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An elevated serum alkaline phosphatase (ALP) level is one of the markers for the presence of rickets in children, but it is also associated with bone formation. However, its role in diagnosing genu varum in pediatric patients with vitamin D-deficient rickets is still unknown. To clarify the role of the serum ALP level in assessing the severity of genu varum, we retrospectively investigated this issue statistically using data on rickets such as serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, the level of creatinine as the percentage of the median according to age (%Cr), and the metaphyseal diaphyseal angle (MDA) in the lower extremities as an index of the severity of genu varum. A multiple regression analysis revealed that log ALP and %Cr values were negatively associated with MDA values. The former association was also confirmed by a linear mixed model, while iPTH was positively associated with MDA by path model analysis. To elucidate the association of ALP with MDA in the presence of iPTH, we investigated three-dimensional figures by neural network analysis. This indicated the presence of a biphasic association of ALP with MDA: the first phase increases while the second decreases MDA. The latter phenomenon is considered to be associated with the increase in bone formation due to the mechanical stress loaded on the lower extremities. These findings are important and informative for pediatricians to understand the significance of the serum ALP level in pediatric patients with genu varum caused by vitamin D deficiency.

Hypophosphatasia (HPP; OMIM 241510, 241500, and 146300) is an inherited metabolic disease characterized by defects of bone and tooth mineralization, which is caused by loss-of-function mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP). In the last three decades, several studies have focused on the genotype-phenotype correlation in hypophosphatasia (HPP). In particular, functional tests based on in vitro analysis for the residual enzymatic activities of mutations have revealed a clear but imperfect genotype-phenotype correlation, suggesting that multiple potential factors modulate the phenotype. One of the missense variants identified in the tissue non-specific alkaline phosphatase (ALPL) gene, c.787T>C, has been considered as a benign polymorphism in HPP; however, its pathogenicity and role in disease manifestation remain controversial. We here report our recent experience of three unrelated families harboring the c.787T>C variant, suggesting clinical implications regarding the controversial pathogenicity of c.787T>C. First, despite the lack of obvious clinical phenotypes, homozygous c.787T>C would decrease the serum level of ALP activity. Second, c.‍787T>C might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144G>A variant. These cases contribute to the recent advances in understanding HPP to facilitate clinical recognition of more subtle phenotypes, further providing insights into the pathogenesis of HPP.

This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin® (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

This randomized double-blind multicenter trial (NCT01927861) evaluated the growth-promoting effect and safety of Norditropin® (NN220; somatropin) in Japanese children with short stature due to Noonan syndrome. Prepubertal children aged 3

Vitamin D is indispensable for the maintenance of bone and mineral health. Inadequate vitamin D action increases the risk for various musculoskeletal/mineral events including fracture, fall, secondary hyperparathyroidism, diminished response to antiresorptives, rickets/osteomalacia, and hypocalcemia. Its most common cause in recent years is vitamin D deficiency/insufficiency, clinically defined by low serum 25-hydroxyvitamin D [25(OH)D] level. Guidelines for vitamin D insufficiency/deficiency defined by serum 25(OH)D concentrations have been published all over the world. In Japan, however, the information on the associations between serum 25(OH)D and bone and mineral disorders has not been widely shared among healthcare providers, partly because its measurement had not been reimbursed with national medical insurance policy until August 2016. We have set out to collect and analyze Japanese data on the relationship between serum 25(OH)D concentration and bone and mineral events. Integrating these domestic data and published guidelines worldwide, here we present the following assessment criteria for vitamin D sufficiency/insufficiency/deficiency using serum 25(OH)D level in Japan. 1) Serum 25(OH)D level equal to or above 30 ng/mL is considered to be vitamin D sufficient. 2) Serum 25(OH)D level less than 30 ng/mL but not less than 20 ng/mL is considered to be vitamin D insufficient. 3) Serum 25(OH)D level less than 20 ng/mL is considered to be vitamin D deficient. We believe that these criteria will be clinically helpful in the assessment of serum 25(OH)D concentrations and further expect that they will form a basis for the future development of guidelines for the management of vitamin D deficiency/insufficiency.

This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naive children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency.

With recent improvements in the diagnosis and treatment of cancer, the number of childhood cancer survivors (CCSs) has been increasing in Japan. The importance of quality of life during the lifetime of CCSs has now been recognized, and the late effects of cancer treatments are essential and important issues. In this study we analyzed the endocrinological abnormalities of CCSs by retrospectively evaluating 122 outpatients (62 males and 60 females) who had been referred from pediatric oncologists to our follow-up clinic among 151 CCSs attending our hospital more than two years after their cancer treatment. Follow-up duration varied from 2 to 30 (median 8.0) years. Their average age was 17.3 (range 4-36, median 17.0) years, and 38 patients (31.1%) reached adulthood. Endocrinological abnormalities were found in 82 (67%) of 122 survivors. Gonadal dysfunction was observed in 60 patients (49%). Thirty-nine patients (32%) were short or grew at a slower rate. Twenty-six patients (21%) showed thyroid dysfunction. Other abnormalities were as follows: obesity in 20 patients (16%), leanness in 10 (8%), central diabetes insipidus in 11 (9%) and adrenocortical dysfunction in 9 (7%). Low bone mineral density was observed in 41 (42%) of 98 patients evaluated. These endocrinological abnormalities were caused by the combined effects of cancer itself and various treatments (chemotherapy, radiation therapy, surgery, and hematopoietic stem cell transplantation). Lifetime medical surveillance and continuous follow-up are necessary for CCSs, because treatment-related complications may occur during childhood and many years after the therapy as well. Endocrinologists should participate in long-term follow-up of these survivors in collaboration with pediatric oncologists.

Frasier syndrome is characterized by slowly progressive nephropathy, male pseudohermaphroditism, streak gonad, and high risk of gonadoblastoma development. Here we report a case of a 46,XY phenotypic female with Frasier syndrome, who was under hemodialysis. While her serum estradiol level was gradually increasing annually, gonadotropin level was constantly extremely high, and her appearance was still prepubertal. She was heterozygous for a novel guanine>adenine point mutation at position +1 of the splice donor site within intron 9 (IVS 9 + 1G>A) of the Wilms' tumor 1 gene. The possibility of this disease should be taken into consideration whenever we encounter a patient with steroid-resistant nephrotic syndrome and delayed puberty.

We present a 10-year old boy with central diabetes insipidus (CDI) showing hyperintensity in a normal-sized posterior pituitary on magnetic resonance (MR) T1-weighted image (T1WI). He complained of nocturnal enuresis and polyuria. Daily urine volume increased to 4 to 5 L, and AVP plasma level was very low. Polymerase chain reaction (PCR)-amplified exons of the arginine vasopressin (AVP)-neurophysin (NP) II gene were sequenced. Nucleotide-1884 guanine in Exon 2 was substituted with thymine, which induced a substitution of glycine for valine at amino acid position 65 in the NP II moiety. However, MR imaging showed hyperintensity in the posterior pituitary on T1WI. These results suggest that the MR findings of the posterior pituitary in CDI may vary.