Novel variants ensued genomic imprinting in familial central precocious puberty.

INTRODUCTION: Central precocious puberty (CPP) is characterized by the early onset of puberty and is associated with the critical processes involved in the pubertal switch. The puberty-related gene pool in the human genome is considerably large though few have been described in CPP. Within those genes, the genomic imprinting features of the MKRN3 and DLK1 genes add additional complexity to the understanding of the pathologic pathways. This study aimed to investigate the molecular etiology in the CPP cohort. METHODS: Eighteen familial CPP cases were investigated by Sanger sequencing for five CPP-related genes; DLK1, KISS1, KISS1R, MKRN3, and PROKR2. Segregation analysis was performed in all patients with pathogenic variants. Using an ELISA test, the functional pathogenicity of novel variants was also investigated in conjunction with serum delta-like 1 homolog (DLK1) concentrations. RESULTS: In three probands, a known variant in the MKRN3 gene (c.982C>T/p.(Arg328Cys)) and two novel variants in the DLK1 gene (c.357C>G/p.(Tyr119Ter) and c.67+78C>T) were identified. All three were inherited from the paternal allele. The individuals carrying the DLK1 variants had low detectable DLK1 levels in their serum. CONCLUSIONS: The frequencies were 5.5% (1/18) for MKRN3 11% (2/18) for DLK1, and none for either KISS1, KISS1R, and PROKR2. Low serum DLK1 levels in affected individuals supported the relationship between here described novel DLK1 gene variants with CPP. Nonsense nature of c.357C>G/p.(Tyr119Ter) and an alteration in the evolutionarily conserved nucleotide c.67+78C>T suggested the disruptive nature of the variant's compatibility with CPP.

High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

PURPOSE: We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers in Türkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. METHODS: This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6 years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). RESULTS: Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0 µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value < 45 µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1 µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. CONCLUSION: According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0 µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45 µIU/mL as the best cut-off limits to predict TCH.

SLC34A3 GENE MUTATION AS A RARE CAUSE OF HYPOPHOSPHATEMIA IN TWO SIBLINGS.

Context: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder, which is characterized by renal phosphate wasting, hypercalciuria, increased 1,25-dihydroxyvitamin D, and decreased parathormone (PTH) levels. Objective: Here we report different clinical features of two siblings with HHRH, confirmed with molecular diagnosis. Subjects and methods: 16.4 years old boy (P1), and 8.7 years old girl (P2) were referred to our outpatient clinic due to clinical suspicion of metabolic bone diseases. Results: P1 had severe hypophosphatemia. Additionally, PTH concentration was near to the lower limit, 1,25-dihydroxyvitamin-D concentration was near to the upper limit. P2 had relatively milder clinical and laboratory findings. Bilateral renal calculi were detected on ultrasound in both of them. HHRH was suspected due to their described biochemistry and the presence of bilateral renal calculi. Molecular analysis of SLC34A3 gene revealed a homozygous variant c.756G>A (p.Gln252=) and a splice donor variant c.1335+2T>A. After oral phosphate treatment, clinical and biochemical improvements were observed. However treatment nonadherence of patients was a barrier to reach treatment goal. Conclusion: The clinical phenotype due to the same mutation in the SLC34A3 gene may vary even among the members of the same family. An accurate diagnosis is important for the appropriate treatment.

Heart and Aorta Anomalies in Turner Syndrome and Relation with Karyotype.

OBJECTIVES: Turner Syndrome (TS) is associated with a high risk of cardiac anomalies and cardiovascular disease. We aimed to evaluate patients with TS (n=33) for cardiac and aortic pathology using thorax magnetic resonance angiography (MRA). SUBJECTS AND METHODS: Clinical findings, karyotypes, echocardiogram (ECHO) findings and thorax MRA results were evaluated. Aortic dimensions were measured and standard Z scores of aortic diameters along with aortic size index (ASI) were calculated. RESULTS: Mean age of the patients was 13.7±3.4 years. MRA revealed cardiovascular pathology in 10 patients (30%). CoA (n=4), aberrant right subclavian artery (n=3), dilatation of the ascending aorta (n=1), tortuosity of the descending aorta (n=1) and fusiform dilatation of the left subclavian artery (n=1) were found. Two of the four patients with CoA found on MRA were detected with ECHO. Mean diameter of the sinotubular junction was found to be elevated [mean±SD: 2.4±1.5]. Z scores for the diameters of the isthmus, ascending aorta and descending aorta were in normal ranges. 45,X patients were found to have significantly higher ASI values than non 45,X patients (p=0.036). CONCLUSION: Our findings indicate that patients with TS should be evaluated with MR imaging studies in addition to ECHO to reveal additional subtle cardiac and vascular anomalies. CoA which is very distally located or which has mild nature may not be seen by ECHO. The increase in ASI observed in 45,X patients may herald the development of life-threatening complications. Therefore, frequent follow-up is warranted in these patients.

THE ROLE OF THYROID FINE-NEEDLE ASPIRATION CYTOLOGY IN THE TREATMENT AND FOLLOW-UP OF THYROID NODULES IN THE PEDIATRIC POPULATION.

OBJECTIVE: Thyroid fine-needle aspiration (FNA) and cytology is a reliable diagnostic method used in the assessment of malignancy when evaluating thyroid nodules, in conjunction with clinical and ultrasonographic findings. The aim of this study is to compare clinical, ultrasonographic, cytological and histopathological findings in children who underwent thyroid FNA. METHODS: Subjects comprised 80 patients (52 female) aged 13.7±2.8 years at the time of FNA who where evaluated for thyroid nodules. Clinical, ultrasonographic and cytological findings of patients were evaluated retrospectively. RESULTS: Autoimmune thyroiditis was present in 30% and history of radiotherapy to the head or neck in 10%. The cytological diagnosis of patients included: inadequate or hemorrhagic sample in 10%; benign in 42.5%; atypia or follicular lesion of undetermined significance (AUS/FLUS) in 15%; suspicion of follicular neoplasia (SFN) in 7.5%; suspicion of malignancy (SM) in 8.8%; and malignant in 16.3%. Thirty-seven patients underwent thyroidectomy. Malignancy rates for histopathologic follow-up were 75%, 85.7% and 100% for SFN, SM and malignant categories, respectively. Only one benign and two AUS/FLUS FNAs were found to be malignant on histopathological examination. Among patients who had received radioiodinetherapy, 87.5% had malignancy. In this study, the sensitivity of FNA was 96%, specificity 50%, positive predictive value 90.9%, negative predictive value 75%, and diagnostic value of FNA was 89.2%. CONCLUSION: Thyroid FNA results were highly compatible with histopathological examination. Sensitivity, positive predictive value and diagnostic value of FNA were high.

Assessment of paediatric Hashimoto's thyroiditis using superb microvascular imaging.

AIM: To evaluate the role of superb microvascular imaging along with greyscale and Doppler imaging for thyroid gland evaluation in Hashimoto's thyroiditis (HT) versus control subjects. MATERIALS AND METHODS: The study included 33 healthy volunteers with normal ultrasound and laboratory findings and 70 patients with HT based on laboratory and sonographic findings who were undergoing follow-up and receiving medical treatment. HT patients were classified based on the modification of the scheme proposed by Sostre and Reyes that incorporates the extent of hypoechoic foci or patchy infiltration as grade A (foci involving <50% of the gland) and B (foci involving >50% of the gland). Thyroid volume, mean resistive indices, peak-systolic and end-diastolic velocities based on Doppler imaging, and vascularity index via superb microvascular imaging were obtained using a Canon Aplio 500 ultrasound device using a linear 10-14 MHz transducer. RESULTS: Patients with HT had significantly higher median thyroid volume and peak-systolic velocities (7.32 ml and 19 cm/s, respectively) compared to control subjects (4.62 ml and 16 cm/s, respectively). HT patients had significantly higher median vascularity index (VI; 13.5%) compared to control subjects (7.95%). A significant fair positive correlation with VI and anti-thyroglobulin antibody levels (r=0.356, p<0.05) and significant moderate positive correlation with VI and anti-thyroid peroxidase antibody levels (r=0.503, p<0.05) were found. In HT diagnosis, the optimal VI cut-off value was 10.58% with a sensitivity and specificity of 67.1% and 90%, respectively. CONCLUSION: Superb microvascular imaging appears to allow assessment of subtle vascularity changes in early HT stages that cannot be detected by Doppler parameters. This technique demonstrates excellent visualization of the microvascular structures and quantitative assessment based on a novel parameter such as VI.

Factors affecting physicians' perception of the overuse of antibiotics.

OBJECTIVE: We aimed to determine the reasons for irrational antibiotic use, to evaluate knowledge, attitudes, and behaviors of physicians regarding such use, to find factors affecting knowledge of physicians, and to explore precautions that need to be taken to stop irrational antibiotic use. MATERIAL AND METHODS: We performed the study between January 2014 and June 2014. We included 202 physicians who answered a questionnaire with 22 multiple-choice questions about knowledge (eight questions), behavior and attitudes of physicians (nine questions), and recommendations for reducing antibiotic consumption (five questions). Answers to all questions were assessed according to the physician's age, educational status, metropolitan areas, and healthcare facilities. RESULTS: The effects of parents' expectations and satisfaction (7.4%-40.0%) (P<0.0001) and socioeconomical status of families (33%-62%) (P=0.007) increased as the participants' age decreased. Participants working at public hospitals (42.6%) considered expectations and satisfaction of parents more important than other participants (10.5%-26.9%; P=0.002). Rapid recovery of patients was not an essential determinant for administering antibiotics for pediatricians (25.7%) and pediatric assistants (26.9%). However, it was important for emergency physicians (55.6%) and family physicians (60%, P=0.016). Physicians working at university hospitals did not consider this determinant as important as physicians working in other healthcare facilities (P=0.001). CONCLUSION: To determine the obstacles associated with promoting rational antibiotic usage, every country should assess the attitudes, behavior, and knowledge of physicians related to such use. The present study is one of the few in Turkey to address the problems associated with irrational antibiotic use.

The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene.

BACKGROUND: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. OBJECTIVE: To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis. METHODS: Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR. RESULTS: The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 and 10, respectively (P = .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P = .004). All cases with an AR mutation had gynecomastia, compared to 9% of those without an AR mutation. Of the six men who had a mastectomy, five (83%) had an AR mutation. CONCLUSIONS: Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable AR mutation. Routine genetic analysis of AR to confirm PAIS informs long-term prognosis and management.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Response to growth hormone with respect to pubertal status on increased dose in idiopathic growth hormone deficiency: an analysis of Turkish children in the KIGS database (Pfizer International Growth Study).

AIM: To compare the growth response to growth hormone (GH) treatment in patients with idiopathic GH deficiency (IGHD) who were prepubertal with the response of those who were pubertal at the onset of GH therapy on an increased GH dose. PATIENTS AND METHODS: Among the Turkish patients enrolled in the Pfizer International Growth Study (KIGS) database with the diagnosis of IGHD, the growth data over 2 years of GH therapy were analyzed longitudinally of 113 (79 M) prepubertal (Group 1) and 44 (33 M) pubertal (Group 2) patients. Pubertal signs were reported to be present initially or to have appeared within 6 months of GH therapy in Group 2. Mean +/- SD age at onset of therapy was 8.7 +/- 3.5 and 13.5 +/- 1.8 years; height SDS -4.2 +/- 1.4 and -3.2 +/- 1.1 (p < 0.05) in Groups 1 and 2, respectively. Mid-parental height (MPH) SDS did not show a significant difference between the two groups (-1.5 +/- 1.1 vs -1.7 +/- 1.1). RESULTS: Delta height SDS over 2 years of therapy was significantly higher in Group 1 (1.1 +/- 1.0) than in Group 2 (0.7 +/- 0.6) (p <0.05) in spite of a significantly lower dose of GH (14.6 +/- 3.3 in Group 1 vs 17.0 +/- 3.1 IU/m2/week in Group 2, p < 0.05). Ht--MPH SDS showed an increase from -2.4 +/- 1.7 to -1.4 +/- 1.5 in Group 1 and from -1.5 +/- 1.5 to -0.8 +/- 1.3 in Group 2. Overall delta height SDS showed negative correlations with age (r = -0.32), height SDS (r = -0.41) and height--MPH SDS (r = -0.40) at onset of therapy (p < 0.001). CONCLUSIONS: These data show that in IGHD the slight increase (15-20%) in the dose of GH during puberty was not adequate to maintain height velocity at the same magnitude as in prepuberty, and thus was not cost effective.

HLA-DR and -DQ associations with insulin-dependent diabetes mellitus in a population of Turkey.

Genetic susceptibility to insulin-dependent diabetes mellitus (IDDM) has been shown to be associated with MHC in many studies. To extend this data with a population with relatively low IDDM incidence, MHC DRB, DQA, and DQB have been investigated by polymerase chain reaction and sequence specific oligonucleotide probe hybridization (PCR/SSO) in 178 IDDM patients from Turkey and compared to 248 healthy controls. Significant differences are detected between IDDM and control groups in the frequencies of DRB1*0402 DQA1*03 DQB1*0302 (28.1% vs. 5.2%, p < 0.0001, OR: 7.1) and DRB1*0301 DQA1*0501 DQB1*02 (57% vs. 18.1%, p < 0.0001, OR: 6.1). Among the negative associations, the most strong ones are with DRB1*1401 DQA1*0101 DQB1*0503 (0.6% vs. 8.9%, p < 0.0001, OR: 0.1), DRB1*1502 DQA1*0103 DQB1*0601 (1.1% vs. 7.7%, p = 0.0023, OR: 0.1), DRB1*1301 DQA1*0103 DQB1*0603 (0.6% vs. 6.9%, p = 0.0039, OR: 0.2) and DRB1*1101 DQA1*0501 DQB1*0301 (3.9% vs. 12.1%, p < 0.0001, OR: 0.2). When the DRB, DQA or DQB genotypes of the susceptible alleles are compared, the most strong susceptibility marker of the disease is found to be DRB1*0301/*04 (31.4% vs. 2.8%, p < 0.0001, OR: 15.8) and among these, heterozygote genotype DRB1*0301/*0401 (4.5% vs. 0, p = 0.0008, OR: 24.8). These results confirm the positive associations with IDDM previously observed in other Caucasian populations and reveal many negative and strong associations which maybe underlining several characteristics that distinguish Turkish diabetics form other Caucasians.

Dose-response curves for treatment with biosynthetic human growth hormone.

We have studied the effect of varying doses of biosynthetic human GH on the growth response over the first year of therapy in 90 short prepubertal children (67 males and 23 females, aged 3.1-12.9 years). As pretreatment height velocity was the predominant determinant of response, the children were divided into three groups on the basis of their pretreatment height velocity standard deviation scores (SDS). Group A (n = 27) had pretreatment height velocity SDS between +1.3 and -0.8 (short normal growing children), group B (n = 35) between -0.9 and -2.0 (moderate GH insufficiency) and group C (n = 28) less than -2 (severe GH insufficiency). Within each group, the dose of GH administered was the dominant factor in the regression. At a mean dose of 16 units/m2 body surface area per week, the change in height velocity SDS over the first year of therapy was +2.9 (95% confidence interval (CI) 2.4, 3.5) in group A, +4.3 (95% CI 3.9, 4.6) in group B and +7.0 (95% CI 6.0, 8.0) in group C. These values translate into increases in growth rate of 2.2, 3.4 and 5.5 cm/year for an 8-year-old in each group respectively. These results have important implications in planning the treatment of children with GH insufficiency.

Heterogeneity of X-linked recessive (spino)cerebellar ataxia with or without spastic diplegia.

Ataxia with spastic diplegia was seen in seven males of a Turkish family, obviously transmitted as an X-linked recessive trait. The first clinical sign in infancy was nystagmus; ataxia and pyramidal signs were noted at age 2-3 years. Patients were never able to walk. Dysarthria, orthopedic impairment, and mild mental retardation appeared later as the disorder progressed. Death occurred in the 3rd or 4th decade from infectious diseases. The syndrome resembles X-linked spinocerebellar ataxia and X-linked spastic paraplegia in some aspects but is different if compared with previously published reports. Laboratory and neurophysiological studies showed no abnormalities. Various aspects of X-linked ataxia are discussed: genetic heterogeneity is apparent from observations reported.

Spironolactone therapy in hypertrichosis.

Although regarded as a benign condition, simple hypertrichosis may be very disturbing to a child cosmetically. An abnormality in androgen metabolism has been implied in the etiology of simple hypertrichosis recently. This study was undertaken to investigate the effect of spironolactone therapy for its antiandrogenic property in 12 prepubertal girls with hypertrichosis with no underlying etiology. The girls, with a mean age of 6.9 (1.2) years, had normal height and bone age. Basal hormone levels and adrenocorticotropin stimulation test results were in the normal ranges. Pelvic and adrenal ultrasound did not reveal pathology. Total and medullary hair width were measured from hair taken from preauricular, anterior midthigh, distal and proximal forearm areas. Spironolactone was started at an oral dose of 25 and increased to 100 mg x m(-2) x day(-1) twice daily for 1 year. Total hair width decreased significantly in the preauricular and anterior midthigh regions up to 6-9 months of treatment. Medullary hair width, which was affected by therapy to a greater extent, decreased significantly in all regions up to 6 months. Both total and medullary hair width showed a tendency to increase afterwards. No side effects were encountered. Spironolactone may be used in the treatment of simple hypertrichosis; however, more data are needed to clarify the efficacy and safety of anti-androgen therapy in hypertrichosis.

A comparison of the use of premixed insulins in pen-injectors with conventional patient-mixed insulin treatment in children and adolescents with IDDM. Is there a decreased risk of night hypoglycemia?

Insulin injection is a problem in pediatric and adolescent age, and premixed insulin therapy given in pen-injectors (Novopen II) is expected to increase compliance. Compliance with treatment and safety of this kind of insulin substitution was investigated in 20 IDDM patients (8.2-19.6 years old). The study was of randomized cross-over design and its duration was 6 (2x3) months. Metabolic parameters were compared between premixed insulin therapy via pen-injector and patient-mixed insulin therapy via conventional syringe, and no differences were observed except for the postponing of night hypoglycemic attacks to 07.00 a.m. during premixed insulin therapy. No technical or medical problems occurred. Patients were more satisfied with the new therapy regimen as determined by questionnaire. We concluded that this kind of insulin substitution is safe in pediatric and adolescent IDDM patients.

Long-term diazoxide treatment in persistent hyperinsulinemic hypoglycemia of infancy: a patient report.

Long-term diazoxide and somatostatin analogue have been used in the treatment of persistent hyperinsulinemic hypoglycemia of infancy albeit with some side effects. We report a case with persistent hyperinsulinemic hypoglycemia who has been on diazoxide therapy for 4.5 years. Diazoxide treatment maintained normoglycemia without causing any side effects, including hypertrichosis.

Growth hormone treatment in short children with intrauterine growth retardation.

The aim of this prospective controlled study was to assess the effect of rhGH in short prepubertal children with intrauterine growth retardation and normal growth hormone status. Twenty-six children were randomized into treatment (12F, 4M) and control (6F, 4M) groups. Mean ages were 5.3 (1.3) yr and 4.3 (1.7) yr, respectively. rhGH (Genotropin) was used at a dose of 0.2 IU/kg/day as daily s.c. injections for two years. In the treated group, mean height SDS increased from -3.0 (0.5) to -1.9 (0.7) and height velocity SDS showed a significant increase from -1.3 (2.0) to 3.7 (1.8) in the first year (p < 0.001) and 1.6 (1.8) (p < 0.01) in the second year of treatment. In the controls, height SDS, initially -2.7 (1.4), and height velocity SDS, initially -0.9 (1.1), remained essentially the same during two years of follow-up. Height SDS for bone age changed by 0.6 in the treated group and 0.4 in the control group. Target height SDS--initial height SDS in the treated group improved by 1.1 SD but declined in the control group. IGF-I levels increased from 9.5 (4.2) nmol/l (72 [31.8] ng/ml) to 32.5 (27.0) nmol/l (244.4 [202.8] ng/ml) (p = 0.004) in the treated group while no change was observed in the controls. No adverse effects were encountered during rhGH therapy. It was concluded that rhGH treatment induces a significant increase in growth velocity in the short term. This outcome, as opposed to the unchanged indices in the control group over the same period, may be indicative of an improved height prognosis in short children born with intrauterine growth retardation treated with rhGH.

Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycemia of infancy.

The appropriate management of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) still remains controversial. Some patients show a response to treatment with diazoxide or somatostatin, but a number of children require total or near-total pancreatectomy to control hyperinsulinism. Recent studies suggest a dysfunction in the adenosine triphosphate-sensitive potassium channel present in the plasma membrane of pancreatic beta-cells in PHHI. The closure of these channels initiating the depolarization of the beta-cell membrane and opening of calcium channels results in an increase in intracellular calcium which triggers insulin secretion. A calcium channel blocking agent has been shown to block this process and decrease insulin secretion of the nesidioblastotic beta-cells in vitro and to control the hyperinsulinemic hypoglycemia of the patient in vivo. To examine the efficacy of calcium channel blocker therapy, three patients with PHHI were treated with nifedipine. PHHI was diagnosed by inappropriately high insulin levels for low blood glucose levels at 8-10 days of age. Normoglycemia was maintained by a high dose of glucose infusion at a rate of 14-16 mg/kg/min. Therapy using diazoxide and/or somatostatin analogue failed to restore euglycemia in these three patients. The first patient underwent near-total pancreatectomy; however, hyperinsulinism recurred 30 days after surgery. All patients were started on short acting nifedipine at a dose of 0.3 mg/kg/day per os in four doses. To maintain blood glucose levels in normal ranges, the dose of nifedipine was progressively increased to 0.7-0.8 mg/kg/day. Glucose infusion rate to restore euglycemia decreased and was discontinued on the 4th to 10th day of nifedipine treatment. The patients, who have now been followed on nifedipine therapy for over 12 months, are normoglycemic with normal insulin levels. The growth and neuromotor development of the patients are unremarkable except for mild developmental delay of the patient who underwent near-total pancreatectomy. No side effects were encountered at the doses used. In conclusion, calcium channel blocking agents can be used with efficacy and safety in PHHI to control the hyperinsulinemia.

Bilateral ovarian steroid cell tumor in congenital adrenal hyperplasia due to classic 11beta-hydroxylase deficiency.

An 8.7 year-old patient, raised as a boy, presented with premature appearance of pubic hair and accelerated growth since 2 years of age and ambiguous genitalia noted at birth. There was first degree consanguinity between his parents. A similar problem was reported in a cousin. Examination of the external genitalia revealed complete scrotal fusion, a 5 cm long phallus, urogenital sinus at base of phallus with no gonads palpable. Pigmentation was increased. His blood pressure was 150/100 mm Hg. Pubic and axillary hair were at stage 3. Bone age was 17 years. Adrenal ultrasound was normal. Pelvic ultrasound showed relatively enlarged uterus and ovaries with normal echogenicity. Karyotype was 46,XX. Hormone profile was compatible with congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency (11-deoxycortisol: 11.5 nmol/l [400 ng/dl] [normal: 0.6-4.5 nmol/l [20-155 ng/ml]], androstenedione: 17.4 nmol/l [5 ng/ml] [normal: 0.1-1.2 nmol/l [0.03-0.35 ng/ml]]). Prednisolone and antihypertensive drugs were started. The patient underwent bilateral salpingo-oophorectomy and hysterectomy at 9.1 years. Histopathological examination of both ovaries revealed steroid cell tumor. The type of the tumor was "not otherwise specified" (NOS). Basal hormone levels and ACTH test performed 10 months after the operation and 7 days off treatment reconfirmed the diagnosis of 11beta-hydroxylase deficiency. Steroid cell tumors are extremely rare forms of steroid hormone-reducing ovarian neoplasms in childhood and may coexist with or imitate virilizing CAH.

Glucocorticoid receptors in patients with congenital adrenal hyperplasia.

To determine the glucocorticoid receptor (GC-R) status in congenital adrenal hyperplasia (CAH) we examined 11 patients (5 female, 6 male) with 21-hydroxylase deficiency and 3 patients (2 female, 1 male) with 11beta-hydroxylase deficiency. The mean age at investigation was 8.9+/-3.5 yr. Age of diagnosis was 4.4+/-3.2 yr and all patients were being treated with hydrocortisone. The control group included 10 (5 female, 5 male) age-matched healthy children. Blood samples were drawn at 0800 a.m. after an overnight fast in all subjects and after 5 days off treatment in patients with CAH. Serum cortisol (in all children), and serum 17-hydroxyprogesterone and androstenedione (in the patient group) were measured by radioimmunoassay. Mononuclear leukocytes were isolated from peripheral blood and the binding of [3H]dexamethasone to GC-R was examined. GC-R number and the dissociation constant (Kd), which is inversely proportional to its binding affinity, were determined. Mean GC-R numbers were 5814+/-1574 and 6816+/-1647; mean Kd values were 3.6+/-1.5 nM and 4.2+/-0.7 nM in patient and control groups, respectively. There were no significant differences in these parameters between the two groups. Neither receptor number nor binding affinity correlated with basal serum cortisol levels in either group. In the patient group, no correlation was observed between replacement hydrocortisone doses and either morning serum cortisol levels or GC-R number. The higher binding affinity and requirement of higher hydrocortisone dose might have been due to a compensatory response to increased clearance of glucocorticoids. In conclusion, GC-R parameters are not changed in patients with CAH and the variability of glucocorticoid replacement doses may be related to other functional defects of GC-R and glucocorticoid pharmacokinetics.