Yi-Ching Tung

Long-term outcome of hormonal status in Taiwanese children with Hashimoto’s thyroiditis

The objective of this prospective study was to evaluate both thyroid function in children with Hashimoto’s thyroiditis and the necessity of lifetime thyroxine replacement therapy. A total of 47 patients with goiter and positive thyroid auto-antibodies participated in the study. Serum thyroxine and thyrotropin levels and titers of thyroid auto-antibodies were checked regularly throughout the follow-up period. At the beginning of the study, 25 patients were diagnosed as euthyroid, but at the end of the study, 22 patients initially diagnosed with euthyroidism remained euthyroid, while eight patients with subclinical hypothyroidism and three patients with overt hypothyroidism had become euthyroid. Thus, of the 22 patients with thyroid dysfunction at diagnosis, subclinical or overt, 11 became euthyroid during the follow-up period. The effect of thyroxine treatment on thyroid auto-antibody titers was not significant. Conclusion: Our data shows that Hashimoto’s thyroiditis in children has a benign course and that thyroid function in one half of the patients with thyroid dysfunction at diagnosis reverts to normal. Careful follow-up of thyroid function is important in order to determine the necessity and timing of thyroxine replacement therapy.

Transient Pseudohypoparathyroidism as a Cause of Late-onset Hypocalcemia in Neonates and Infants

BACKGROUND/PURPOSE Transient pseudohypoparathyroidism is a rare cause of late-onset hypocalcemia in neonates and infants. The purpose of this study was to investigate the clinical presentation and natural course of transient pseudohypoparathyroidism in neonates and infants. METHODS From 1995 to 2006, 21 patients under 3 months of age were admitted to our department because of late-onset neonatal hypocalcemia. Among these, five were noted to have transient hypocalcemia, hyperphosphatemia and elevated serum parathyroid hormone levels. Their clinical data, biochemical findings and natural course were thoroughly analyzed. RESULTS All five patients were boys with increased neuromuscular irritability as their initial clinical manifestation. Initial biochemical data showed calcium 1.5 +/- 0.16 mmol/L, phosphorus 9.6 +/- 1.5 mg/dL, intact parathyroid hormone 182 +/- 93 pg/mL and tubular reabsorption of phosphorus 94.8 +/- 3.7%. Two of the patients had magnesium deficiency. After reduction of phosphorus intake and supplementation with calcium and/or magnesium as indicated, the biochemical derangements resolved in 28 +/- 3 days. CONCLUSION Neuromuscular irritability is usually the initial clinical presentation of transient pseudohypoparathyroidism. Aside from delayed renal maturation, pseudohypoparathyroidism is also caused by magnesium deficiency. Such a disturbance usually resolves before 3 months of age.

The Effects of Gonadotropin Releasing Hormone Analogue Therapy on Girls with Gonadotropin-dependent Precocious Puberty

BACKGROUND/PURPOSE It has been reported that gonadotropin releasing hormone analogue (GnRHa) therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. The purpose of this study was to evaluate the effect of GnRHa on the adult height of girls with gonadotropin-dependent precocious puberty and the adverse effects of such therapy. METHODS Between 1989 and 2006, 11 girls with gonadotropin-dependent precocious puberty who had been treated with GnRHa and reached their adult height were enrolled in the present study. Follow-up studies of bone age, pelvic sonography and GnRH test were done regularly during the period of treatment. All patients had bone mineral density examined at least 2 years after completion of GnRHa therapy. RESULTS GnRHa therapy was initiated at the age of 8.0 +/- 1.5 years. The predicted adult height immediately before GnRHa therapy was 146.7 +/- 4.8 cm (-2.3 +/- 0.9 standard deviation [SD]). The duration of GnRHa therapy was 4.7 +/- 1.8 years. The adult height of the patients was 156.3 +/- 4.3 cm (-0.6 +/- 0.8 SD), which is similar to their target height of 157.0 +/- 4.5 cm (-0.5 +/- 0.8 SD). The uterine sizes and gonadotropin responses to GnRH stimulation were well suppressed during treatment. Menstruation resumed 9.2 +/- 5.9 months after the discontinuation of treatment in these patients. Forty-five percent of patients had lumbar bone mineral density less than 1 SD below that of normal young Taiwanese adults in the Taipei region. CONCLUSION GnRHa therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. However, 45% of patients had decreased bone accretion during therapy.

Arachnoid cyst with GnRH-dependent sexual precocity and growth hormone deficiency

The coexistence of gonadotropin-releasing hormone (GnRH)-dependent sexual precocity and growth hormone deficiency in patients with arachnoid cysts is rarely reported, and its pathogenesis is not well recognized. This report describes an 11-year-old female who had a huge intracranial arachnoid cyst with initial symptoms and signs of sexual precocity. Her brain magnetic resonance imaging revealed distorted hypothalamus with a thin and stretched pituitary stalk. After treatment with cysto-peritoneal shunting and gonadotropin-releasing hormone analogue, her puberty was arrested and subnormal growth rate was observed. Catch-up growth was detected after growth hormone therapy. Hence, coexistence of gonadotropin-releasing hormone-dependent sexual precocity and growth hormone deficiency in this patient was confirmed.

Effect of Growth Hormone Therapy on Adult Height of Children with Turner Syndrome

BACKGROUND/PURPOSE Short stature is a common manifestation of Turner syndrome. The purpose of this study was to evaluate the effect of growth hormone (GH) therapy alone on the adult height of children with Turner syndrome. METHODS From 1987 to 2006, 21 Turner syndrome patients who had been treated with GH for >2 years and had reached adult height were enrolled in the study. The dosage of GH was 0.33 mg/kg/week. Estrogen replacement therapy was prescribed at the age of 15.6+/-0.9 years, if indicated. The patients had been followed-up until they reached their adult height. During the same period, 28 Turner syndrome patients who were not treated with growth-promoting agents were enrolled for comparison. Mann-Whitney U test and Wilcoxon signed rank test were used for comparison. RESULTS Twenty-one patients in the study group started GH therapy at the age of 11.5+/-1.8 years. The duration of GH therapy was 4.0+/-1.5 years. The growth rate before treatment was 3.8+/-0.7 cm/year, which increased to 7.1+/-1.4, 5.4+/-1.4 and 4.7+/-0.9 cm/year during the first 3 years of GH therapy, respectively. Patients who received GH reached an adult height of 150.0+/-5.1 cm, which was significantly higher than the 144.7+/-5.9 cm of the control group (p<0.05). The adult height of the study group was 6.3+/-3.3 cm taller than their projected adult height upon enrolment. No major adverse events were detected during GH therapy. CONCLUSION GH alone is safe and effective for the promotion of growth in children with Turner syndrome in Taiwan.

β-Cell Autoantibodies and Their Function in Taiwanese Children With Type 1 Diabetes Mellitus

BACKGROUND/PURPOSE To understand the importance of autoimmunity in the development of type 1 diabetes in Taiwanese children, we evaluated the presence of beta-cell autoantibodies and their correlation with residual beta-cell function. METHODS From 1989 to 2006, 157 Taiwanese children with newly diagnosed type 1 diabetes were enrolled in this study. We determined the presence of beta-cell autoantibodies, such as glutamic acid decarboxylase autoantibodies (GADAs), insulinoma antigen 2 autoantibodies (IA-2As), and insulin autoantibodies (IAAs). A 6-minute glucagon test was also performed at diagnosis. RESULTS At diagnosis, 73% of children tested positive for GADAs, 76% for IA-2As and 21% for IAAs. Ninety-two percent of them had at least one of the beta-cell autoantibodies detected. Positivity for IAAs was more frequent in patients younger than 5 years than in those older than 5 years (45% vs. 13%). Using multiple regression analysis, the presence of GADAs or IAAs, or age of onset of these patients was an independent factor for residual beta-cell function. Younger patients and those with GADAs had less residual beta-cell function at disease onset, whereas those with IAAs had more insulin reserve. CONCLUSION Autoimmunity plays an important role in the pathogenesis of type 1 diabetes in Taiwanese children, and the presence of IAAs tends to be more common in younger children.

Clinical Characteristics of Taiwanese Children With Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency in the Pre-screening Era

BACKGROUND/PURPOSE Data about the clinical manifestations of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21-OHD) are lacking in Taiwan. Therefore, this study analyzed the clinical features of 21-OHD in Taiwanese children to improve the diagnosis of this disorder, and to provide background information regarding the ongoing neonatal screening program for 21-OHD in Taiwan. METHODS Eighty children with 21-OHD, 39 with the salt-wasting (SW) type and 41 with the simple-virilizing (SV) type, were evaluated by a review of their medical records. Their clinical symptoms and signs, laboratory findings, and genetic mutations were analyzed. RESULTS The most frequent features in 21-OHD patients were hyperpigmentation and signs of androgen excess. Clinical manifestations related to hyponatremia such as poor feeding, poor weight gain, and dehydration were noted most frequently in patients with SW-type 21-OHD. Five patients had low serum cortisol with elevated plasma adrenocorticotropic hormone levels, and 22 patients had elevated dehydroepiandrosterone sulfate levels. All had elevated blood levels of 17-hydroxyprogesterone, androstenedione and testosterone. Hyponatremia and hyperkalemia were detected in 29 patients with SW-type 21-OHD. In terms of molecular diagnosis, mutations at IVS2-12A/C --> G and gene deletion were the most frequent mutations detected in SW-type 21-OHD, while I172N and mutation at IVS2-12A/C --> G were most frequent in SV type. CONCLUSION Taiwanese children with 21-OHD have characteristic clinical findings such as hyperpigmentation, androgen excess, and failure to thrive. There is a good correlation between genotype and pheno-type. Laboratory tests, including serum 17-hydroxyprogesterone, androstenedione, and testosterone levels are more sensitive than serum cortisol or dehydroepiandrosterone sulfate levels for diagnosing 21-OHD in prepubertal children.

Mutations of T-Cell Epitopes in the Hepatitis B Virus Surface Gene in Children With Chronic Infection and Hepatocellular Carcinoma

BACKGROUND AND OBJECTIVES:Hepatitis B virus (HBV) infection induces an interaction of host immune responses against virus antigen-presenting hepatocytes. The emergence of mutants is a strategy through which the virus can escape host attacks and produce chronic infection. In this study, we aimed to investigate mutations of the human leukocyte antigen-A2-restricted T-cell epitope (TCE) in chronic HBV-infected children.METHODS:In total, 441 chronic HBV-infected children were longitudinally followed-up every 6 months. They were divided into hepatitis B e antigen (HBeAg) (−) (N = 60) and HBeAg (+) (N = 381) groups according to this seromarker at their enrollment. The HBeAg (+) group was further divided into HBeAg (+/−) (N = 229) and HBeAg (+/+) (N = 152) groups, depending on the occurrence of spontaneous HBeAg seroconversion. Twenty-five children with HBV-related hepatocellular carcinoma (HCC) were also recruited. TCE mutations were examined using the latest serum samples, and serum samples at enrollment were used if TCE mutations were present in the latest serum samples in the seroconverters. HBV genotypes and liver enzymes were also analyzed.RESULTS:The HBeAg (+/+) group had a lower TCE mutation rate (7.9%) than that of the HBeAg (+/−) (29.2%), HBeAg (−) (26.7%), and HCC (28.0%) groups. In the HBeAg (+/−) group, TCE mutations were present before HBeAg seroconversion in 11.9% of the subjects. Those with TCE mutations showed HBeAg seroconversion at an older age (16.1 ± 5.3 yr vs 12.7 ± 5.7 yr, P < 0.001) and with higher peak alanine aminotransferase (ALT) levels (median 175 U/L vs 119 U/L, P = 0.03) than those without TCE mutations.CONCLUSIONS:TCE mutations tended to be positively associated with HBeAg seroconversion and higher ALT levels in chronic HBV-infected children.

Slipped Capital Femoral Epiphysis as a Complication of Growth Hormone Therapy

Slipped capital femoral epiphysis (SCFE) is a rare complication of growth hormone (GH) therapy. Here, we report three patients who developed SCFE during GH therapy. The first two patients had hypopituitarism and had started GH therapy at the age of 15 years 6 months and 13 years 9 months, respectively. SCFE developed 4 years and 1 year after GH therapy, respectively. The third patient had Prader-Willi syndrome with obesity and hypogonadism and began GH therapy at the age of 12 years and 11 months. SCFE developed 2 months after starting GH therapy. Pain over the hip joints or over the knees is an early sign of SCFE. Despite recommendation, none of the three patients continued GH therapy. A high index of suspicion during GH therapy in patients at high risk of SCFE is important for early diagnosis and appropriate management.

Novel deletion mutations of the DAX1 (NR0B1) gene in two Taiwanese families with X-linked adrenal hypoplasia congenita.

OBJECTIVE To analyze the DAX1 (NROB1) gene in Taiwanese families with adrenal hypoplasia congenita. PATIENTS AND METHODS Two unrelated Taiwanese patients were followed up at our pediatric endocrine clinic. Both patients presented with adrenal crisis. One patient entered puberty spontaneously. However, arrest of puberty was noted in the following years and hypogonadotropic hypogonadism was confirmed by GnRH test. The other patient was still prepubertal. Sequencing of the DAX1 (NROB1) gene was carried out in both patients and their respective family members. RESULTS Two different novel mutations were identified. The first patient had one base (G) deletion at nucleotide 159, resulting in a frame-shift and a premature stop codon at position 84. The other patient had one base (G) deletion at nucleotide 831, leading to a frameshift and a premature stop codon at position 371. Family studies revealed that their mothers and sisters were heterozygotes for the mutations while their maternal grandmothers did not carry the mutations. CONCLUSIONS Two Taiwanese patients with adrenal hypoplasia congenita were detected to have novel mutations of the DAX1 (NR0B1) gene. Family studies suggested that such mutations resulted from de novo mutation of the DAX1 (NROB1) gene in their mothers. These data indicate that molecular analysis of the DAX1 (NR0B1) gene is important for the diagnosis and genetic counseling of children with primary adrenal insufficiency.