In this study we measured bone age ultrasonically with Sunlight BonAge (SBA) and report the results of comparisons with radiographs. The subjects were 37 children, who examined at the Pediatric Department of Dokkyo University Hospital, for whom it was thought necessary to measure bone age because of suspicions of body height and pubertal abnormalities. The measurements of bone age were made with SBA during examinations in the outpatient department. In addition, one experienced physician interpreted bone age by the Japanese standard TW2 method (RUS method) and the CASMAS from radiographs taken of their left hands. The results of SBA and TW2 (RUS), and SBA and CASMAS estimations correlated well (r=0.89, r=0.85). The inter-measurer error and inter-measurement error were 0.54 ± 0.36 yr and 0.51 ± 0.42 yr, respectively. SBA calculates bone maturity by an algorithm based on measurements of the width (distance) and speed of sound (SOS) in bones in the wrist. The results of this study show good correlations between the data obtained by SBA and both the RUS method and the CASMAS method. The SBA ultrasound-based skeletal development measurement device is non-invasive, quick and accurate at assessing the bone age of children aged 5 to 15 yr old.

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We studied whether insulin-like growth factor-I (IGF-I) is attributable to nutrition during inpatient treatment in anorexia nervosa (AN) in childhood and adolescence. Nineteen Japanese females with AN, aged 12-19, were enrolled in this study. They were admitted to our hospital during 1993∼2003 and treated by the "Keio Method". They had complete bed rest during the first 2 mo of treatment. We studied a possible correlation between serum IGF-I level and obesity index (OI) by using the Spearman rank correlation test. The serum IGF-I level (SDS) and OI (%) was significantly positively correlated on admission (p=.009), at 1 mo (p=.0227), and 2 mo (p=.0063) after admission. These results indicate that the serum IGF-I level is determined by nutritional status in AN in childhood and adolescence under complete bed rest.

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The notification of Turner syndrome (TS) is an important task for clinicians who are treating the condition. To clarify the situation regarding the notification process, we performed a questionnaire survey among 104 clinicians who were involved in the treatment of GH and estrogen for TS in the Kanto and Koshinetsu area of Japan. We distributed a questionnaire concerning both the ideal and actual timings of notifying the name of "Turner", short stature, hypogonadism, fertility, complications, karyotype, as well as asking "Who is the best person to notify the patient?" We received 34 completed questionnaires, 30 pediatricians, two physicians, and two gynecologists, who were treating a total of 352 cases with TS. Although most clinicians understood the gradual notification process, there were difference between the ideal and actual timings of notifying the name of the condition, short stature, hypogonadism/fertility and karyotype. To the question "Who is the best person to notify the patient?", replies were, ideally: the doctor followed by parent(s), and, actually: the parent(s). Only five institutes had medical teams to care for TS. The team consisted of clinicians, nurses, and genetic counselors. Concerning the notification process of TS, it is important for us to tell patients that Turner syndrome is a condition, not a disease, at an appropriate time with a gentle attitude. At the same time, we should realize TS support groups could play an important role in contributing to how to take care of the many problems of TS.

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We present the case of a 1 yr and 9 mo old girl with McCune-Albright syndrome (MAS), who was identified as having a GNAS1 activation mutation in peripheral blood cells. Our clinic was consulted because of the patient's recurrent vaginal bleeding from the early infantile period. We noticed that she had gonadotropin independent precocious puberty due to autonomic functioning ovarian cysts and subclinical hyperthyroidism without autoimmunity. Radiological studies indicated bone lesions as fibrous dysplasia in her right femur and tibia. We diagnosed this case as MAS, and GNAS1 mutation analysis using genomic DNA from whole blood was performed by nested PCR and restriction endonuclease digestion. The patient had a GNAS1 activating mutation of Arg(CGT)201→His(CAT). Previously GNAS1 mutation has been reported in extracted tissues such as bone lesions or affected endocrine organs. Our mutation analysis using blood cells with sensitive PCR and restriction enzyme is a non-invasive method for the genetic diagnosis of MAS, and would also be useful for early definitive diagnosis of non-classic MAS a wide clinical spectrum.

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A 4.5-yr-old boy with Down syndrome showed stunted growth for 2 yr. The patient was endocrinologically evaluated as having complete growth hormone deficiency with low serum level of IGF-I, 8.2 ng/ml, and no response of growth hormone secretion to an arginine provocation test. He was diagnosed with psychosocial dwarfism induced by his mother. Without any specific treatment, separation of the patient from his mother normalized his growth and IGF-I, 51 ng/ml. Psychosocial dwarfism should be considered as a cause of growth retardation with pituitary malfunction.

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A 6-yr-old boy was seen at our hospital due to short stature (-2.0 SD) and frequent vomiting. Peak GH response to arginine and insulin was >10 ng/ml at 10.5 yr of age. Growth retardation was progressive. At 12 yr of age, he was still in prepubertal status with a bone age of 8. His height and body weight were 121.6 cm (-3.57 SD) and 19.0 kg (-2.05 SD). Serum level of IGF-1 was low (35 ng/ml), with marginal hypothyroidism due to non-thyroidal illness (T3 0.93 ng/ml, T4 6.7 μg/dl and TSH 0.08 μU/ml). Serum levels of prealbumin and retinol binding protein were also decreased. Achalasia was diagnosed by esophagography. At the age of 12 yr and 6 mo he underwent laparoscopic extramucosal myectomy with fundoplication, and subsequently his nutritional status improved dramatically. At 15.5 yr old, he had gained height and body weight, 153.2 cm (-2.61 SD) and 38.9 kg (-1.95 SD), respectively, and sexual development had advanced too. The clinical course of this boy revealed that achalasia should be added to the list of causes of nutritional growth retardation in children.

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We report a 17 yr old male with short stature and delayed adolescence due to distorted body image. He was admitted to our hospital because of growth failure at the age of 15 yr 7 mo. His growth had been normal, but after entering a junior high school, he began to take an interest in physical exercise and protein diet. His endocrine data and psychopathological profiles such as eating, training pattern and extreme diet and failure to make expected growth and puberty were compatible with DSM-IV and ICD-10 criteria for the diagnosis of anorexia nervosa (AN). The symptoms of male AN are different from female AN and it is difficult to diagnose. We emphasize the necessity of considering AN in the differential diagnosis of growth retardation and delayed adolescence in young males.

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We have experienced three patients of autism combined with precocious puberty. Their age at diagnosis of precocious puberty ranged from 6 yr and 9 mo to 9 yr and 6 mo. All patients showed pubertal growth spurt and elevated levels of basal LH and FSH, and experienced menstruation. One patient was diagnosed as having central precocious puberty according to the diagnostic guidelines. The other two patients were on borderline sexual precocity. They have been treated with GnRH analog for the purpose of stopping menstruation, which was not tolerated for their mentality. Similar to known combination of CNS disorders and precocious puberty, patients with autism may be susceptible to the early onset of puberty.

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The increasing frequency and the younger onset of eating disorder is becoming a social problem in Japan. The diagnostic criteria of anorexia nervosa according to DSM IV include weight loss and amenorrhea, however, it does not include "no or low weight gain" and "stunted growth" in growing children and adolescents. In this study, we analyzed the growth and endocrine function in 45 patients (39 females and 6 males) with anorexia nervosa. The age at the onset of disease (the onset of weight loss) varied from 10 to 16 yr old. When plotting the changes of height and weight in each individual on the growth chart for Japanese children, 8 out of 45 showed decreased or no weight gain before the apparent onset of weight loss, for more than two years. The stunted growth was associated with decreased weight gain. Endocrine function was tested in 36 patients. Approximately half of the children and adolescents showed exaggerated growth hormone response to provocative tests, while the rest showed low growth hormone levels. Gonadotrophins and thyrotropin responses to LHRH and TSH stimulation were decreased in most of the cases tested. About 80% of the patients recovered from the critical weight loss, but the recovery of height is not always successful. In conclusion, eating disorders with severe weight loss in growing children sometimes result in irreversible growth failure. Plotting the growth chart is helpful for finding the "true" onset of eating disorder.

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We present a case of Marshall-Smith syndrome, characterized by accelerated osseous maturation, craniofacial anomalies, failure to thrive, psychomotor delay, pulmonary dysfunction, and limited life expectancy. Recently, Marshall-Smith syndrome's clinical variability is becoming apparent and the phenotype is expanding. Our case had craniofacial anomalies, including prominent eyes, external strabismus, blue sclera, flat nasal bridge, and micrognatia. Moreover, she showed extension of the hip joint, hypotonia, and arachnodactyly. She was referred to our hospital due to dysmorphic facies at 7 mo and overgrowth was noticed with a height of 74.2 cm (+2.7 SD). Radiographic surveys demonstrated accelerated osseous maturation with a bone age of 1 yr 6 mo at the chronological age of 10 mo and broad proximal phalanges. We diagnosed this case as Marshall-Smith syndrome according to clinical features and radiographic findings. Except for one episode of broncho-pulmonitis which required hospitalization, she has not had other severe infections up to date. Presently, she is 1 yr 9 mo; 88.0 cm (+2.1 SD) and 10.4 kg (-0.3 SD). This case suggests that there are patients with Marshall-Smith syndrome without life-threatening complications.

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We report the case of an 8-yr-old girl with short stature. Her height was -2.65 SD and blood examination revealed hypokalemia (2.9 mEq/l), hypomagnesaemia, hypocalsiuria (Ca/Cr=0.0039) and metabolic alkalosis (pH 7.454, HCO₃^- 24.9 mmol/l). For differential diagnosis between Gitelman's syndrome (GS) and Bartter syndrome (BS), we performed the loop diuretic furosemide (FUR) test and hydrochlorothiazide (HCT) double dose (2 and 4 mg/kg) test. Even the higher dose of HCT induced significantly lower increase of urinary Na and Cl excretions than the FUR. Growth hormone (GH) secretion tests (insulin and arginine) revealed GH deficiency. In addition to growth hormone injection, administration of Mg and spironolactone was started. After the replacement therapy started, the girl's height gain was improved (9.7 cm/yr) and her serum potassium became within the reference range. One year after GH replacement therapy was performed and GH replacement therapy was discontinued for two months, and GH secretion tests (insulin and arginine) showed GH deficiency again. We discussed previous reports of the clinical signs and test results of GS with regard to the relation between hypokalemia, hypomagnesemia and short stature.

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Dyskeratosis congenita (DKC) is an inherited disease characterized by the triad of mucosal leukoplakia, abnormal skin pigmentation and nail dystrophy, and it usually appears between the ages of 5 and 10 yr. Reports show that 19.5% of DKC patients have short stature (1). A major complication of DKC is progressive development of pancytopenia and there is also an increased incidence of malignancies. The X-linked form accounts for the majority of cases and is caused by mutations in the DKC1 gene. We report a 9 yr old boy, who presented with the triad of DKC, a mutation in the DKC1 gene and short stature, who was treated with human recombinant growth hormone (hGH). This is the first report of a DKC patient treated with hGH.

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We report the case of 15-mo-old girl who manifested neonatal diabetes mellitus associated with IUGR, developmental delay, epilepsy dysmorphic features and growth disturbance. She was born at 38 wk of gestation after normal pregnancy. Her birth weight was 2262 g (<10%tile) and height 45.0 cm (<10%tile). Since birth she gradually presented failure to thrive and presented hyperglycemia (glucose 692 mg/dl), ketoacidosis and elevated HbA1c level (7.7%) at 3 mo of age. The anti-GAD antibody was negative and the serum CPR level was 0.5 ng/ml. The girl was treated with intensive insulin therapy from 3 mo of age, however, her weight did not improve and was only 3305 g (-4.6 SD) at 5 mo of age. When admitted to our hospital, she was recognized as having dysmorphic features such as prominent forehead, downturned mouth, bilateral ptosis, arthrogryposis, hypertonia and umbilical hernia. Because she presented frequent hypoglycemic episodes under the intensive insulin injection regimen, treatment was changed to a twice a day injection schedule. Subsequently, the patient did not show any hypoglycemic episodes and she gradually gained a weight. However, at 7 mo of age, seizures developed and her EEG was hypsarrhythmic. She is now 15 mo of age but she cannot sit without support. She is still short and her height is 64.8 cm (-3.9 SD).

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Patients with growth hormone deficiency (GHD) often have obesity, hyperlipidemia, fatty liver and diabetes mellitus which are similar to metabolic syndrome. Recently, it has been reported that non-alcoholic fatty liver disease (NAFLD), especially with non-alcoholic steatohepatits (NASH) are associated with metabolic syndrome. Therefore, it is interesting to know the relationship between GHD and NASH/NAFLD. In the present study, we investigated NASH/NAFLD in patients with childhood-onset adult GHD. A retrospective chart analysis was performed on 38 patients (M/F 19/19, age 35 ± 11, range 18-62) with childhood-onset GHD who visited our outpatient clinic. Clinical course, symptoms and laboratory data were reviewed in these patients. The average body mass index (BMI) and the value of HOMA-R of the patients were 24.9 ± 3.8 kg/m² and 3.09 ± 2.9, respectively. Liver dysfunction was found in 17 patients. We performed abdominal ultrasonography on 7 of 17 patients with liver dysfunction, and observed fatty liver change in all patients. The majority of these patients had impaired glucose tolerance and dyslipidemia by the time of diagnosis of NAFLD. Moreover, microscopic examination of liver biopsy specimens from one patient revealed NASH with fibrosis. In conclusion, patients with GHD are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of NAFLD. As NAFLD is related to the occurrence of NASH and cirrhosis, this novel evidence that GHD may be accompanied by progressive NAFLD has important implications for follow-up and management of patients with GHD.

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The author reports an unusual case of fertile Turner's syndrome with 45,X/46,XX mosaicism, premature menopause, primary hypothyroidism due to chronic thyroiditis and type 1 diabetes.

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We report a case of male neonatal onset congenital hypopituitarism with an invisible pituitary stalk and pituitary aplasia. He had a micropenis at birth and experienced multiple episodes of apnea, cyanosis, hypotonia and hypothermia, associated with severe hypoglycemia during the first few days of life. He was diagnosed as having congenital hypopituitarism due to the findings of low serum GH and cortisol levels during hypoglycemia, low free T4 and pituitary magnetic resonance imaging findings. He was started on hydrocortisone and levothyroxine at 12 d of life and GH replacement at 1 mo of life. Early GH replacement is effective not only for stabilizing blood glucose but also for improving the quality of life.

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We report a 3-yr-old male with short stature, speech delay, episodes of convulsion, and right morning glory syndrome. He had four episodes of febrile convulsion from the age of 1 yr 6 mo, and two episodes of afebrile convulsion with hypoglycemia. His height was 90.2 cm (-2.3 SD) and his growth rate was decreased from about 2 yr of age. Magnetic resonance imaging of the brain showed an atrophic anterior pituitary lobe, invisible stalk, and ectopic posterior lobe. Septo-optic dysplasia was deniable. We tested pituitary function. Cortisol response to CRH was normal (peak: 21.0 μg/dl). TSH response to TRH was prolonged and exaggerated (peak: 33.0 μU/ml at 120 min), and FT4 response was absent (peak: 0.74 ng/dl). After supplement of l-T4, GH response to arginine was decreased (peak: 5.1 ng/ml). We diagnosed hypothalamic hypopituitarism. We started treatment with l-T4 and growth hormone. Patients with congenital ocular anomaly including morning glory syndrome should be evaluated for brain and pituitary structure with MRI, and further endocrinological examinations should also be considered.

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