Slower progression of central puberty in overweight girls presenting with precocious breast development

Purpose@#Overweight (OW)/obese girls tend to have an earlier pubertal onset than girls with normal weight. However, only a few studies have reported the progression of puberty in these girls. This study aimed to identify risk factors for rapid pubertal progression in OW/obese girls presenting with precocious breast development. @*Methods@#This retrospective cohort study reviewed the medical records of 110 OW (body mass index [BMI] ≥85th percentile for age and sex) and 213 nonoverweight (NW, BMI <85th percentile for age and sex) girls who presented with breast budding before 8 years of age. OW girls were divided into 2 subgroups: girls with central puberty progression before 9 years of age (OW-RP) and those without (OW-SP). @*Results@#Progression to central puberty before the age of 9 was more common in NW girls than in OW girls (83.8 % vs. 65.2 % in NW vs. OW group, p<0.001), and progression-free survival for 1, 2, and 3 years was higher in the OW group (p<0.001). In a subgroup analysis of OW girls, the OW-RP subgroup had more advanced bone age (BA) at the first visit (p=0.047) and higher initial luteinizing hormone (LH, p=0.010) levels than the OW-SP subgroup. Being NW (p=0.001) and having more advanced BA (p=0.023) at the initial workup were the risk factors for pubertal progression before age 9. @*Conclusion@#Pubertal progression seems to be slower in OW girls than in NW girls presenting with precocious breast development. However, it can progress rapidly in OW girls with particularly pronounced BA advancement and high LH levels at the initial workup.

A 14-year-old male with rhabdomyolysis associated with psychogenic polydipsia and hyponatremia

Rhabdomyolysis associated with psychogenic polydipsia and hyponatremia is a rare condition that can cause substantial morbidity and mortality. We report a 14-year-old boy with psychogenic polydipsia who experienced recurrent hyponatremia and subsequent rhabdomyolysis. Treatment involved intravenous fluids and restriction of oral water intake. This case emphasizes the importance of early recognition and management of this condition. The possibility of rhabdomyolysis should be considered in patients with hyponatremia who have myalgia.

Bone Age Estimation and Prediction of Final Adult Height Using Deep Learning

Purpose@#The appropriate evaluation of height and accurate estimation of bone age are crucial for proper assessment of the growth status of a child. We developed a bone age estimation program using a deep learning algorithm and established a model to predict the final adult height of Korean children. @*Materials and Methods@#A total of 1678 radiographs from 866 children, for which the interpretation results were consistent between two pediatric endocrinologists, were used to train and validate the deep learning model. The bone age estimation algorithm was based on the convolutional neural network of the deep learning system. The test set simulation was performed by a deep learning program and two raters using 150 radiographs and final height data for 100 adults. @*Results@#There was a statistically significant correlation between bone age interpreted by the artificial intelligence (AI) program and the reference bone age in the test set simulation (r=0.99, p<0.001). In the test set simulation, the AI program showed a mean absolute error (MAE) of 0.59 years and a root mean squared error (RMSE) of 0.55 years, compared with reference bone age, and showed similar accuracy to that of an experienced pediatric endocrinologist (rater 1). Prediction of final adult height by the AI program showed an MAE of 4.62 cm, compared with the actual final adult height. @*Conclusion@#We developed a bone age estimation program based on a deep learning algorithm. The AI-derived program demonstrated high accuracy in estimating bone age and predicting the final adult height of Korean children and adolescents.

A 1-month-old infant with chylomicronemia due to GPIHBP1 gene mutation treated by plasmapheresis

Chylomicronemia is a severe type of hypertriglyceridemia characterized by chylomicron accumulation that arises from a genetic defect in intravascular lipolysis. It requires urgent and proper management, because serious cases can be accompanied by pancreatic necrosis or persistent multiple organ failure. We present the case of a 1-month-old infant with chylomicronemia treated by plasmapheresis. His chylomicronemia was discovered incidentally when lactescent plasma was noticed during routine blood sampling during a hospital admission for fever and irritability. Laboratory investigation revealed marked triglyceridemia (>5,000 mg/dL) with high chylomicron levels. We therefore decided to perform a therapeutic plasmapheresis to prevent acute pancreatitis. Sequence analysis revealed a homozygous novel mutation in exon 4 of GPIHBP1: c.476delG (p.Gly159Alafs). Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) stabilizes the binding of chylomicrons near lipoprotein lipase and supports lipolysis. Mutations of GPIHBP1, the most recently discovered gene, can lead to severe hyperlipidemia and are known to make up only 2% of the monogenic mutations associated with chylomicronemia. The patient maintains mild hypertriglyceridemia without rebound after single plasmapheresis and maintenance fibrate medication so far. Here, we report an infant with chylomicronemia due to GPIHBP1 mutation, successfully treated by plasmapheresis.

Insulin resistance and bone age advancement in girls with central precocious puberty

PURPOSE: Precocious puberty has significantly increased recently. While obesity is associated with puberty timing, the relationship between obesity and central precocious puberty (CPP) remains controversial. The purpose of this study was to determine whether insulin resistance is associated with bone age (BA) advancement in girls with CPP. METHODS: We retrospectively analyzed the records of 804 girls referred for puberty evaluation. Anthropometric measurements, BA, sex hormone, sex hormone binding globulin (SHBG), and insulin levels, lipid profiles, and gonadotropin releasing hormone stimulation tests were assessed. Insulin resistance parameters were calculated using the homeostasis model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) models. RESULTS: BA, BA advancement, free estradiol index, insulin, and HOMA-IR increased significantly in girls with high body mass index (BMI) compared with that of girls with low BMI in cases of CPP. HOMA-IR was positively correlated with BA advancement and BMI but negatively correlated with SHBG. QUICKI was negatively correlated with BA advancement and BMI and positively correlated with SHBG. When HOMA-IR increased by 1, the odds for BA advancement increased 120% after adjusting for age and BMI (P=0.033). CONCLUSION: Insulin resistance could be associated with BA advancement in girls with CPP.

Clinical manifestations of Rathke’s cleft cysts and their natural progression during 2 years in children and adolescents

PURPOSE: Rathke’s cleft cyst (RCC) is an asymptomatic benign lesion. With increased interest in pediatric endocrinology, the prevalence of RCCs in children is also increasing. However, the clinical relevance and proper management of RCC is not well defined in children. Therefore, we investigated the clinical manifestations and radiologic features of RCC in children and adolescents, as well as the natural progression of RCC. METHODS: We retrospectively reviewed the medical records of 91 children and adolescents with RCC diagnosed with magnetic resonance imaging (MRI) in Severance Children’s Hospital from January 2006 to December 2015. The clinical, hormonal, and imaging findings were analyzed in patient groups classified according to age. The size of each cyst was assessed in sixty patients who underwent follow-up MRI during the 2 years. RESULTS: Female patients were predominant (64 vs. 27). The common clinical features at presentation were endocrine dysfunction (59.3%), headache (23.0%), and dizziness (4.4%). Symptoms related to endocrine disorders were more frequent in younger patients. In 7 patients managed surgically, the cysts were significantly larger and more frequently located in the suprasellar region. Of 60 nonsurgical patients with a follow-up MRI performed within 2 years after the diagnosis, the RCC size increased in about 26.7% (n=16). CONCLUSION: Although 94.4% of the patients with RCC had clinical symptoms, surgery was performed in only about 7.5% of patients. RCC is associated with pituitary insufficiency, thus, baseline and follow-up endocrine function tests are required. Additionally, regular MRI follow-up is required in long-term period to monitor change in size.

Diabetes mellitus due to agenesis of the dorsal pancreas in a patient with heterotaxy syndrome

Heterotaxy syndrome (HS) is a congenital disorder resulting from an abnormal arrangement of visceral organs across the normal left-right axis in the embryonic period. HS is usually associated with multiple anomalies, including defects of the major cardiovascular system and the extracardiovascular system such as intestinal malrotation, abnormal lung lobulation, bronchus anomalies, and pancreatic dysplasia. Although pancreatic dysplasia is occasionally accompanied with HS, the occurrence of diabetes mellitus (DM) due to pancreatic dysplasia in HS is rarely reported. We here report a case involving 13-year-old girl with DM caused by agenesis of the dorsal pancreas and HS diagnosed on the basis of the presence of a double-outlet right ventricle with bilateral pulmonary stenosis and intestinal malrotation with duodenal cyst. Timely diagnosis and treatment with insulin improved glycemic control.

Ultrasound measurement of pediatric visceral fat thickness: correlations with metabolic and liver profiles

PURPOSE: Abdominal obesity is a fundamental factor underlying the development of metabolic syndrome. Because of radiation exposure and cost, computed tomography or dual-energy X-ray absorptiometry to evaluate abdominal adiposity are not appropriate in children. Authors evaluated whether ultrasound results could be an indicator of insulin resistance and nonalcoholic fatty liver disease (NAFLD). METHODS: We enrolled 73 subjects (aged 6-16 years) who were evaluated abdominal adiposity by ultrasound. Subcutaneous fat thickness was defined as the measurement from the skin-fat interface to the linea alba, and visceral fat thickness (VFT) was defined as the thickness from the linea alba to the aorta. Anthropometric and biochemical metabolic parameters were also collected and compared. The subjects who met 2 criteria, radiologic confirmed fatty liver and alanine aminotransferase >40, were diagnosed with NAFLD. RESULTS: There was a strong positive correlation between VFT and obesity. VFT was highly correlated with the homeostasis model assessment for insulin resistance score (r=0.403, P<0.001). The area under the curve for VFT as a predictor of NAFLD was 0.875 (95% confidence interval [CI], 0.787-0.964). VFT of 34.3 mm was found to be the discriminating cutoff for NAFLD (sensitivity, 84.6%; specificity, 71.2%, respectively). CONCLUSION: Ultrasound could be useful in measuring VFT and assessing abdominal adiposity in children. Moreover, increased VFT might be an appropriate prognostic factor for insulin resistance and NAFLD.

Ultrasound measurement of pediatric visceral fat thickness: correlations with metabolic and liver profiles

PURPOSE: Abdominal obesity is a fundamental factor underlying the development of metabolic syndrome. Because of radiation exposure and cost, computed tomography or dual-energy X-ray absorptiometry to evaluate abdominal adiposity are not appropriate in children. Authors evaluated whether ultrasound results could be an indicator of insulin resistance and nonalcoholic fatty liver disease (NAFLD). METHODS: We enrolled 73 subjects (aged 6-16 years) who were evaluated abdominal adiposity by ultrasound. Subcutaneous fat thickness was defined as the measurement from the skin-fat interface to the linea alba, and visceral fat thickness (VFT) was defined as the thickness from the linea alba to the aorta. Anthropometric and biochemical metabolic parameters were also collected and compared. The subjects who met 2 criteria, radiologic confirmed fatty liver and alanine aminotransferase >40, were diagnosed with NAFLD. RESULTS: There was a strong positive correlation between VFT and obesity. VFT was highly correlated with the homeostasis model assessment for insulin resistance score (r=0.403, P<0.001). The area under the curve for VFT as a predictor of NAFLD was 0.875 (95% confidence interval [CI], 0.787-0.964). VFT of 34.3 mm was found to be the discriminating cutoff for NAFLD (sensitivity, 84.6%; specificity, 71.2%, respectively). CONCLUSION: Ultrasound could be useful in measuring VFT and assessing abdominal adiposity in children. Moreover, increased VFT might be an appropriate prognostic factor for insulin resistance and NAFLD.

Male patients presenting with rapidly progressive puberty associated with malignant tumors

In males, precocious puberty (PP) is defined as the development of secondary sexual characteristics before age 9 years. PP is usually idiopathic; though, organic abnormalities including tumors are more frequently found in male patients with PP. However, advanced puberty in male also can be an important clinical manifestation in tumors. We report 2 cases of rapidly progressive puberty in males, each associated with a germ-cell tumor. First, an 11-year-old boy presented with mild fever and weight loss for 1 month. Physical examination revealed a pubertal stage of G3P3 with 10-mL testes. Investigations revealed advanced bone age (16 years) with elevated basal luteinizing hormone and testosterone levels. An anterior mediastinal tumor was identified by chest radiography and computed tomography, and elevated α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG) levels were noted. Histopathologic analysis confirmed a yolk-sac tumor. Second, a 12-year-old boy presented with diplopia, polydipsia, and polyuria for 4 months. Physical examination revealed a pubertal stage of G3P3 with 8-mL testes. Bone age was advanced (16 years) and laboratory tests indicated panhypopituitarism with elevated testosterone level. A mixed germ-cell tumor was diagnosed with elevated AFP and β-hCG levels. Of course, these patients also have other symptoms of suspecting tumors, however, rapidly progressive puberty can be the more earlier screening sign of tumors. Therefore, in male patients with accelerated or advanced puberty, malignancy should be considered, with evaluation of tumor markers. In addition, advanced puberty in male should be recognized more widely as a unique sign of neoplasm.

A patient with Cushing disease lateralizing a pituitary adenoma by inferior petrosal sinus sampling using desmopressin: a case report

A 14-year-old girl was referred for evaluation of the etiology of Cushing syndrome. During the previous 2 years, she had experienced weight gain, secondary amenorrhea, growth retardation, and back pain. Random serum cortisol level, 24-hour urinary free cortisol excretion, and overnight and low-dose dexamethasone suppression tests suggested Cushing syndrome. Midnight adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance imaging was suspicious for microadenoma. To eliminate ectopic ACTH syndrome, and lateralize the pituitary tumor, inferior petrosal sinus sampling (IPSS) was performed by desmopressin use to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to ACTH-secreting pituitary microadenoma, lateralized to the left side; subsequently underwent transsphenoidal surgery. Here we report a case of a 14-year-old girl diagnosed with Cushing disease with a pituitary tumor lateralized by IPSS using desmopressin, which is very rare in pediatric Cushing disease.

Turner syndrome with spinal hemorrhage due to vascular malformation

Turner syndrome (TS) is a relatively common chromosomal disorder and is associated with a range of comorbidities involving the cardiovascular system. Vascular abnormalities, in particular, are a common finding in cases of TS. However, dissection involving the vertebral arteries is rare. Here, we report the case of a 9-year-old girl with TS who had been treated with growth hormone replacement therapy for the past 3 years. She presented with weakness of both lower legs, and was ultimately diagnosed with spinal hemorrhage due to vascular malformation. We treated her with intravenous high dose dexamethasone (0.6 mg/kg) and she could walk without assistance after 6 days of treatment. In conclusion, when a patient with TS shows sudden weakness of the lower limbs, we should consider the possibility of spinal vessel rupture and try to take spine magnetic resonance imaging as soon as possible. We suggest a direction how to make a proper diagnosis and management of sudden vertebral artery hemorrhage in patients with TS.

XYY syndrome: a 13-year-old boy with tall stature

When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out.

Hypotonic hyponatremia by primary polydipsia caused brain death in a 10-year-old boy

Hypotonic hyponatremia by primary polydipsia can cause severe neurologic complications due to cerebral edema. A 10-year-and-4-month-old boy with a psychiatric history of intellectual disability and behavioral disorders who presented with chief complaints of seizure and mental change showed severe hypotonic hyponatremia with low urine osmolality (serum sodium, 101 mmol/L; serum osmolality, 215 mOsm/kg; urine osmolality, 108 mOsm/kg). The patient had been polydipsic for a few months prior, and this had been worse in the previous few days. A diagnosis of hypotonic hyponatremia caused by primary polydipsia was made. The patient was in a coma, and developed respiratory arrest and became brain death shortly after admission, despite the treatment. The initial brain magnetic resonance imaging showed severe brain swelling with tonsillar and uncal herniation, and the patient was declared as brain death. It has been reported that antidiuretic hormone suppression is inadequate in patients with chronic polydipsia, and that this inadequate suppression of antidiuretic hormone is aggravated in patients with acute psychosis. Therefore, hyponatremia by primary polydipsia, although it is rare, can cause serious and life-threatening neurologic complications.

Clinical manifestations of testicular adrenal rest tumor in males with congenital adrenal hyperplasia

PURPOSE: In male patients with congenital adrenal hyperplasia (CAH), the presence of testicular adrenal rest tumors (TARTs) have been reported, however their prevalence and clinical manifestations are not well known. Untreated TARTs may lead to testicular structural damage and infertility. This study was conducted to investigate the prevalence of TARTs in male patients with CAH, and characterize the manifestations to identify contributing factors to TART. METHODS: Among 102 CAH patients aged 0-30 years, 24 male patients have been regularly followed up in our outpatient clinic at Severance Children's Hospital from January 2000 to December 2014. In order to reveiw the characteristics of TART patients, we calculated the mean levels of hormones during the 5 years before the time of investigation. Five patients underwent follow-up scrotal ultrasonography (US) after adjusting the dosage of glucocorticoids. RESULTS: TARTs were detected in 8 of the 13 patients (61.5%). The median age of TARTs diagnosis was 20.2 years with the youngest case being 15.5 years old. The mean serum level of adrenocorticotropic hormone (ACTH) was higher in the TARTs patient group compared to the non-TARTs group (P<0.05). The tumor size decreased in 3 cases, slightly increased in 1 case, and had no change in another case. CONCLUSION: The serum ACTH level might be associated with the growth promoting factor for TARTs, but the exact mechanism has not been clearly identified. Screening for TARTs using US is important in male patients with CAH for early-detection and prevention of ongoing complications, such as infertility.

Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone agonist with or without growth hormone

PURPOSE: There is controversy surrounding the growth outcomes of treatment with gonadotropin-releasing hormone agonist (GnRHa) in central precocious puberty (CPP). We analyzed height preservation after treatment with GnRHa with and without growth hormone (GH) in girls with CPP. METHODS: We reviewed the medical records of 82 girls with idiopathic CPP who had been treated with GnRHa at Severance Children's Hospital from 2004 to 2014. We assessed the changes in height standard deviation score (SDS) for bone age (BA), and compared adult height (AH) with midparental height (MPH) and predicted adult height (PAH) during treatment in groups received GnRHa alone (n=59) or GnRHa plus GH (n=23). RESULTS: In the GnRHa alone group, the height SDS for BA was increased during treatment. AH (160.4+/-4.23 cm) was significantly higher than the initial PAH (156.6+/-3.96 cm) (P<0.001), and it was similar to the MPH (159.9+/-3.52 cm). In the GnRHa plus GH group, the height SDS for BA was also increased during treatment. AH (159.3+/-5.33 cm) was also higher than the initial PAH (154.6+/-2.55 cm) (P<0.001), which was similar to the MPH (158.1+/-3.31 cm). Height gain was slightly higher than that in the GnRHa alone group, however it statistically showed no significant correlation with GH treatment. CONCLUSION: In CPP girls treated with GnRHa, the height SDS for BA was increased, and the AH was higher than the initial PAH. Combined GH treatment showed a limited increase in height gain.

A Case of Tuberous Sclerosis with Subependymal Giant Cell Astrocytoma (SEGA) Treated with Gamma Knife Surgery / 대한소아신경학회지

Subependymal giant cell astrocytoma (SEGA) is the most common brain tumor that develops in 5-20% of patients with tuberous sclerosis complex. Although these lesions are slowly growing tumor, they can cause morbidity and mortality due to acute hydrocephalus because of their prevalent location near the foramen of Monro. Surgery has been the standard care for SEGAs demonstrating serial growth and symptomatic hydrocephalus. However, not all SEGAs are treatable by complete surgical resection. Gamma Knife stereotactic radiosurgery can be considered as a second option, but it has shown highly variable responses in patients with limited data. In recent years, drugs with novel mechanism, sirolimus and other mammalian target of rapamycin (mTOR) inhibitors have been found to reduce the size of SEGAs. We report a case of treatment of SEGA with gamma knife surgery which continued for two years without progression, even though surgical resection was done, finally.