Factors contributing to sex assignment and reassignment decisions in Turkish children with 46,XY disorders of sex development.

BACKGROUND: Sex assignment decisions for children with disorders of sex development (DSD) should be based on integrative assessments of relevant biological and psychosocial characteristics. AIM: To investigate the factors that contributed to sex assignment decisions for children with 46,XY DSD. PATIENTS: Sixty-one children recruited from a clinical sample were evaluated. METHODS: Findings of endocrinological and psychiatric evaluations were entered into a logistic regression analysis. RESULTS: Gender identity was the strongest correlate of assigned sex. External genital under-virilization, sex announced at birth and toy/ activity preferences were predominant predictors. Twelve children, six of whom were prepubertal, were reassigned to male sex. CONCLUSIONS: Psychological factors seem to be as influential on sex reassignment decisions as are endocrinological and social factors, especially if the disorder is diagnosed at an older age. Prepubertal gender conversion is possible, which implies the importance of follow-up during childhood.

Plasminogen activator inhibitor-1 (PAI-1) gene polymorphism (-675 4G/5G) associated with obesity and vascular risk in children.

UNLABELLED: Atherothrombotic complications in insulin resistance are partly attributed to impaired fibrinolysis caused by increased PAI-1 plasma levels, and 4G/5G promotor polymorphism of the PAI-1 gene may modulate PAI-1 transcription. OBJECTIVE: To investigate PAI-1-675 4G/5G allele gene polymorphism and its relationship with obesity in children. CHILDREN AND METHOD: The study participants were 133 apparently healthy non-obese children, 24 probable exogenously obese without family history (Group I), 66 probable familial obese (Group II), and 44 obese children who were referred to the pediatric endocrinology department with any complication of obesity (Group III). Group I and Group II obese children were gathered from a school-based epidemiological study. RESULTS: Incidence of obesity was 19% in a school with high socio-economic status, whereas it was 4% in a school with low socio-economic status. Frequencies of 4G/4G gene polymorphisms were 24.81%, 37.50%, 64.80% and 61.11% in the control group, and groups I, II, and III, respectively. In groups II and III, 4G/4G gene polymorphism, and in non-obese control children 5G/5G gene polymorphism, was common. In obese children in the presence of family history for obesity and metabolic syndrome (odds ratio [OR]: 4.48, 95% confidence interval [CI]: 1.26-15.82), carriage of the 4G allele either in heterozygous or homozygous state increased the risk of vascular disease (OR: 6.10, 95% CI 1.64-22.90). In patients with acanthosis nigricans, high HOMA-IR values, hypertriglyceridemia and elevated atherogenic index, 4G/4G genotype frequency was remarkably higher compared to patients with other features of metabolic syndrome. CONCLUSION: The increasing prevalence of childhood obesity in high socio-economic status is associated with health risks. In obese children with family history of obesity and cardiovascular disease or type 2 diabetes mellitus and in obese children who had any feature of metabolic syndrome, frequency of 4G/4G genotype was more than the 4G/5G and 5G/5G genotypes in the PAI-1 gene. These patients can be at increased risk for developing vascular disease. Acanthosis nigricans, high HOMA-IR value, hypertriglyceridemia and high atherogenic index can also reflect the high risk of vascular disease in metabolic syndrome.

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.

Congenital early onset isolated adrenocorticotropin deficiency associated with a TPIT gene mutation.

TPIT is a highly cell-restricted transcription factor that is required for the expression of the propiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary ACTH. We present a neonate with the diagnosis of congenital early onset isolated ACTH deficiency (IAD) associated with a loss of POMC function as a result of a missense mutation in the TPIT gene. A 5 day-old male infant was admitted for hypoglycemia, limpness and conjugated hyperbilirubinemia. Laboratory investigations indicated low plasma cortisol concentration (0.1 microg/dl) accompanying a very low ACTH (<5 pg/ml) concentration. An increase in plasma cortisol concentration following stimulation with low dose exogenous ACTH was observed. On replacement therapy with hydrocortisone (15 mg/m2/day orally), cholestatic jaundice and hypoglycemia resolved and subsequent normal growth (weight, height and head circumference, 25th, 10th and 50th percentile, respectively) and development was achieved without recurrence of hypoglycemic episodes.

Alterations in serum growth hormone (GH)/GH dependent ternary complex components (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio) and the influence of these alterations on growth pattern in female rhythmic gymnasts.

BACKGROUND AND AIM: Normal growth in children is regulated to a great extent through the actions of the GH/IGF-I axis, a system consisting of GH and its mediators (ternary complex) that modulate growth in many tissues. The ternary complex (IGF-I/IGFBP-3/ALS) provides an acute regulatory mechanism in which IGF-I may be mobilized from the circulating reservoir of 150 kDa complexes to the tissues. Acute exercise is known to be a stimulus for GH secretion. The beneficial effects of scheduled exercise on body composition are also well established. However, the impact of strenuous exercise on the pubertal development of child athletes is still not well understood. The first goal of this study was to assess the acute effects of high intensity exercise training on GH-dependent ternary complex components in female rhythmic gymnasts compared to age-matched healthy female controls with normal physical activity. The second goal was to explore the influence of these exercise-induced changes on skeletal and pubertal growth in the same group prospectively over a period of 4 years. SUBJECTS AND METHODS: Seventeen female rhythmic gymnasts, aged 11.4 +/- 0.9 years, who had 10 h per week intense exercise for at least 4 months volunteered to participate in this study. Anthropometric measurement of height (Height SDS for chronological age [HtSDS(CA)], parentally adjusted height, predicted adult height), bone age and weight (BMI) were made using standard techniques in gymnasts and controls (aged 12.5 +/- 3.0 years, n = 12). Gymnasts were followed up to 4 years to observe growth velocity and pubertal progression. In order to determine the acute impact of exercise on levels of GH and GH-dependent ternary complex component (IGF-I, IGFBP-3, ALS, IGF-I/IGFBP-3 molar ratio), blood samples were obtained from gymnasts after a routine 2-h high-intensity training program and then after a 2-day rest period. These results were compared with age-matched controls with no scheduled sports activity. RESULTS: Despite the significant increment in serum GH and GH-dependent components immediately following the exercise, serum GH/IGF-I levels showed a significant decrement (p < 0.01) after a 2-day rest in gymnasts, to a nadir as low as those of the control subjects' baseline levels (p < 0.01). There was no difference in anthropometric characteristics of gymnasts and controls except BMI; gymnasts were leaner than controls. During a 4-year follow up, there were no differences between the gymnasts and controls in regard to skeletal growth and reaching their predicted height. However, in gymnasts there was a delay in pubertal tempo but not in growth. CONCLUSION: Intense exercise induces an acute rise in GH levels, but this acute elevation rapidly normalizes after a 2-day rest in female rhythmic gymnasts. These fluctuations in serum GH and GH-dependent ternary complex components had no reflection on the skeletal growth patterns in gymnasts over the 4-year follow up but there was a delay in their pubertal progression.

Management of central diabetes insipidus with oral desmopressin in a premature neonate.

The effect of oral administration of desmopressin (DDAVP) solution was investigated in a very low birth weight premature infant with central diabetes insipidus that was associated with grade four germinal matrix hemorrhage. As an alternative to the nasal route, long-term successful management resulting in favorable growth and development during infancy was achieved using the oral route.

Seckel-like syndrome: a patient with precocious puberty associated with nonclassical congenital adrenal hyperplasia.

Seckel syndrome is a rare, recessively inherited disorder of severe growth retardation with low birth weight and distinct craniofacial, orodental and skeletal anomalies. In addition to these characteristics, some cardiovascular, hematopoietic, endocrine and central nervous system abnormalities have also been described. We report a patient with Seckel-like syndrome who has precocious puberty associated with non-classical congenital adrenal hyperplasia (NCCAH). She was admitted to our clinic three times. She was diagnosed as having Seckel-like syndrome and premature thelarche at the age of 8.9 years. At 10.9 years old she was admitted to our clinic with pubic hair and cliteromegaly. Hormonal findings revealed NCCAH and hydrocortisone therapy was offered but the patient was non-compliant. At 13.6 years she had acanthosis nigricans as an additional clinical finding and her pubertal stage was 4. She had irregular menses. On hormonal evaluation she had euglycemic hyperinsulinism accompanying mild hypertriglyceridemia and functional ovarian hyperandrogenism. Premature pubarche, hyper-insulinism, dyslipidemia, and hyperandrogenism, and some combinations of these, can be associated with reduced fetal growth. This is the first report of hyperinsulinism, and probably NCCAH, in association with Seckel syndrome.

Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village.

We describe six Turkish patients with 5alpha-steroid reductase type 2 deficiency from unrelated Turkish families and a large pedigree of one of these patients who reside north-west of Anatolia. Patients NA, KS, BD and SY presented for evaluation of bilateral inguinal masses with female phenotypes. Patient ABE had penoscrotal hypospadias with male phenotype. Homozygous mutation of the 5alphaSR2 gene was identified in five of these patients by genomic DNA analysis. These mutations were Leu55Gln in exon 1 (in patients FG, BD and ABE), deltaMet157 in exon 3 (in patient NA), and splice junction abnormality in intron 1 (in patient SY). One individual (patient KS) was found to be a compound heterozygous carrier of two different mutations, Leu55Gln in exon 1 and Arg171Ser in exon 3. Patient FG had a large pedigree with the Leu55Gln mutation in exon 1. The pedigree of this family with marital consanguinity is remarkable, and possibly due to the isolation of this family because of economic and social problems. A further 85 individuals belonging to this family were analyzed for exon 1 Leu55Gln mutations in the 5alphaSR2 gene. Forty-two of these 85 individuals (49.41%) had this alteration; 11 were homozygous (8 genetic male, 3 genetic female) and 31 heterozygous (18 genetic male, genetic female) for this mutation. It was interesting to see asymptomatic homozygous female carriers. In conclusion, according to our results and those of other Turkish patients reported by different investigators, 5aSR2 gene mutation analysis, especially for Leu55Gln in exon 1 and deltaMet157 in exon 3, must be carried out in Turkish patients with male pseudohermaphroditism. Homozygous asymptomatic female carriers must be taken into consideration in this clinical entity, especially in a closed population, because of the risk of transmitting the disease to their offspring.

Syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six patients.

Familial glucocorticoid deficiency (FGD) or unresponsiveness to ACTH at the receptor level is a rare autosomal recessive hereditary syndrome characterized by a low cortisol level despite high serum ACTH concentration. Aldosterone levels are normal. The clinical entity generally presents in the first year of life with skin hyperpigmentation and hypoglycemic convulsions. Cortisol response to exogenous ACTH is also absent. Unresponsiveness to ACTH may be due to a mutation in the ACTH receptor; sometimes no mutation is found. We discuss the clinical and laboratory findings and genetic studies in six patients with a diagnosis of FGD. A homozygous V142L mutation was detected in three of the patients and a homozygous D103N mutation was detected in two patients.

Severe hypercalcemia of an infant due to vitamin D toxicity associated with hypercholesterolemia.

We report an 11 month-old infant with severe hypercalcemia associated with hyperlipidemia following bolus vitamin D administration. At the time of admission, serum concentration of calcium was 5.5 mmol/l (22 mg/dl); total cholesterol, high density lipoprotein cholesterol (HDL-C), very low density lipoprotein (VLDL), low density lipoprotein cholesterol (LDL-C), and triglyceride levels were respectively: 6.37 mmol/l (246 mg/dl), 0.77 mmol/l (30 mg/dl), 1.37 mmol/l (54 mg/dl), 4.1 mmol/l (162 mg/dl), 3 mmol/l (271 mg/dl). Physical examination revealed dehydration and irritability that was inappropriately mild according to the serum calcium level. On the 16th day of therapy that consisted of intravenous fluids with furosemide (sodium diuresis), steroid, calcitonin, magnesium sulfate, and phosphorus, serum calcium level declined below 3 mmol/l (12 mg/dl). The hyperlipidemia resolved gradually with a concomitant decline in serum calcium. This report is interesting in that hypercalcemia was associated with transient hyperlipidemia that disappeared with normocalcemia, which might suggest protection against hypercalcemic symptoms.

Association of partial gonadal dysgenesis, nephropathy and WT1 gene mutation without Wilms' tumor: incomplete Denys-Drash syndrome.

The concurrence of ambiguous genitalia, nephropathy and predisposition to Wilms' tumor are characteristics of Denys-Drash syndrome. Some of the reported patients do not express the full spectrum of the syndrome, while the occurrence of nephropathy has become a generally accepted common feature of this syndrome. We report an infant with male pseudohermaphroditism due to partial gonadal dysgenesis and nephropathy without Wilms' tumor but with a Wilms' tumor suppressor gene (WT1) mutation. The high risk of Wilms' tumor mandates regular surveillance and the use of prophylactic bilateral nephrectomy as a treatment is not yet clear.

Osteopetrosis, renal tubular acidosis without urinary concentration abnormality, cerebral calcification and severe mental retardation in three Turkish brothers.

Deficiency of carbonic anhydrase II (CA II) isoenzyme produces metabolic disorders of bone, kidney and brain. In this report we describe the clinical, radiological, pathological and genetic findings in three brothers who were affected with the autosomal recessive syndrome of osteopetrosis, renal tubular acidosis (RTA) and cerebral calcification. The RTA was hybrid type, but urinary concentration ability was intact. Additional features were severe mental retardation, stunted growth, microcephaly, dental malocclusion, high-arched palate, and broad thumbs. Previous reported patients with this syndrome were predominantly from the Middle East and Mediterranean region. This is the first report with CA II deficiency from the Turkish population. The presence of mental retardation and relative infrequency of skeletal fractures in our patients resembles the clinical course of patients with the Arabic mutation of the CA II gene, but this mutation was not found in our patients.

Evaluation of the pancreas reserve in siblings of type I diabetic children.

INTRODUCTION: The purpose of this study was to determine the pancreas reserve in siblings of diabetic patients by screening islet cell antibodies (ICA), insulin auto antibodies (IAA), reduced C-peptide levels, first-phase insulin release and the derangement of cellular immunity (reduction of natural killer cells, abnormality of the T cell subpopulations). METHODS AND RESULTS: Twelve siblings (aged 9.3 +/- 2.8 years) of diabetic children were evaluated and results were compared with the control group (12.1 +/- 3.5 years). For siblings of the diabetic children, fasting, post-prandial and glucagon response C-peptide mean values were 2.2 +/- 1.2, 7.2 +/- 7.1 and 5.3 +/- 3.6 ng/mL, respectively, while in the control group they were 1.5 +/- 0.8, 3.6 +/- 2.0 and 5.1 +/- 2.9 ng/mL, respectively. There were no differences between the two groups. In 33%, postprandial C-peptide, and in 11% of the siblings, glucagon response C-peptide values were exaggerated. In siblings the first phase insulin release (FPIR) during an intravenous glucose tolerance test was 128.5 +/- 96.6 (above the 50th percentile) and stimulated insulin release (SIR) was 103.8 +/- 92.5 (above 25th percentile). Sibling values were significantly lower than the control group (FPIR 152.4 +/- 42.5, P = 0.01; SIR 134.9 +/- 38.2, P = 0.01). Values for FPIR (in two children) and SIR (three cases) were below the 5th percentile. In one, FPIR and SIR levels were both below the 1st percentile. Islet cell antibodies and IAA were also present in this subject. Treatment with nicotinamide was started in the cases with FPIR and SIR below the 5th percentile. We did not observe overt diabetic symptoms during the follow-up period of more than 3 years. CONCLUSION: We recommend that borderline insulin secretion be tested annually in siblings who show insufficient FPIR.

Recombinant human growth hormone treatment in children with thalassemia major.

BACKGROUND: To evaluate the growth hormone reserve and the growth hormone response to recombinant human growth hormone (GH) in prepubertal thalassemic children with growth retardation. METHODS: Twenty thalassemic patients with short stature and delayed bone age were studied. Patients were randomized into GH-treated (n = 10) and non-GH treated (control; n = 10) groups. The GH-treated group received recombinant human (rh)-GH (Genotropin) at the dose of 0.7 IU/kg per week for 12 months. RESULTS: There was a significant discordance between GH response to pharmacologic stimuli and physiological secretion of GH/GHRH testing. Following the administration of rhGH, growth velocity increased from 2.47 +/- 0.48 cm/year to 6.27 +/- 0.76 cm/year (P = 0.005), whereas there was not a similar change in the non-GH-treated group. The height velocities of the two groups during the 1 year follow-up period were significantly different (6.27 +/- 0.76 vs 3.99 +/- 0.34 cm/year; P = 0.025). There were significant differences between the height velocity improvements and height velocity standard deviation scores of the two groups as well. CONCLUSION: The present study has demonstrated that rhGH is a safe and efficacious mode of treatment in thalassemic children.