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Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in normal fetal and postnatal growth. Over 30 pathogenic variants of IGF1R have been identified in patients with short stature. Yet, 20 years after the first report, a variety of phenotypes remain poorly defined. We analyzed the genetic and clinical data and responses to GH therapy in 11 patients using results from questionnaires. Eight of the 11 patients have already been reported in previous articles, and all of the identified mutations were heterozygous. The patients exhibited various phenotypes. At least two patients did not meet the criteria for GH treatment for small for gestational age (SGA) short stature, and two more patients showed lower serum IGF1 levels. Nine of the 11 patients had thin upper lips. Five patients with heterozygous IGF1R treated with GH exhibited similar height gains to those reported in previous Japanese studies on SGA short stature, which also led to extremely high serum IGF1 levels. Patients with short stature due to IGF1R mutations exhibit various phenotypes. Their presentation at diagnosis may be indistinguishable from common short stature. More specific clinical scoring that considers elevated IGF1 levels after GH treatment is needed to better detect IGF1R mutations., Competing Interests: None of the authors have any potential conflicts of interest associated with this research., (2022©The Japanese Society for Pediatric Endocrinology.)

This multicenter prospective cohort study followed up Japanese children who had just started GH therapy using a drug delivery device (GROWJECTOR® L) linked to a newly developed smartphone application and analyzed precise medication adherence data stored in GROWJECTOR® L to evaluate the usefulness of the application in improving GH therapy adherence over a 24-wk observation period. Moreover, a questionnaire survey on GH therapy and the smartphone application was conducted, and factors affecting adherence to GH therapy were assessed. This study enrolled 60 children with short stature who had GH deficiency or Turner syndrome or were small for gestational age from 28 Japanese medical institutions and analyzed 57 of them. The median and mean adherence rates after 24 wk of observation were 96% and 93%, respectively. Although adherence rates were significantly lower from wk 16 to wk 20 than from wk 1 to wk 4, cumulative adherence rates remained high throughout the observation period. The questionnaire analysis revealed that most patients actively used the application. Overall, our results suggest that active discussion regarding the development of healthcare systems that contribute toward improving the patient quality of life is warranted., Competing Interests: The author received research funding from JCR Pharmaceuticals Co., Ltd. (Hyogo, Japan)., (2021©The Japanese Society for Pediatric Endocrinology.)

In Japan, anabolic steroid hormone (ASH) treatment for Turner syndrome (TS) to promote growth had been provided before GH therapy for TS was approved. ASH effectively improved the adult height (AH) of TS patients without spontaneous puberty but decreased the AH of TS patients with spontaneous puberty. Although GH therapy for TS was approved in 1991, the approved dosage remained 0.5 IU/kg/wk for GH-deficient TS patients and improved AH by approximately 7 cm. However, AH did not reach -2 standard deviations in healthy girls. In 1999, the requirement of GH deficiency was removed and a dose of 1.0 IU/kg/wk was approved. Although an increase in AH was expected, no reports showed significant improvements in AH at a high dose of GH. GH + ASH combination therapy was reevaluated and recommended for TS patients with gonadal failure and an extremely short stature or those who respond poorly to GH therapy. Although early estrogen replacement therapy is recommended to improve psychological quality of life and prevent osteoporosis, it lowered AH even at a low dose of ethinyl estradiol (25 ng/kg/d). The initiation of ethynyl estradiol at an extremely low dose (1-5 ng/kg/d) at a relatively young age successfully improved AH., Competing Interests: The authors declare no conflicts of interest., (2020©The Japanese Society for Pediatric Endocrinology.)

We describe the case of a short-statured 12-yr-old boy who developed a Chiari type 1 malformation associated with central sleep apnea after administration of high-dose GH therapy, which he had been receiving since the age of 10 yr and 4 mo. He responded well to GH therapy, and his height increased by 18.8 cm in 2 yr. At 12 yr and 4 mo of age, his mother reported that he had developed sleep apnea during the previous year and it had worsened over a month prior to presentation at our hospital. Otolaryngological examination did not reveal tonsillar or adenoidal hypertrophy. Polysomnography demonstrated severe central sleep apnea with an apnea-hypopnea index of 46.5/h. Sagittal T1-weighted magnetic resonance imaging (MRI) demonstrated herniation of the cerebellar tonsils 15 mm below the foramen magnum into the cervical spinal cord. Continuous positive airway pressure therapy initiated prior to performing neurosurgery was ineffective. Following uncomplicated foramen magnum decompression, his breathing pattern during sleep returned to normal. Sagittal MRI examination should be considered in patients who develop sleep apnea during/following administration of GH therapy.

Pain resulting from needle injection is a serious problem for patients that self-administer medication at home. We studied impressions of needle use by comparing PenNeedle® 32G Taper (NovoFine® 32G Tip), developed to reduce the sense of fear and pain of injection, with a conventional needle, in children self-injecting GH. A total of 34 patients self-injected themselves with needles coupled with Norditropin® NordiFlex® pre-filled recombinant human GH, and impressions of use were evaluated by a series of questionnaires. Compared to the conventional needle, PenNeedle 32G Taper was slightly less painful at time of insertion according to patient responses, though the difference was not statistically significant (P=0.06). PenNeedle 32G Taper has the same inner diameter as the conventional needle, thus there was no difference in the pain felt at time of injection between these two needles. Large differences in pain perception between the two needles were not seen probably due to their similar shape and appearance and as the subjects of this study were young. Nevertheless, based on the results of post-study questionnaires, significantly more patients (68%, P=0.02) expressed a desire to use PenNeedle 32G Taper for daily injections of GH. PenNeedle 32G Taper thus appears to be a superior needle which reduces insertion-associated pain in children receiving recombinant GH and improves patient QOL.

In estrogen replacement therapy in Turner syndrome, there is no report which recommends the timing of the start of estrogen therapy in relation to height or adult height prediction. We have established a prediction model for pubertal growth (height difference from the start of estrogen therapy until adult height) at the start of estrogen replacement therapy. Twenty-seven Turner girls without spontaneous puberty were divided into two groups according to birth years; Group I consisted of 16 patients born from 1980-1989 and Group II consisted of 11 patients born before 1980. Using clinical characteristics from Group I, stepwise multiple regression analysis taking pubertal growth as an independent factor, and chronological age, bone age (TW2 RUS method standardized for Japanese children), height and height SDS as dependent factors revealed following formula (p<0.001, R2=0.737): (pubertal growth) = - 1.01x (Chronological age at start of E) - 0.326x (height at start of E) - 1.779x (bone age at start of E) + 90.997. Predicted adult height was obtained by adding predicted pubertal growth to height at the start of estrogen therapy. The mean absolute difference between real adult height (tallest height after height velocity less than 1 cm/yr) and predicted adult height was 1.6 ± 0.9 cm (0.3-2.8 cm) in Group I. When this prediction model was applied to Group II, The mean absolute difference between real adult height and predicted adult height was 1.0 ± 0.7 cm (0.1-2.0 cm). A prediction model for pubertal growth at start of estrogen therapy in Turner syndrome was obtained. Using this prediction model, the timing of the start of estrogen therapy can be decided in consideration of the patient's desired adult height.

Unlabelled: We report the case of a 7-yr-old girl with Turner syndrome, ulcerative colitis (UC) and coarctation of the aorta. The diagnosis of Turner syndrome was made in early infancy (karyotype analysis 45, X). Growth hormone treatment was started at 3 yr and 2 mo of age. From the age of 4 yr and 5 mo, the patient suffered from persistent diarrhea with traces of blood and intermittent abdominal discomfort. As these symptoms gradually deteriorated, she was referred to our clinic at the age of 7 yr for further evaluation. Barium enema showed aphtha and loss of the fine network pattern in the descending colon and rectum. An endoscopic examination showed ulceration, edema, friability, and erythema beginning in the rectum and extending up to the splenic flexure of the descending colon. The histology of the descending colon area showed severe stromal infiltration of inflammatory cells. These endoscopic findings and the histological findings were consistent with UC. Thus, based on these findings, the patient was diagnosed as having UC. Mesalazine therapy was initiated at this time. The patient is currently being treated with mesalazine (1,000 mg/day) and abdominal symptoms and bloody diarrhea have disappeared. GH therapy was not interrupted during the therapy for UC. Retrospectively, growth hormone improved growth velocity (9 cm/year) during the first year of treatment, however from the age of 4 yr, growth velocity decreased (4-5 cm/yr) in spite of the GH treatment., Conclusion: Patients with Turner syndrome and gastrointestinal symptoms should be investigated for inflammatory bowel diseases. Growth velocity is useful for evaluating the presence of inflammatory bowel diseases and other systemic diseases.

The aim of this study was to compare the therapeutic effects of rhGH administered either by subcutaneous needle-injection (pens) or subcutaneous needle-free jet-injection (VISION(®)). Furthermore, a survey was carried out after using VISION(®) for 12 mo. A needle-free injection group consisting of 18 subjects (11 males and 7 females, mean age 5.87 ± 2.05 yr at the start of hGH therapy) who have not used pen injectors to date, were allowed to use VISION(®) in their third to fifth years of GH therapy. In addition, a group of 8 subjects who had been using pen injectors at our clinic (6 males and 2 females, mean age 6.54 ± 2.78 at the start of GH therapy) was monitored as a control. The results indicate that there are no significant differences between the mean growth rates, growth rate SD scores or height SD scores when comparing injection devices. Furthermore, the survey of VISION(®) revealed that 70% of the subjects found it slightly or not painful at or after injection, 70% found VISION(®) very easy or easy to use, and 80% found the weight of the device appropriate. All subjects expressed a desire to continue using VISION(®) in the future. Our results suggest that there are no problems with the effectiveness of hGH treatment with VISION(®), a needle-free jet-injection device and that VISION(®) is an effective device for children who have an aversion to needle injection.