluate and present the data regarding clinical, laboratory, radiological and the results of molecular genetic analysis of patients with hyperinsulinemic hypoglycemia in our clinics. METHODS: A total of 9 patients with CHI followed at Istanbul Medipol University. Data related to gender, age at presentation, birth weight, gestational age, consanguinity, glucose and insulin levels at diagnosis, treatment modalities, response to treatment, the results of genetic analysis and radiological evaluation were gathered from the files. RESULTS: The oldest age at presentation was 6 months. KATP channel mutation was detected in 55% (n: 5). Diazoxide unresponsiveness was seen in 55% (n: 5). Octreotide was effective in 3 of them. 18F-DOPA PET performed in 4 diazoxide unresponsive patients revealed focal lesion in 3 of them. Spontaneous remission rate was 66% (n:6). All the patients with normal genetic result achieved spontaneous remission. Spontaneous remission was even noted in diazoxide unresponsive patients and in patients with focal lesion on 18F-DOPA PET. CONCLUSIONS: Clinical presentation of patients with congenital hypereinsulinism is heterogeneous. Spontaneous remission rate is quite high even in patients with severe clinical presentation. It is important to develop methods that can predict which patients will have spontaneous remission. Reporting the clinical and laboratory data of each patient is important and will help to guide the management of patients with hyperinsulinemic hypoglycemia.

Cranial MRI Abnormalities and Long-term Follow-up of the Lesions in 770 Girls With Central Precocious Puberty.

CONTEXT: Central precocious puberty (CPP) may arise from central nervous system (CNS) lesions in a few affected girls. Recently, the incidence of girls with CPP has increased mostly in 6-8 year olds, in whom the necessity of magnetic resonance imaging (MRI) is debated. OBJECTIVE: To investigate the frequency, long-term outcome and potential predictors of CNS lesions in a large cohort of girls with CPP. METHODS: A multicenter cohort of 770 Turkish girls with CPP who had systematic cranial MRI between 2005 and 2017. Age at puberty onset was <6 years in 116 and 6-8 years in 654. CNS lesions were followed until final decision(6.2 ± 3.1 years). Potential predictors of CNS lesions were evaluated by univariate analyses. RESULTS: A total of 104/770 (13.5%) girls had abnormal brain MRI. Of these, 2.8% were previously known CNS lesions, 3.8% had newly detected and causally related CNS lesions, 3.1 % were possibly, related and 3.8% were incidental. Only 2 (0.25%) neoplastic lesions (1 low grade glioma and 1 meningioma) were identified; neither required intervention over follow-up of 6 and 3.5 years respectively. Age at breast development <6 years (odds ratio [OR] 2.38; 95% CI 1.08-5.21) and the peak luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio >0.6 (OR 3.13; 95% CI 1.02-9.68) were significantly associated with CNS lesions. However, both patients with neoplastic lesions were >6 years old. CONCLUSION: Although age and LH/FSH ratio are significant predictors of CNS lesions, their predictive power is weak. Thus, systematic MRI seems to be the most efficient current approach to avoid missing an occult CNS lesion in girls with CPP, despite the low likelihood of finding a lesion requiring intervention.

The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty.

BACKGROUND: There is no data regarding the interrelationships of circulating Makorin Ring Finger Protein-3 (MKRN3), Kisspeptin (KISS1), and Neurokinin B (NKB) concentrations during minipuberty in humans. OBJECTIVE: To determine temporal changes in circulating concentrations of MKRN3, KISS1, NKB, and gonadotropins and investigate interrelationships between them in healthy full-term (FT) and preterm (PT) infants during minipuberty period. METHODS: A prospective study of 6-month follow-up performed. Eighty-seven healthy newborns, 48 FT (19 boys/29 girls), and 39 PT (21 boys/18 girls) (gestational age 31-37 weeks), were included. Blood samples were taken at 7 days (D7), 2 months (M2), and 6 months (M6) of age. Serum MKRN3, KISS1, NKB, LH, FSH, total testosterone (TT), and estradiol (E2) concentrations were measured. RESULTS: Seventy infants completed the study. MKRN3, KISS1, and NKB concentrations were similar in FT girls and boys. PT boys and girls also had similar concentrations of MKRN3, KISS1, and NKB. FT babies had significantly higher NKB concentrations than PT babies at D7, M2, and M6. MKRN3 and KISS1 concentrations do not differ between FT and PT babies. A strong positive correlation was found between MKRN3 and KISS1 at each time point and in all groups. FSH, LH, TT/E2 concentrations decrease while those of MKRN3 and KISS1 have a trend to increase toward the end of minipuberty. No correlation was detected between gonadotropins and MKRN3, KISS1, NKB concentrations. CONCLUSION: Strong positive correlation demonstrated between KISS1 and MKRN3 suggests that interrelationship between molecules controlling minipuberty is not similar to those at puberty.

Revisiting Classical 3ß-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases.

CONTEXT: The clinical effects of classical 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency are insufficiently defined due to a limited number of published cases. OBJECTIVE: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3ßHSD2 deficiency. DESIGN: Multicenter, cross-sectional study. SETTING: Nine tertiary pediatric endocrinology clinics across Turkey. PATIENTS: Children with clinical diagnosis of 3ßHSD2 deficiency. MAIN OUTCOME MEASURES: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3ßHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. RESULTS: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ±â€…5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3ßHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. CONCLUSIONS: Genetically-documented 3ßHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3ßHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3ßHSD2 deficiency.

Restoration of Height after 11 Years of Letrozole Treatment in 11ß-Hydroxylase Deficiency.

11ß-hydroxylase deficiency (11ß-OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Males with 11ß-OHD CAH are often diagnosed late with a significantly advanced bone age leading to a poor height prognosis due to early closure of epiphysis. Delaying epiphyseal fusion by treatment of aromatase inhibitors (AIs) might be a useful strategy in patients with very advanced bone ages. However, there are limited data regarding the effect on final height and long-term safety of this approach. We report our experience with 11 years of letrozole treatment and 17 years of follow-up in a boy with 11ß-OHD. He presented at 2 years and 11 months of age with a bone age of 13 years (predicted adult height, PAH, 129.5 cm). Letrozole was added after 1 year of glucocorticoid treatment due to no improvement in height prognosis (130 cm), and continued until the age of 14 years and 11 months. He also received GnRH analog treatment at 10 years and 3 months of age for 2.5 years due to central activation of puberty. He reached a final height of 165.2 cm (35.2 cm above his PAH). This long-term treatment with letrozole was associated with changes in vertebral morphology such as vertebral body end-plate changes, Schmorl nodes, and mild protrusions in the intervertebral discs. Testicular volumes, gonadotropins, testosterone, and anti-Müllerian hormone were normal at age 20 years. A spermiogram showed a normal count but impaired sperm motility and morphology. This unique case represents the longest duration of AI treatment reported in CAH and the first case in which letrozole was started before puberty with the final height reported. We conclude that AIs may restore height in selected patients with CAH with very advanced bone age and severely compromised height prognosis.

Clinical and Laboratory Characteristics of Hyperprolactinemia in Children and Adolescents: National Survey

Objective: We aimed to report the characteristics at admission, diagnosis, treatment, and follow-up of cases of pediatric hyperprolactinemia in a large multicenter study. Methods: We reviewed the records of 233 hyperprolactinemic patients, under 18 years of age, who were followed by different centers. The patients were divided as having microadenomas, macroadenomas, drug-induced hyperprolactinemia and idiopathic hyperprolactinemia. Complaints of the patients, their mode of treatment (medication and/or surgery) and outcomes were evaluated in detail. Results: The mean age of the patients with hyperprolactinemia was 14.5 years, and 88.4% were females. In terms of etiology, microadenomas were observed in 32.6%, macroadenomas in 27%, idiopathic hyperprolactinemia in 22.7% and drug-induced hyperprolactinemia in 6.4%. Other causes of hyperprolactinemia were defined in 11.3%. Common complaints in females (n=206) were sorted into menstrual irregularities, headaches, galactorrhea, primary or secondary amenorrhea and weight gain, whereas headache, gynecomastia, short stature and blurred vision were common in males (n=27). Median prolactin levels were 93.15 ng/mL, 241.8 ng/mL, 74.5 ng/mL, 93.2 ng/mL, and 69 ng/mL for microadenomas, macroadenomas, idiopathic hyperprolactinemia, drug-induced hyperprolactinemia, and other causes of hyperprolactinemia, respectively. Of 172 patients with hyperprolactinemia, 77.3% were treated with cabergoline and 13.4% with bromocriptine. 20.1% of the patients with pituitary adenomas underwent pituitary surgery. Conclusion: We present the largest cohort of children and adolescents with hyperprolactinemia in the literature to date. Hyperprolactinemia is more common in females and cabergoline is highly effective and practical to use in adolescents, due to its biweekly dosing. Indications for surgery in pediatric cases need to be revised.

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development.

PURPOSE: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. METHODS: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-ß (ER-ß) was performed in an 8-week-old human male embryo. RESULTS: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-ß, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-ß, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-ß immunostaining was positive in the developing intestine and eyes. CONCLUSION: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.

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

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: Height, weight, body mass index (BMI), hemoglobin A1c (HbA1c), and Forced expiratory volume (FEV1%) were measured in children with CF (aged 5-18 years). Following OGTT, CGM was installed for 3 days. The total hypoglycemic and hyperglycemic time (%) during 3 days was measured. Subjects were categorized according to hypoglycemic time <3% (hypo -) and ≥3% (hypo +). Each category was further divided according to hyperglycemic time <3% (hyper -) or ≥3% (hyper +). RESULTS: OGTT and CGM were sequentially performed in 45 CF patients. The frequency of hypoglycemia in OGTT and hypoglycemic time ≧3% of CGM were 13.3% and 27.5%, respectively. After 5 cystic fibrosis-related diabetes (CFRD) subjects were excluded, the number of subjects in each subgroup was 17 (hypo-/hyper-), 12 (hypo-/hyper+), 6 (hypo+/hyper-), and 5 (hypo+/hyper+). Significantly higher insulin at 120 minutes was observed in OGTT in (hypo+/hyper-), as compared with subgroup (hypo-/hyper-) (P = .018). Total insulin levels were also significantly higher in (hypo+/hyper-), than (hypo-/hyper-), but were similar to those in the healthy control group (P = .049 and P = .076, respectively). There was a female predominance in hypoglycemic subjects both in OGTT and subgroup (hypo+/hyper-) in the CGM group (P = .033 and P = .033, respectively). FEV1 was significantly lower in hypo + group as a whole, and (hypo+/hyper+) subgroup than in (hypo-/hyper-), (P = .044 and P = .042, respectively); the difference was independent of body mass index-standard deviation score (BMI-SDS) (P = .15 and P = .12, respectively). CONCLUSION: The frequency of hypoglycemia in children with CF was higher in CGM than that in OGTT. Insulin secretion was delayed and total insulin levels increased in the hypoglycemic patients. Glucose instability/hypoglycemia is associated with poorer lung function in patients with CF, independent of nutritional status.

The Etiology and Clinical Features of Non-CAH Gonadotropin-Independent Precocious Puberty: A Multicenter Study.

AIM: The causes of gonadotropin-independent precocious puberty are diverse, and often have overlapping clinical and biochemical features. With the exception of congenital adrenal hyperplasia (CAH), disorders that cause gonadotropin-independent precocious puberty (GIPP) are uncommon. The literature is devoid of any large-scale studies on the etiologic distribution of GIPP. The aim of this study was to determine the frequency of each etiology in a cohort of patients with GIPP (excluding those with CAH), and to evaluate the clinical and laboratory features of these patients. MATERIALS AND METHODS: This multicenter, nationwide web-based study collected data on patients who presented with non-CAH GIPP in Turkey. RESULTS: Data were collected for 129 patients (102 girls and 27 boys) from 29 centers. Based on the data collected, the estimated prevalence of non-CAH GIPP in the studied population was 14 in 1 000 000 children. Functional ovarian cyst was the most common etiology, accounting for 37% of all cases, followed by McCune-Albright syndrome (MAS) (26%). Among the patients with MAS, 11.7% had fibrous dysplasia, 32.3% had café-au-lait spots, and 52.9% had both. Human chorionic gonadotrophin-secreting tumors included choriocarcinoma of the liver, hepatoblastoma, and germ cell tumors of the sellar-suprasellar region and mediastinum. Patients with adrenocortical tumors presented at an earlier age than those with other etiologies. Ovarian tumors included mature cystic teratoma, dysgerminoma, juvenile granulosa tumor, and steroid cell tumor. Despite overlapping features, it was possible to identify some unique clinical and laboratory features associated with each etiology. CONCLUSION: This largest cohort of patients with non-CAH GIPP to date yielded an estimation of the frequency of non-CAH GIPP in the general pediatric population and showed that girls were affected at a rate 4-fold greater than that of boys owing to functional ovarian cysts and MAS, which were the two most common etiologies. The data collected also provided some unique characteristics associated with each etiology.

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.

Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function.

BACKGROUND: Stuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis. OBJECTIVES: HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function. DESIGN: Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived. RESULTS: All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (<18 µg/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 µg) ACTH stimulation consistent with central adrenal insufficiency. CONCLUSIONS: STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.

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.

A novel homozygous TMEM70 mutation results in congenital cataract and neonatal mitochondrial encephalo-cardiomyopathy.

Mutations in the TMEM70 gene are the most common cause of nuclear encoded ATP synthase deficiency resulting in a syndrome characterized by neonatal lactic acidosis, cardiomyopathy, and encephalomyopathy. Here we report on the first Turkish patient who presented after birth with lactic acidemia, severe hpotonia, hypertrophic cardiomyopathy and bilateral congenital cataract. TMEM70 genetic analysis revealed the causative homozygous c.535C>T novel mutation that result in substitution of a highly conserved tyrosine into histidine at position 179. In this report we focused on a detailed description of the clinical features of this syndrome with special emphasis on the typical facial dysmorphic features. Our report underscores TMEM70 deficiency as a pan-ethnic well defined phenotype. In cases with high suspicion sequencing of TMEM70 should be performed even before the traditional invasive muscle biopsy to confirm the diagnosis.

Radiologic and hormonal evaluation of pituitary abnormalities in patients with Bardet-Biedl syndrome.

To describe the structural changes in the pituitary gland and accompanying pituitary hormonal problems in patients with Bardet-Biedl syndrome (BBS), 11 patients with BBS (median age: 12.8 years, range: 2.5-17.8 years; four boys and seven girls) have been examined for the anomalies of the pituitary region detected by MRI. Accompanying clinical, biochemical, and hormonal profiles concerning the pituitary function of the patients have also been investigated. We have found a high incidence of pituitary anomalies on MRI (63%) and a considerable percentage of hormonal derangements (45%) accompanying these. Among the structural pituitary abnormalities, tumoral changes (n=2), hypoplastic hypophysis, and/or sella (n=4) and rathke cleft cyst (n=2) were detected, whereas disturbances of the pituitary hormones such as growth hormone deficiency, hyperprolactinemia, hypogonadotrophic hypogonadism, and central precocious puberty accompanied the pituitary anomalies in these patients. Pituitary abnormalities and pituitary hormonal dysfunction are common findings and, therefore, should be included in the diagnostic criteria of BBS.