Adipsic hypernatremia is a rare disease presenting as persistent hypernatremia with disturbance of thirst regulation and hypothalamic dysfunction. As a result of congenital disease, tumors, or inflammation, most cases are accompanied by structural abnormalities in the hypothalamic-pituitary area. While cases with no hypothalamic-pituitary structural lesion have been reported, their etiology has not been elucidated. Recently, we reported three patients with adipsic hypernatremia whose serum-derived immunoglobulin (Ig) specifically reacted with mouse subfornical organ (SFO) tissue. As one of the circumventricular organs (CVOs) that form a sensory interface between the blood and brain, the SFO is a critical site for generating physiological responses to dehydration and hypernatremia. Intravenous injection of the patient’s Ig fraction induced hypernatremia in mice, along with inflammation and apoptosis in the SFO. These results support a new autoimmunity-related mechanism for inducing adipsic hypernatremia without demonstrable hypothalamic-pituitary structural lesions. In this review, we aim to highlight the characteristic clinical features of these patients, in addition to etiological mechanisms related to SFO function. These findings may be useful for diagnosing adipsic hypernatremia caused by an autoimmune response to the SFO, and support development of new strategies for prevention and treatment.
Septo-optic dysplasia (SOD) is a congenital anomaly in which agenesis of the septum pellucidum and optic nerve hypoplasia are accompanied by hypopituitarism. Typically, the symptoms develop in 3 organs, the brain, eyes, and pituitary, and approximately one third of the patients present with all of the three cardinal features. The diagnostic criteria for SOD were established in Japan in 2015. The purpose of this study is to review clinical features regarding SOD patients with hypopituitarism in Japan. In this study, 21 patients with SOD were identified by a questionnaire survey for congenital central hypothyroidism. All 3 symptoms of SOD, agenesis of the septum pellucidum, optic nerve hypoplasia, and endocrine abnormalities, were noted in 8 of the 21 patients. Various combinations of pituitary hormone deficiencies were observed in patients with SOD, although SOD is a rare, heterogeneous, and phenotypically variable disorder, some patients develop hypoglycemia and convulsions after birth, and early intervention with hormone replacement is necessary in severe cases. In addition, 14 cases were complicated by both developmental delay and epilepsy, and 16 cases involved eye abnormalities. Therefore, in addition to an early endocrinological diagnosis and hormone replacement, consultation with both pediatric neurologists and pediatric ophthalmologists is necessary.
Vitamin D deficiency is a common health problem in infancy. Breast-fed infants are at a higher risk of rickets than formula-fed infants. We observed fluctuations in vitamin D levels in infancy (phase I, 2009–2010) and considered the benefits of vitamin D supplementation specifically in exclusively breast-fed infants in Japan (phase II, 2015). Infants born at our hospital were enrolled in this study. In phase I, we measured 25-hydroxyvitamin D [25(OH)D] levels at 1- to 6-mo intervals from birth. In phase II, we measured 25(OH)D levels before and after supplementation. Vitamin D deficiency was defined as 25(OH)D levels of < 20 ng/mL. All 38 infants in phase I were deficient at birth, and none of the exclusively breast-fed infants achieved 25(OH)D sufficiency by 5 mo of age. Formula-fed infants achieved 25(OH)D sufficiency earlier. The majority of the 71 infants in phase II were deficient at birth. We recommended an oral vitamin D supplement at a daily dose of 4.0 µg for the 15 exclusively breast-fed infants, starting at 1 mo of age; 14 (93.3%) of them achieved 25(OH)D sufficiency by 5 months of age. Exclusively breast-fed infants are at a high risk of vitamin D deficiency; adequate supplementation is an effective preventative strategy.
Acanthosis nigricans (AN) is observed in some cases of skeletal dysplasia. However, AN has occasionally been reported in patients with hypochondroplasia (HCH), and a clinical diagnosis is sometimes difficult when its physical and radiological features are mild. Mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) have been identified as the cause of some types of skeletal dysplasia, which is diagnostically useful. Here, we report the case of a 3-yr-old Japanese boy who presented with AN. His height, weight, head circumference, and arm span were 91.7 cm (–1.95 SD), 16.3 kg, 54.0 cm (+2.6 SD), and 88.0 cm, respectively. In addition to the AN, he also exhibited a mild height deficit and macrocephaly, which prompted a search for FGFR3 mutations, although no skeletal disproportion, exaggerated lumbar lordosis, or facial dysmorphism was observed, and only slight radiological abnormalities were noted. A definitive diagnosis of HCH was made based on FGFR3 gene analysis, which detected a heterozygous K650T mutation. Insulin insensitivity was not found to have contributed to the development of AN. In individuals with AN, careful assessments for symptoms of HCH are important, regardless of the presence or absence of a short stature, and FGFR3 gene analysis is recommended in such cases.
The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope®, a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.
Medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder caused by the mutation of the RET proto-oncogene, that shows nearly complete penetration. The American Thyroid Association guidelines recommend prophylactic thyroidectomy for patients with high-risk RET mutations. However, in Japan, ethical and medical issues may preclude prophylactic treatment in young patients. Hence, an early diagnosis of MTC is necessary to ensure a favorable outcome. Here, we report the case of a young Japanese girl with a high-risk RET mutation, diagnosed with very early stage MTC using serum calcitonin (Ctn) values measured using an electro chemiluminescence immuno-assay (ECLIA). The Japanese girl with a family history of MEN2 had been followed at our hospital since she was 5-mo-old. RET analysis revealed that she displayed a Cys634Gly mutation. The patient underwent annual neck ultrasonography and calcium infusion testing. When she was 8-yr-old, the Ctn level, measured using ECLIA, dramatically increased with calcium stimulation, from a baseline of 11.3 pg/mL to 333 pg/mL. She subsequently underwent total thyroidectomy and was diagnosed with stage I MTC. Detecting early stage MTC by monitoring serum Ctn measured by ECLIA, may represent a useful strategy for patients with high-risk RET mutations.
Congenital combined pituitary hormone deficiency (CPHD) may present with cholestasis in the neonate or during early infancy. However, its precise mechanism is unknown. A 3-mo-old boy presented with cryptorchidism and hypoplastic scrotum after birth. Neonatal jaundice was noted but temporarily improved with phototherapy. Jaundice recurred at 2 mo of age. Elevated direct bilirubin (D-Bil) and liver dysfunction were found but cholangiography showed no signs of biliary atresia (BA). Liver biopsy findings showed giant cell formation of hepatocytes with hypoplastic bile ducts. Subsequent magnetic resonance imaging (MRI) of the head revealed a hypoplastic pituitary gland with an ectopic posterior lobe, and the patient was diagnosed with congenital CPHD based on decreased secretion of cortisol and GH by the pituitary anterior lobe load test. D-Bil levels promptly improved after hydrocortisone (HDC) replacement. We subsequently began replacement with levothyroxine (L-T4) and GH, and liver histology showed normal interlobular bile ducts at 8 mo old. This is the first case report of proven histological improvement after hormone replacement therapy. This suggested that pituitary-mediated hormones, especially cortisol, might be involved in the development of the bile ducts.
Patients with Turner syndrome (TS) frequently show short stature and skeletal deformities, such as kyphosis and scoliosis. However, to the best of our knowledge, limb length discrepancy (LLD) has not yet been reported in patients with TS. The case of a 12-yr-old girl with 45,X/47,XXX mosaic TS showing LLD is herein presented. She was on GH therapy for short stature and was noted to have scoliosis in the standing position at a regular examination; however, the scoliosis became less evident in the supine position, which is indicative of LLD. The length of the left leg was 5.0 cm shorter than that of the right leg when measured. She was referred to orthopedics and underwent right distal femoral and right proximal tibial staple epiphysiodesis to shorten the abnormally long limb at 10 yr 6 mo of age. One year after the operation, the LLD decreased from 5.0 to 1.5 cm. During this period, GH was continued. LLD is a rare complication in TS, but when patients with TS show scoliosis in the standing position, re-evaluation for scoliosis in the supine position should be performed and the lengths of both legs should be measured.
There are three major therapeutic options for the treatment of Graves’ disease (GD): antithyroid drugs (ATDs), thyroidectomy, and radio-iodine (RAI) therapy. ATDs are the initial treatment option for children. However, some pediatric GD patients who are initially treated with ATDs require other type of treatments later on. We reviewed the medical records of childhood-onset GD cases retrospectively to report the clinical course of patients who received either surgery or RAI therapy subsequent to treatment with ATDs. Childhood-onset GD was successfully managed in five girls with non-ATD treatments at the age of 7–14 yr following an unfavorable outcome of initial ATD treatment. Four cases had surgery and one case was managed with RAI therapy. The reasons for switching to non-ATD treatment included poor compliance, failure to maintain remission, serious adverse events resulting from ATDs, and religious background. In conclusion, surgery and RAI therapy could be good alternative treatment options for children with GD.