Case report of two siblings with familial ovarian dysgenesis.

Two sisters were admitted separately at different times (ages 15 and 12 years, respectively) to our unit because of amenorrhea, lack of secondary sex characteristics, and short stature. No evidence of other congenital anomalies was found. Laboratory studies indicated hypergonadotropic hypogonadism. Peripheral blood samples revealed normal 46,XX karyotype for both patients. No gonads were visualized by ultrasonography. The two cases underline the need to take familial ovarian dysgenesis into consideration in female patients with short stature, lack of secondary sex characteristics, normal karyotypes, and similar sibling histories.

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.

Amelogenesis imperfecta with growth hormone deficiency in a 12 year-old boy.

Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.

New autosomal recessive mutation of the TSH-beta subunit gene causing central isolated hypothyroidism.

We identified a new nonsense mutation of the TSH-beta subunit gene responsible for a severe isolated TSH deficiency in two children from the same consanguineous kindred. These affected children are homozygous for a C-to-T transition at nucleotide 654 of the TSH-beta subunit gene, leading to the conversion of a glutamine (CAG) to a premature stop codon (TAG) in the codon 49 (Q49X). The resulting nascent peptide does not contain the seat belt region (amino acid residues 88-105), a TSH-beta subunit region crucial for the dimerization with the alpha-subunit, and, hence, the correct secretion of the mature TSH heterodimer is hampered. Free T(3), free T(4) as well as basal TSH levels were extremely low in both affected individuals and, importantly, TRH stimulations failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. Using the new StyI endonuclease restriction site generated by the mutation, we confirmed that the affected children were homozygous for the Q49X TSH-beta mutation whereas their unaffected parents as well as their unaffected brother were heterozygous. Consequently, this isolated TSH deficiency follows an autosomal recessive mode of inheritance.

Autoimmune polyglandular endocrinopathy and anterior hypophysitis in a 14 year-old girl presenting with delayed puberty.

We report a 14 year-old peripubertal girl who presented at our clinic with the primary complaint of delayed puberty. She was asymptomatic except for vague complaints of fatigue. Physical examination was significant for mucosal hyperpigmentation and lack of secondary sexual characteristics. Laboratory evaluation revealed a morning cortisol concentration of <0.1 microg/dl (normal range [n.r.]: 4.3-22.4 microg/dl) and a simultaneous ACTH concentration of 2 pg/ml (n.r. 25-62 pg/ml); FSH 66.8 IU/l (n.r. for age: 1-12.8 IU/l); LH 41.1 IU/l (n.r. for age: 1-12 IU/l); E2 38 pg/ml (n.r. for age: 7-60 pg/ml). She had a flat cortisol response to an ACTH stimulation test. MRI of the pituitary gland failed to reveal a lesion. Plasma renin activity, thyroid function tests, parathyroid hormone, prolactin, IGF-I, IGFBP-3 concentrations and serum electrolytes were normal. However, her urinary sodium concentration was high. She was diagnosed with autoimmune polyglandular endocrinopathy including ovarian failure, adrenal failure and autoimmune anterior hypophysitis presenting as isolated ACTH deficiency. We emphasize that autoimmune etiology should be considered in the differential diagnosis of delayed puberty and ovarian failure and that the presence of other endocrinopathies should be searched for even in asymptomatic patients.

Helicobacter pylori infection in children with constitutional delay of growth and puberty.

Helicobacter pylori is a gastroduodenal pathogen strongly associated with chronic gastritis and duodenal ulceration. It is thought that H. pylori infection might be one of the causes of growth retardation in children. The aim of this study was to evaluate the seroprevalence of H. pylori in children with constitutional delay of growth and puberty (CDGP). H. pylori seropositivity was studied in 24 children with CDGP (22 M, 2 F) and 32 healthy age-matched children with normal pubertal development. Mean age of the children with CDGP was 14.53 +/- 1.12 yr and all of them had been diagnosed as CDGP after physical and laboratory assessment. H. pylori IgG positivity was detected in 16 of the 24 children with CDGP (66.6%) and 12 of 32 controls (37.5%) (p <0.05). This finding is consistent with the hypothesis that H. pylori infection could be one of the environmental factors causing CDGP.

Partial remission phase and metabolic control in type 1 diabetes mellitus in children and adolescents.

A better understanding of the remission phase, while residual beta-cell function is still present in recently diagnosed type 1 (insulin dependent) diabetes mellitus (IDDM), is very important because of the potential for pharmacological intervention to preserve this function. To evaluate the natural course and characteristics of the remission phase in children and adolescents with IDDM, a retrospective study was performed on patients diagnosed with IDDM under the age of 18 years during the years 1991-1998. Sixty-two patients whose medical records were available were included in the study. Data were collected by reviewing the hospital records of patients from the time of diagnosis through the first 24 months after diagnosis. The duration of symptoms and history of infection prior to presentation, diabetic ketoacidosis (DKA) at diagnosis, length of hospitalization, initial glucose level, basal C-peptide levels at diagnosis, daily insulin requirements per kg body weight and HbA1c at diagnosis and at each visit were recorded. Thirty-five patients (56.5%) entered partial remission. We observed similar remission rates in those aged <10 and > or =10 years at diagnosis and in boys and girls. History of infection and presentation with DKA were associated with a lower rate of remission (p<0.001, p<0.0001, respectively) and were more commonly observed under the age of 10 years (p<0.0001, p<0.0001, respectively). The average insulin requirements per kg body weight calculated at diagnosis decreased with increasing age (r = -0.31, p = 0.012). The length of time until remission was 1.36+/-1.03 (mean +/- SD) months and positively correlated with insulin requirements at discharge from the hospital (r = 0.63, p<0.0001). Mean duration of remission was 11.67+/-5.82 months and was much longer in boys than girls (p<0.05). Six patients, all boys, entered total remission for 3.80+/-3.73 months. HbA1c concentrations in the first year of the disease were significantly lower in patients who underwent a remission phase (7.31+/-1.24% vs. 8.24+/-1.47%, p <0.05). However, this difference was not observed during the second year of the disease. In conclusion, history of infection prior to presentation and DKA at diagnosis were associated with young age and were the most important factors negatively influencing the remission rate in newly diagnosed IDDM patients.

Factors influencing remission phase in children with type 1 diabetes mellitus.

Type 1 diabetes mellitus (DM) is characterized by selective and progressive autoimmune destruction of beta-cells of the pancreas in genetically susceptible individuals. This autoimmune process takes years before the patient eventually develops clinical DM. Over the course of the disease, some patients regain their ability to secrete endogenous insulin to some extent for a period of few months to years. This partial remission phase has drawn a lot of attention since it offers a window of opportunity to intervene in an attempt to restore pancreatic beta-cell function or to prevent development of the disease in the prediabetic population at risk. Several factors, including age, sex, pubertal status, metabolic findings at the time of presentation, HLA types, presence of diabetes-associated autoantibodies, have been recognized to affect the likelihood of partial or complete remission in children with type 1 DM. Several interventions in patients with new-onset type 1 DM have been tried, including oral nicotinamide and immunomodulatory and immunosuppressive treatments, in an attempt to preserve beta-cell function and to promote or prolong the remission phase, but no conclusive data have been obtained so far. This review summarizes current knowledge on the factors that possibly influence the remission phase in children with type 1 DM.

Primary antiphospholipid syndrome: an unusual cause of adrenal insufficiency.

We describe a boy, 10 years and 5 months old, who developed acute adrenal gland insufficiency which was confirmed by hormonal investigation. Abdominal magnetic resonance imaging showed unilateral enlargement of the right adrenal gland, whereas the other gland seemed normal - no cause was apparent. Three months later the patient presented with thrombosis in the right femoral vein and in the veins of the right leg. Autoantibodies against cardiolipin were strongly positive, while antinuclear antibodies and antibodies against double-stranded deoxyribonucleic acid were absent. There was no evidence of antiphospholipid syndrome associated with drugs, connective tissue disorders, or malignancies, strongly suggesting the diagnosis of primary antiphospholipid syndrome. The development of adrenal insufficiency has been reported in primary antiphospholipid syndrome due to adrenal hemorrhage following vascular occlusion of adrenal vessels or secondary to anticoagulant therapy. It was interesting to note that in our patient adrenal gland insufficiency preceded other clinical evidence of the syndrome by 3 months. The primary antiphospholipid syndrome should be considered a possible cause of Addison's disease when the etiology is not obvious.

Dilated cardiomyopathy as the first early complication in a 14 year-old girl with diabetes mellitus type 1.

Diabetic cardiomyopathy (DC) has been reported in type 2 diabetics with short duration of clinically overt diabetes. Impaired left ventricular function has been reported in young patients with diabetes mellitus type 1 (IDDM), but severe cardiomyopathy as the first early major complication of IDDM is very rare. We report a 14 year-old girl with a 5-year history of IDDM and very poor compliance with treatment and follow-up. She was referred to our clinic upon the development of congestive heart failure and dilated cardiomyopathy was diagnosed based on clinical findings, electrocardiogram, chest X-ray and echocardiography. She had no evidence of other major complications of IDDM such as retinopathy, nephropathy or neuropathy.

Chronic hypoxemia leads to reduced serum IGF-I levels in cyanotic congenital heart disease.

Cyanotic congenital heart disease in children commonly causes more pronounced growth retardation in comparison with acyanotic congenital heart disease. Chronic hypoxemia has been suggested as the cause of poor growth in these patients, but the relationship between serum IGF-I levels and chronic hypoxemia is unclear. Serum IGF-I concentrations, oxygen saturation and nutritional status were evaluated in 29 patients with cyanotic congenital heart disease, and serum IGF-I levels were compared with a group of 20 well-nourished, age-matched control children to assess the relationship between IGF-I levels and chronic hypoxemia. The nutritional status of each patient was determined by using anthropometric parameters and calorie and protein intake ratios. The patients were divided into malnourished and well-nourished groups (21 and 8 patients, respectively) according to their nutritional status. Serum IGF-I concentrations were measured in the two patient groups and the controls. The malnourished group had the lowest IGF-I levels (48.14 +/- 21.8 ng/ml, p<0.05). However, the well-nourished group's IGF-I levels were significantly lower than the control subjects' despite improved nutritional status (85.5 +/- 30.2 and 107 +/- 19.7 ng/ml, respectively, p<0.05). In addition, we found a positive correlation between serum IGF-I levels and oxygen saturation of the patients (r=0.402, p<0.05). These findings indicate that chronic hypoxemia has a direct or indirect effect to reduce serum IGF-I concentrations and this may be a cause of the increased growth failure in patients with cyanotic congenital heart disease.

Associations of IGF-I, IGFBP-1 and IGFBP-3 on intrauterine growth and early catch-up growth.

Fetal cord blood IGF-I, IGFBP-1 and IGFBP- 3 levels of appropriate-for-gestational-age (AGA) and intrauterine growth retardation (IUGR) babies are studied and followed up for 6-9 months, reevaluated for anthropometric measures and the effects of IGF-I, IGFBP-1 and IGFBP-3 on fetal growth and early catch-up growth is investigated. 23 AGA and 21 IUGR babies, totally 44 newborns, were included in the study protocol. IGF-I and IGFBP-3 levels were found to be high in AGAs with respect to IUGR babies and IGFBP-1 is found to be high in IUGR with respect to AGAs. IGF-I was significantly lower in IUGR babies without catch-up growth (group 2b) with respect to AGAs (group 1) and neonates with IUGR and catch-up growth (group 2a) and group 2a infants had higher IGF-I values than group 2b infants (p < 0.05). IGFBP-3 levels in group 1 were significantly higher than in the other two groups (p < 0.05), but not significantly different in group 2a with respect to group 2b (p > 0. 05). IGFBP-1 values showed no statistically significant difference with respect to the three different groups (p > 0.05). A good correlation was found between birth weight, postnatal weight and postnatal height and IGF-I and IGFBP-3 levels (p < 0.05) but not with IGFBP-1 levels. Aside from the height of the 3 groups of infants which were similar to each other after the follow-up period, IGF-I was significantly high in IUGR infants with catch-up growth with respect to IUGR infants without catch-up growth, indicating its importance in early catch-up growth of IUGR babies.

Precocious puberty in a patient with indicanuria.

A 7-5/12 year-old girl, who was followed-up after diagnosis of indicanuria, presented with symptoms of bilateral breast enlargement. Her breast development was at Tanner stage II. No pubic or axillary hair was observed. Pelvic ultrasonography revealed multiple follicles on both ovaries. Basic endocrinological evaluation and cranial magnetic resonance imaging (MRI) were normal. The diagnosis of precocious puberty was established with respect to the pubertal response to GnRH stimulation test. Although precocious puberty has been reported associated with some metabolic diseases, this is the first description in a patient with indicanuria. The question of whether precocious puberty in our patient with indicanuria is a coincidence or whether it is related to metabolic changes activating the hypothalamo-pituitary-gonadal axis remains open.

Localized lipoatrophy due to recombinant growth hormone therapy in a child with 6.7 kilobase gene deletion isolated growth hormone deficiency.

Local lipoatrophy is a well known complication of insulin treatment at injection sites and the etiology is thought to be a cross reaction with lipid tissues and insulin antibody. Although mild lipoatrophy during growth hormone treatment has been reported in the literature, severe local lipoatrophy in injection sites in the extremities has not yet been published. We report a patient with isolated GH deficiency due to 6.7 kb gene deletion who received high dose rhGH treatment and developed local lipoatrophies at injection sites without any antibody detection after 6 years of therapy. The etiology of the lipoatrophy is suspected to be by the direct lipolytic effect of high doses of rhGH.

"Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency.

As pituitary function depends on the integrity of the hypothalamic-pituitary axis, any defect in the development and organogenesis of this gland may account for a form of combined pituitary hormone deficiency (CPHD). Although pit-1 was 1 of the first factors identified as a cause of CPHD in mice, many other homeodomain and transcription factors have been characterized as being involved in different developmental stages of pituitary gland development, such as prophet of pit-1 (prop-1), P-Lim, ETS-1, and Brn 4. The aims of the present study were first to screen families and patients suffering from different forms of CPHD for PROP1 gene alterations, and second to define possible hot spots and the frequency of the different gene alterations found. Of 73 subjects (36 families) analyzed, we found 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PROP1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be caused by any 2-bp GA or AG deletion at either the 148-GGA-GGG-153 or 295-CGA-GAG-AGT-303 position. As any combination of a GA or AG deletion yields the same sequencing data, the frameshift mutations were called 149delGA and 296delGA, respectively. All but 1 mutation were located in the PROP1 gene encoding the homeodomain. Importantly, 3 tandem repeats of the dinucleotides GA at location 296-302 in the PROP1 gene represent a hot spot for CPHD. In conclusion, the PROP1 gene seems to be a major candidate gene for CPHD; however, further studies are needed to evaluate other genetic defects involved in pituitary development.

MHC class I antigen expression in patients with IDDM and their siblings.

MHC class I antigen expression was found to be low on the lymphocytes of patients with insulin dependent diabetes mellitus (IDDM). Thus, it has been proposed that the defective expression of MHC antigens could lead to faulty immunological responses with the eventual destruction of the pancreatic beta cells. The objective in this study was to compare MHC antigen expression in IDDM patients and their presently healthy siblings. Nineteen children (mean age 10.8 +/- 3.9 years) with diabetes and their 25 siblings (mean age 10.7 +/- 4.6 years) were enrolled in the study. Peripheral blood lymphocytes isolated from venous blood samples were incubated with FITC conjugated monoclonal antibody W6/32. The amount of antibody binding by cell surface MHC class I antigens was assessed by flow cytometry. MHC class I molecule expression did not differ significantly among IDDM patients and their siblings. It was concluded that MHC class I antigen expression did not appear to be indicative of a susceptibility to develop autoimmune diabetes.

Renal, gastric and thyroidal amyloidosis due to familial Mediterranean fever.

Chronic renal failure developed in a 10-year-old girl due to renal amyloidosis secondary to familial Mediterranean fever (FMF). During management of the chronic renal failure by hemodialysis and of FMF with colchicine, goiter and hypothroidism were observed. Thyroid fine-needle aspiration and gastric endoscopical biopsies, performed when recurrent abdominal pain could not be controlled, revealed amyloid deposits in both thyroid and gastric tissues. After 6 months' therapy with colchicine and levothyroxine, there was no significant change in the thyroid volume. This is the first case in which gastric amyloidosis secondary to FMF in childhood has been demonstrated. Patients with amyloidosis secondary to FMF who have thyroid enlargement and unexplained gastrointestinal symptoms despite adequate therapy should be evaluated with imaging studies and biopsy examinations.