Kazumichi Onigata

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation

OBJECTIVE Mutations in the selenocysteine insertion sequence binding protein 2 gene (SECISBP2 also known as SBP2) lead to a multisystemic disorder. Our objectives are to examine the clinical manifestations of the present patient and evaluate the effects of GH and triiodothyronine (T(3)) for longitudinal bone growth and maturation. METHODS A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)), and elevated free thyroxine (FT(4))), short stature without GH deficiency, and delayed bone maturation. The entire coding region of the patients SBP2 was analyzed. GH treatment was initiated when the patient was 4 years old, and combination therapy with GH plus T(3) was started when the patient was 10 years old. We monitored the patients height and bone age until he was 11 years old. RESULTS The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X). Six years of GH monotherapy improved the patients height s.d. from -3.4 to -1.7 without accelerating bone maturation, whereas 6 months of T(3) treatment combined with GH almost normalized the thyroid function tests and improved both longitudinal bone growth and maturation. CONCLUSIONS In the growth plate, GH may compensate for decreased local T(3) effects on longitudinal bone growth; however, GH does not appear to compensate for the effects of T(3) on bone maturation. We believe that the present case has important implications for understanding the mechanism of thyroid hormone and GH on longitudinal bone growth and maturation.

Clinical and genetic aspects of hypophosphatasia in Japanese patients

Objective We examined the clinical and genetic features of hypophosphatasia (HPP) in Japanese patients. HPP is a rare metabolic bone disorder of bone mineralisation caused by mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene, which encodes tissue-non-specific alkaline phosphatase isoenzyme. Methods We retrospectively investigate the incidence and clinical features of 52 patients with paediatric HPP who were born between 1999 and 2010. Mutations of the ALPL gene were analysed in 31 patients. Results The annual incidence of perinatal lethal HPP (PLH) was estimated to be 2–3/1 000 000 births. The most frequent clinical type was PLH followed by prenatal benign. In addition to bone symptoms, cerebral manifestations were frequently observed including convulsion, mental retardation, deafness and short stature with growth hormone deficiency. Respiratory failure was the most significant predictor of a poor prognosis for PLH. The first and second most frequent mutations in the ALPL gene were c.1559delT and c.T979C (p.F327L), respectively. The c.1559delT homozygous mutation was lethal with respiratory failure. Patients with the p.F327L compound heterozygous mutation had the different non-lethal type with short stature and a gradual improvement in ALP level and bone mineralisation. Conclusions The most frequent clinical type was the PLH type with prognosis related to respiratory failure, biochemical/radiological changes and ALPL mutations. Cerebral manifestations frequently occurred. Genotype–phenotype correlations were associated with specific outcomes in the PLH type, whereas different clinical features were associated with the same genotype in the non-lethal type.

Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1–6a and/or the CNEs result in idiopathic short stature (ISS) and Leri–Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3′-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father–daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.

Frequencies of spontaneous breast development and spontaneous menarche in Turner syndrome in Japan.

Abstract. The Growject® database on human GH treatment in Turner syndrome was analyzed in the Turner Syndrome Research Collaboration, and the relationships of the frequencies of spontaneous breast development and spontaneous menarche with karyotype and GH treatment were investigated. One hundred and three cases started GH treatment with 0.5 IU/kg/ week (0.5 IU group), and their dose was increased to 0.35 mg/kg/wk midway through the treatment course. Another 109 cases started GH at a dose of 0.35 mg/kg/wk (0.35 mg group). Spontaneous breast development was observed in 77 (36.3%) of the 212 patients, and spontaneous menarche occurred in 31 patients (14.6%). The frequency of spontaneous breast development was significantly lower in patients with the 45,X karyotype and significantly higher in patients with a structural abnormality of the second X chromosome. The frequency of spontaneous menarche was significantly higher in patients with mosaicism characterized by X monosomy and a cellular line with no structural abnormality of the X chromosome. No significant differences in frequencies of spontaneous breast development and spontaneous menarche were observed between the two dose groups, indicating that GH treatment does not increase the frequency of spontaneous puberty.

Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision)

Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision).

Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The “Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)” published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.

Favorable Impact of Growth Hormone Treatment on Cholesterol Levels in Turner Syndrome

Background: Patients with Turner syndrome (TS) are prone to having metabolic abnormalities, such as obesity, dyslipidemia, hypertension, hyperinsulinemia and type 2 diabetes mellitus, resulting in increased risks of developing atherosclerotic diseases. Objective: To determine the effect of growth hormone (GH) therapy on serum cholesterol levels in prepubertal girls with TS enrolled in the Turner syndrome Research Collaboration (TRC) in Japan. Patients and methods: Eighty-one girls with TS were enrolled in the TRC, and their total cholesterol (TC) levels before GH therapy were compared with reported levels of healthy school-aged Japanese girls. TC levels after 1, 2 and 3 yr of GH treatment were available for 28 of the 81 patients with TS. GH was administered by daily subcutaneous injections, 6 or 7 times/wk, with a weekly dose of 0.35 mg/kg body weight. Results: Baseline TC levels revealed an age-related increase in TS that was in contrast to healthy girls showing unchanged levels. During GH therapy, TC decreased significantly after 1 yr of GH treatment and remained low thereafter. Conclusions: Girls with untreated TS showed an age-related increase in TC that was a striking contrast to healthy girls, who showed unchanged levels. GH therapy in girls with TS brought about a favorable change in TC that indicates the beneficial impact of GH on atherogenic risk.

Japan can learn from the Swedish primary care doctor fostering system

To the Editor A new training program for primary care physicians in Japan started in 2018. However, there are many problems to overcome in the program, especially regarding the fact that the effective role of clinical education and clinical research of primary care physicians in the rural area in Japan are still not being sufficiently discussed. To investigate and improve the clinical research training system for primary care physicians in remote areas in Japan, we visited several primary healthcare centers and Lund University in Sweden between April 19, 2018, and April 26, 2018. In Sweden, there are seven medical schools that were established by their government, and the country has a total of approximately 2000 medical students. Japan has approximately 9000 medical students annually; however, the total population is about 9.5 million in Sweden.1 Although Sweden is referred to as the country with the most sophisticated social health system, an aging society with a declining birthrate is a huge problem as it is in Japan. In this survey, we concluded that primary healthcare centers have an important role not only with clinical manpower in remote areas but also as medical education sites for young physicians at the forefront of clinical research training. After the 18month initial postgraduate training period is finished, approximately 20% of the total trainees will select the primary care physician’s special course (ST: special training) without duty or scholarships, which is considered to be the most important in the Swedish healthcare keeping. Based on the recognition of the importance of highdensity training to become a skilled primary care physician, Swedish primary care physicians must complete at least 5 years of special training with at least 3 years at a primary healthcare center and at least 1.5 years of subspecial training, including internal medicine, obstetrics and gynecology, orthopedics, dermatology, psychiatry, pediatrics, otolaryngology, and ophthalmology, that specially focuses on each primary care setting.2 There is also a clinical scientific methodology course. Surprisingly, this course is mandatory and lasts at least 10 weeks; in the meantime, the trainees must try to acquire a scientific thinking ability to evaluate the appropriateness of their routine medical practice objectively; furthermore, they learn to create clinical questions and how to create a design and gather data, even if statistical analysis. Because many primary care physicians have PhDs in clinical research instead of basic laboratory science, they can conduct clinical research using the local PHC data and properly mentoring young trainees. In addition, primary care physicians who are interested in clinical research during the mandatory period can continue their research and take PhD courses (10% of total trainees) while working as clinicians at each PHC, and they can get strong support from the National Research School in General Medicine to improve the clinical research network among the primary care settings. Thus, we believe that there are many things to learn from Sweden’s style about how to strengthen the Japanese skills of primary care physicians at university hospitals and training systems of clinical research in remote areas.3

Primary care doctor fostering and clinical research training in Sweden: Implications for Japan

In 2018, a new training program for primary care physicians was launched in Japan. As physicians responsible for the training of new primary care physicians, we have faced many problems, particularly in rural areas. The influence of this new program on primary care physicians in rural areas of Japan has not been sufficiently investigated. The aim of this research was to improve training for primary care physicians in Japan by examining training programs in Sweden, where the population challenges are similar to those seen in Japan. In this paper, we will express our opinions and describe the differences in the primary care fostering systems and clinical research training for generalist in Japan and Sweden.