Hideaki Yagasaki

Late-onset circulatory dysfunction after thyroid hormone treatment in an extremely low birth weight infant.

Late-onset circulatory dysfunction (LCD) is a phenomenon specific to premature infants and is characterized by sudden onset of hyponatremia, hypotension, oliguria and non-physiological weight gain, without an obvious cause, in premature infants after stabilization of circulation and respiration. The cause of LCD is not clear, but adrenal insufficiency in premature infants is a severe syndrome because steroid replacement therapy is often essential to treat the symptoms. We report a rare case of a premature infant who developed an LCD crisis the day after thyroxine replacement therapy. The female infant was born at 25 weeks of gestational age, weighing 672 g, and appeared to have hypothyroidism, with free T4 of 0.19 ng/dl and elevated TSH levels of 26.3 microIU/ml at Day 14. She developed an LCD crisis the day after starting thyroxine treatment. She received steroid replacement therapy for 4 weeks and her adrenal function progressively recovered. She also needed thyroxine supplementation for 13 weeks, which maintained her thyroid function as euthyroid. Because she exhibited cortisol insufficiency and thyroid hormone insufficiency, the antecedent thyroid hormone replacement may be responsible for the onset of LCD. We must consider monitoring adrenal function when starting thyroxine therapy in premature infants with hypothyroxinemia.

Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis

The etiology of idiopathic short stature (ISS) and Leri–Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.

Carotid intima media thickness in a girl with sitosterolemia carrying a homozygous mutation in the ABCG5 gene.

Abstract Background: Sitosterolemia is a rare lipid metabolism disorder that involves storage of plant sterols. This disease is associated with atherosclerosis, but detailed vascular endothelial assessment is difficult. Case presentation: We report a 5-year-old girl with sitosterolemia who presented with xanthomas at 23 months of age. Her total cholesterol was 868 mg/dL, and her plasma sitosterol level was 9.48 mg/dL. Direct sequencing detected a homozygous mutation in gene ABCG5 (p.Arg389His). Echocardiographic examination revealed that the carotid artery intima media thickness (cIMT) was 0.4 mm with heterogenous hyperechogenicity inside the arterial wall. She was treated using dietary therapy and ezetimibe, which effectively lowered her sitosterol levels. After 3 years of treatment, her cIMT was stable in diameter and arterial wall echogenicity had improved. Conclusions: Sitosterolemia is a unique disorder in which it is difficult to avoid premature atherosclerosis because of high sitosterol levels. cIMT measurement with arterial wall assessment may improve management.

Use of an appendicitis medical information sheet in the pediatric primary care system.

Accurate and prompt diagnosis is required for the primary evaluation of pediatric appendicitis. Among pediatricians and surgeons working in Yamanashi Prefecture, the pediatric appendicitis medical information (PAMI) sheet was edited in April 2011 to reflect the diagnostic results of the pediatric primary and emergency medical service and used as a referral document for surgical consultation to secondary hospitals.

Performance of the appendicitis medical information sheet in pediatric primary care system

Accurate and prompt diagnosis is required for the primary evaluation of pediatric appendicitis. Among pediatricians and surgeons working in Yamanashi Prefecture, the pediatric appendicitis medical information (PAMI) sheet was edited in April 2011 to reflect the diagnostic results of the pediatric primary and emergency medical service and used as a referral document for surgical consultation to secondary hospitals.

Effect of Sunlight Exposure on Bone Mineral Density in Children with Severe Disability

The aim of this study was to determine the efficacy of sunlight exposure for increasing bone mineral density (BMD) in children with severe disability. The subjects were five children with severe disability, aged 6 to 8 years. BMD was measured at baseline and after 3, 6, 9, and 12 months of starting sunlight exposure. All caregivers of patients were instructed to create opportunities to stay outdoors. Daily sunlight exposure time was defined as hours of staying outdoors. Mean hours of sunbathing per day were calculated at baseline and after 3, 6, 9, and 12 months of starting sunlight exposure. Sunlight exposure tended to be longer after starting than before starting in all patients, but the difference was not significant (p = 0.052). Along with the increase in sunlight exposure, BMD increased significantly after the start of sunlight exposure in all patients (p < 0.01). The serum values of total alkaline phosphatase and intact parathyroid hormone were significantly decreased and that of 25-hydroxyvitamin D was significantly increased 12 months after starting sunlight exposure. No patients had bone fractures after the start of sunlight exposure. These results suggest that sunlight exposure increased BMD, and that this may reduce the risk of bone fracture in children with disability.

Co-occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11

Most cases of Noonan syndrome (NS) result from mutations in one of the RAS‐MAPK signaling genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 (MAP2K1), and CBL. Cardiovascular diseases of varying severity, such as pulmonary stenosis and hypertrophic cardiomyopathy (HCM), are common in NS patients. RAF1 mutations are most frequent in NS with HCM, while PTPN11 mutations are also well known. Thr73Ile is a gain‐of‐function mutation of PTPN11, which has been highly associated with juvenile myelomonocytic leukemia and NS/myeloproliferative disease (MPD), but has not previously been reported in HCM. Here, we report a Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio‐ventricular septal defect, and rapidly progressive HCM. No other HCM‐related mutations were detected in PTPN11, RAF1, KRAS, BRAF, and SHOC2. This patient provides additional information regarding the genotype–phenotype correlation for PTPN11 T73I mutation in NS.

Severe hypothalamopituitary dysfunction accompanied by influenza-associated encephalopathy: report of two pediatric cases.

Abstract Severe influenza infection may lead to neurological damage, such as encephalopathy. This may, in turn, cause acquired hypothalamopituitary dysfunction, which can result in severe morbidity and even death. We herein report two pediatric patients who developed influenza-associated hypopituitarism and were subsequently diagnosed with encephalopathy. They were diagnosed with acute necrotizing encephalopathy and postresuscitation encephalopathy, respectively. Both showed evidence of endocrine dysfunction, and hormone replacement therapy of adrenal, thyroid, and antidiuretic hormones are resulting in continued cardiac activity and resulted in prolonged survival. Screening for endocrine function is important in patients with severe central nervous system dysfunction.

Role of Counterregulatory Hormones for Glucose Metabolism in Children and Adolescents with Type 1 Diabetes

To elucidate the mechanism of insulin resistance due to insulin counterregulatory hormones (ICRHs) and evaluate ICRH secretion kinetics, ICRH concentrations were measured and correlated with blood glucose levels in 28 type 1 diabetic patients. Blood glucose was measured before bedtime. Early morning urine samples were collected the next morning before insulin injection and breakfast. Fasting blood glucose, cortisol, glucagon and HbA1c levels were measured. Growth hormone (GH), adrenaline, cortisol and C-peptide levels in morning urine samples were measured; SD scores were calculated for urine GH. The laboratory values (mean ± SD) were as follows; HbA1c of 8.1% ± 1.4%; pre-bedtime glucose of 203 ± 105 mg/dl; fasting blood glucose of 145 ± 87 mg/dl; serum cortisol of 21.6 ± 5.5 µg/dl; plasma glucagon of 98 ± 41 pg/ml; urinary GH, 27.2 ± 13.0 ng/gCr; urinary cortisol of 238 ± 197 ng/gCr; and urinary Adrenaline of 22.9 ± 21.0 ng/gCr. The mean urinary GH SD score was increased (+1.01 ± 0.70; p=0.000); the mean plasma glucagon lebel (98 ± 41 pg/ml) was not. Fasting blood glucose was positively correlated with plasma glucagon (R=0.378, p=0.0471) and negatively correlated with urinary cortisol (R=–0.476, p=0.010). Urinary adrenaline correlated positively with urinary GH (R=0.470, p=0.013) and urinary cortisol (R=0.522, p=0.004). In type 1 diabetes, GH, glucagon and cortisol hypersecretion may contribute to insulin resistance, but the mechanism remains unclear.

Xanthogranuloma of the sellar region accompanied by growth hormone deficiency: case report and literature review.

Abstract Background Xanthogranuloma of the sellar region is a rare entity. Its pathology is controversial and it is difficult to strictly differentiate it from craniopharyngioma or Rathke’s cyst. Case presentation We report a case of xanthogranuloma accompanied by growth hormone deficiency in an 11-year-old girl. She did not show any other pituitary hormone deficiency or neurological symptoms before operation. The preoperative diagnosis was craniopharyngioma, but histological findings showed small areas of epithelium. Thus, the final diagnosis was xanthogranuloma. Xanthogranuloma is an important cause of growth delay. We reviewed 16 cases reported after 2000, and included our case, of xanthogranuloma in children. Conclusions Endocrinological symptoms are often regarded as one of the few apparent symptoms in xanthogranuloma compared with craniopharyngioma. Therefore, we should follow up carefully and accumulate cases.