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This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < −2.5 SDS at age 2 years or < −2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Artemis is an exonuclease essential for V(D)J recombination and repair of DNA double-stranded breaks. Pathogenic variants in DCLRE1C encoding Artemis cause TClinical data of ART-SCID patients who were diagnosed between 2003 and 2022 in Japan were collected from their physicians using a questionnaire.ART-SCID diagnosis was made in eight patients from seven families with severe infections within 6 months of life. Two patients had missense variants, five patients had large genomic deletions, and one patient was compound heterozygous for a missense variant and large genomic deletion. All eight underwent allogeneic HCT within 4 months after the diagnosis, 7 receiving a conditioning regimen containing alkylating agents, and one patient without conditioning due to uncontrolled infection. Two patients with poor performance status (PS) died of complications 410 days and 32 days post-HCT, respectively. Of the six surviving patients with a median follow-up time of 8.3 (0.5-17.9) years, three patients had growth retardation. The patients with PS of 0-2 showed a tendency for better overall survival than those with PS 3-4.Large deletions were the most common genetic cause of ART-SCID in Japan. To improve HCT outcome, early diagnosis with newborn screening for SCID is urgently needed.

Context There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Objective We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot samples in Tokyo. Methods Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. Samples from 2 cohorts were assayed: Cohort A, 63 “screening positive” neonates who were referred to an endocrinologist (n = 26 with 21OHD; n = 37 false-positive; obtained from 2015 to 2020); and Cohort B, samples (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021. Results Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences. Conclusion Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening.

Autoantibodies (aAbs) to type I interferons (IFNs) have been found in less than 1% of individuals under the age of 60 in the general population, with the prevalence increasing among those over 65. Neutralizing autoantibodies (naAbs) to type I IFNs have been found in at least 15% of patients with life-threatening COVID-19 pneumonia in several cohorts of primarily European descent. We aimed to evaluate the prevalence of aAbs and naAbs to IFN-α2 or IFN-ω in Japanese patients who suffered from COVID-19 as well as in the general population.Patients who suffered from COVID-19 (n = 622, aged 0-104) and an uninfected healthy control population (n = 3,456, aged 20-91) were enrolled in this study. The severities of the COVID-19 patients were as follows: critical (n = 170), severe (n = 235), moderate (n = 112), and mild (n = 105). ELISA and ISRE reporter assays were used to detect aAbs and naAbs to IFN-α2 and IFN-ω using E. coli-produced IFNs.In an uninfected general Japanese population aged 20-91, aAbs to IFNs were detected in 0.087% of individuals. By contrast, naAbs to type I IFNs (IFN-α2 and/or IFN-ω, 100 pg/mL) were detected in 10.6% of patients with critical infections, 2.6% of patients with severe infections, and 1% of patients with mild infections. The presence of naAbs to IFNs was significantly associated with critical disease (P = 0.0012), age over 50 (P = 0.0002), and male sex (P = 0.137). A significant but not strong correlation between aAbs and naAbs to IFN-α2 existed (r = - 0.307, p value 0.0001) reinforced the importance of measuring naAbs in COVID-19 patients, including those of Japanese ancestry.In this study, we revealed that patients with pre-existing naAbs have a much higher risk of life-threatening COVID-19 pneumonia in Japanese population.

The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development—such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)—the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.

Introduction: The variants in the zinc finger (ZF) domains 1–3 in WT1 are one of the major causes of 46,XY disorders of sex development. Recently, the variants in fourth ZF (ZF4 variants) were reported to cause 46,XX DSD. However, all the nine patients reported were de novo, and no familial cases were identified. Case presentation and Results: The proband (16yrs social female), had 46,XX karyotype with dysplastic testes and moderate virilization in genitalia. A ZF4 variant, p.Arg495Gln in WT1 was identified in the proband, her brother and mother. The mother did not show any virilization with normal fertility, and the 46,XY brother developed normal puberty. Discussion/Conclusion: The phenotypic variations due to ZF4 variant are extremely broad in 46,XX cases.

CBL plays a critical role in cellular proliferation. Germline heterozygous CBL variants give rise to CBL syndrome, which is phenotypically similar to RASopathy. Somatic mutations in CBL have been reported in patients with juvenile myelomonocytic leukemia (JMML).Exome analysis was performed in a patient with immunodeficiency who developed Pneumocystis jirovecii pneumonia.Exome analysis identified a homozygous CBL missense variant. Cell biological analysis of this CBL variant confirmed attenuated function.Spontaneous regression of hematological proliferation has been observed in patients with CBL mutated JMML and in patients with CBL syndrome. Intriguingly, immunological impairment was spontaneously ameliorated by aging in this patient.

PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma (ARMS) developed in a patient presenting with intellectual disability and dysmorphic facial features. Whole exome sequencing analysis of a germline sample identified a PACS1 c.607 C>T de novo variant and the patient was diagnosed with Schuurs-Hoeijmakers syndrome (SHS). SHS is a rare disease characterized by intellectual disability and dysmorphic facial features, among various physical abnormalities, due to PACS1 c.607 C>T de novo variant. Due to the rarity of the SHS, diagnosis based on phenotypic information is difficult. To date, there have been no previous reports describing malignancy associated with SHS. Comprehensive somatic mutation analysis revealed a unique pattern of genetic alterations in the PAX3/7-FOXO1 fusion-negative ARMS tumor, including mutations in the oncogene, HRAS; MYOD1, a molecule essential for muscle differentiation; and KMT2C and TET1, genes encoding factors involved in epigenetic regulation. Although the role of PACS1 in tumorigenesis is unclear, it is reported to function in apoptosis regulation. Our case suggests that PACS1 could have a novel role in oncogenesis.

A six-year-old boy was referred with a one-and-a-half months history of polyuria and polydipsia. At the age of two, he had a single lytic bone lesion in his femoral head, diagnosed as Langerhans cell histiocytosis (LCH) by biopsy at another hospital. As no other affected organs were detected and the affected bone lesion was self-limited, he was not followed up afterward and was doing well. He was diagnosed with diabetes insipidus (DI) by confirming hypernatremia (Na: 148 mEq/l) with hyperosmolar serum (s-Osm 298 mOSM/kg) and inappropriately diluted urine (u-Osm 205 mOSM/kg). His polyuria and polydipsia improved dramatically using the perioral diuretic hormone, and other pituitary functions were not impaired. Magnetic resonance imaging revealed an enlarged pituitary stalk. Sensitive and specific biomarkers of germ cell tumors, including alpha-fetoprotein, placental alkaline phosphatase, and β-hCG in the cerebrospinal fluid, were not detected, indicating relapse of LCH. Genetic analysis revealed a BRAF V600E mutation in the primary bone lesion. We recommend systematic follow-up of patients with a history of LCH, even non-CNS single-system single-site disease, especially with BRAF V600E mutation.

In Japan, since the introduction of newborn screening for congenital adrenal hyperplasia in 1989, most patients with 21-hydroxylase deficiency (21OHD) have been treated with glucocorticoid from the neonatal period (1, 2). Although early initiation of glucocorticoid therapy from the neonatal period remarkably improved the outcomes of final height, the average final height in 21OHD patients is below the standard height observed in normal healthy adults by approximately –1 standard deviation (SD) (3, 4), and optimization of glucocorticoid therapy remains challenging (5,6,7, 8). Glucocorticoids have a strong potential for reducing linear growth, whereas undertreatment with glucocorticoids leads to androgen excess, precipitating pubertal development (5,6,7). Recent studies have revealed that the final height positively correlates with height at two years of age (9), and the lowest possible hydrocortisone (HC) dose for maintenance treatment during the first two years of life considered crucial for maximizing the final height of 21OHD patients. For maintenance therapy, 15–25 mg/m2 HC therapy is widely accepted (10). In contrast to maintenance HC therapy, the optimal HC dose for initial treatment has not been established. The consensus statement on 21OHD by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology (ESPE) suggests an HC dose of up to 25 mg/m2 for treatment initiation (11). Conversely, the Japanese Society for Pediatric Endocrinology (JSPE) recommended a considerably higher HC dose of HC (100–200 mg/m2) for the initial treatment (12), and in the revised guideline published in 2014, the recommended dose was lowered to 25–100 mg/m2, which is still higher than that recommended by the ESPE (13). A high initial HC dose may help normalize the elevated adrenal androgen levels during the neonatal and early infantile periods, followed by sufficient control by a lower maintenance dose. Our previous study has revealed that the height at two years of age in patients with 21OHD treated with a higher HC dose during initial therapy could be compared with those receiving lower HC doses (14). However, detailed differences between patients with 21OHD treated with higher and lower doses during initial HC therapy have not been assessed. In the present study, we aimed to evaluate the effects of initial HC treatments on clinical profiles during infancy and early childhood in patients with 21OHD.

Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune hypothyroidism without goiter. TSH receptor-blocking antibodies (TSBAb) are involved in its etiology in adults. Reportedly, this disease is extremely rare in children. In this study, we aimed to investigate the prevalence of TSBAb during AAT onset in children using a commercially available cell-based bioassay TSAb kit. We conducted a multicenter retrospective observational study. We collected data of patients with AAT who were < 15 yr old, enrolled in a collaborative research group, and diagnosed since July 2003. AAT was defined as acquired autoimmune hypothyroidism without thyroid enlargement. Eighteen patients (including 15 females) whose TSH receptor antibody (TRAb) or TSBAb levels were measured within a year from the initial visit were included. The median age at diagnosis was 9.3 years, and the estimated time between onset and diagnosis was 2.6 yr. The positive rate for either TSBAb or TRAb was 38.8% (95% confidence interval: 18.3–59.5%). There were no significant differences in age, the estimated time between onset and diagnosis, and FT4 levels at diagnosis between the TSBAb-positive and -negative groups. Unlike previous reports, we showed that the prevalence of TSBAb-positivity in childhood-onset AATs is not rare, as in adults.

BACKGROUND One of the major purposes of newborn screening for 21-hydroxylase deficiency (21OHD) is preventing life-threatening adrenal crisis. However, the details of adrenal crisis in newborns are not precisely documented. AIM We aimed to clarify the clinical details of salt-wasting in newborn 21OHD patients. METHODS Based on the follow-up survey of the screening in Tokyo from 1989 to 2017, we retrospectively analysed the conditions of classical 21OHD neonates before the initiation of therapy. RESULTS One hundred classical 21OHD patients (55 male, 45 female) were analysed. The age at the first hospital visit was 0-20 days with sex difference (male: 9.0 ± 3.5 days; female: 6.2 ± 3.9 days). Thirty-seven (37.4%) patients exhibited severe salt-wasting (SSW), that is, Na 7 mEq/L or Na/K ratio 7 mEq/L and Na/K

Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of

Background: Slipped capital femoral epiphysis (SCFE) is a displacement of the femoral head epiphysis that is sometimes associated with endocrinopathies. We report the case of a 12-year-old girl with hypergonadotropic hypogonadism (HH) who developed SCFE during growth hormone therapy (GHT). We also performed a systematic review of the cases of SCFE and hypogonadism in the literature. Case presentation: The patient was diagnosed with HH based on the absence of ovaries and a uterus. Her medical history included GHT for 9 years as she was small for gestational age. Chromosomal and genetic analyses revealed no pathogenic abnormalities. Radiographs revealed a left SCFE with a 28.7° posterior tilt angle. GHT was discontinued, and bilateral in situ screw fixation was performed. Sex hormone therapy (SHT) was initiated. Two years later, the patient recovered.Methods: We reviewed the cases of hypogonadism complicated with SCFE. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement were followed. Case reports of patients were retrieved using PubMed on November 17, 2021.Results: A total of 44 cases of SCFE and hypogonadism were identified, including this case. Endocrinological complications included growth hormone deficiency (n = 18), being overweight (n = 9), and hypothyroidism (n = 25). Hormone replacement was administered before (SHT, n = 6; GHT, n = 12) and after surgery (SHT, n = 21; GHT, n = 11). SCFE surgery was invasive (minimal, n = 19; moderate, n = 10; high, n = 8). Orthopedic complications were observed in four cases. Conclusions: If hypogonadism occurs during GHT, SCFE should be noted. Hypogonadism should be studied to determine the effects of hormonal replacement on SCFE.

Atrophic autoimmune thyroiditis (AAT) is a type of autoimmune thyroiditis that causes hypothyroidism without thyroid enlargement. AAT is distinguished from Hashimoto’s disease (HD) by the absence of thyroid enlargement. AAT is rare in children and clinically characterised by severe primary hypothyroidism. Autoimmune thyroiditis, especially HD, is commonly complicated with systemic lupus erythematosus (SLE). Here, we reported the patient with AAT as the initial presentation of SLE complicated with generalised myxoedema, whose presentation was a diagnostic challenge. This patient illustrates the importance of the early recognition of an atypical presentation of SLE patients with autoimmune thyroiditis. It is possible that similar cases have existed in the past but have been overlooked as HD. A large-scale study is necessary to clarify the reality of AAT in SLE.

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.

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.

We herein report a case of a 28-year-old man with generalized lipodystrophy-associated progeroid syndrome treated by leptin replacement. He showed symptoms of generalized lipodystrophy around onset of puberty. His body mass index was 11.9 kg/m2, and he had a short stature, birdlike facies, dental crowding due to micrognathia, partial graying and loss of hair, and a high-pitched voice, all of which are typical features of the progeroid syndrome. Laboratory examinations and abdominal ultrasonography revealed diabetes mellitus, insulin-resistance, dyslipidemia, decreased serum leptin levels (2.2 ng/mL), elevated serum hepatobiliary enzyme levels and fatty liver. Whole exome sequencing revealed de novo heterozygous LMNA p.T10I mutation, indicating generalized lipodystrophy-associated progeroid syndrome, which is a newly identified subtype of atypical progeroid syndrome characterized by severe metabolic abnormalities. Daily injection of metreleptin [1.2 mg (0.04 mg/kg)/day] was started. Metreleptin treatment significantly improved his diabetes from HbA1c 11.0% to 5.4% in six months. It also elevated serum testosterone levels. Elevated serum testosterone levels persisted even 1 year after the initiation of metreleptin treatment. To the best of our knowledge, this is the first Japanese case report of generalized lipodystrophy-associated progeroid syndrome. Furthermore, we evaluated short and long-term effectiveness of leptin replacement on generalized lipodystrophy by monitoring metabolic and endocrine profiles.

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.

Background Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia. Methods Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period. Results Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases. Conclusions Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T-(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β-cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16-year-old adolescent with late-onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin-dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC-peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β-cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D-associated IPEX syndrome improves Treg deficiency and prevents elimination of β-cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β-cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.

AMOTL1 is a member of the Motin protein family and localizes to tight junctions and is involved in cell polarity and paracellular permeability. Pathological variants have been reported in three patients from two separate families in recent years. The clinical spectrum includes cleft lip and palate along with a high incidence of congenital cardiac disease and ear malformations. We report a case of AMOTL1 pathogenic variant in a 11-year-old male patient with nonspecific and chronic liver dysfunction accompanied by persistently elevated liver enzymes since early infancy. Liver biopsy at 8 years of age revealed a mildly dilated central vein and sinusoid with no specific etiology. Liver dysfunction is not a known clinical feature of AMOTL1 malfunction. However, given that the protein is known to be involved in angiogenesis, it may be inferred that abnormalities in this process may lead to liver dysfunction. This is the first report of liver dysfunction identified in a patient with AMOTL1 malfunction, which will shed light on other putative functions of the protein.

Background The most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes, KCNJ11 and ABCC8. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations in ABCC8. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery. Objective To elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation. Patients and methods We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1-bp deletion around the splice acceptor site at the exon 35 mutation of ABCC8, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient's lymphocytes. Results ddPCR of ABCC8 cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery. Conclusion The phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelic ABCC8 mutations may be required.

BackgroundA20 haploinsufficiency (HA20) is an early-onset autoinflammatory disease caused by mutations in theTNFAIP3gene, which encodes the protein A20. Numerous truncating mutations in theTNFAIP3gene have been reported in HA20 patients, whereas fewer missense variants have had their pathogenicity confirmed. Here, we evaluated the pathogenic significance of three previously unreported missense variants of theTNFAIP3gene in suspected cases of HA20.MethodsWe obtained the clinical features and immunological data of three patients with missense variants (Glu192Lys, Ile310Thr, and Gln709Arg) of unknown significance ofTNFAIP3. We then performed in vitro functional assays including analysis of nuclear factor (NF)-κB reporter gene activity, detection of A20 expression and phosphorylation of A20 by IκB kinase β (IKKβ), and K63-deubiquitination assay usingTNFAIP3-deficient HEK293 cells. Three known pathogenic missense mutations reported previously were also investigated.ResultsThe inhibitory effect on NF-κB reporter gene activity was significantly disrupted by A20 Glu192Lys and the three known mutations. The variants Ile310Thr and Gln709Arg did not show a difference from the wild type in any of the assays performed in this study.ConclusionsAmong the three variants in theTNFAIP3gene, Glu192Lys was interpreted as being likely pathogenic, but Ile310Thr and Gln709Arg as being not pathogenic (uncertain significance and likely benign, respectively), based on the American College of Medical Genetics and Genomics standards and guidelines. Our study highlights the necessity of performing in vitro functional assays, notably, NF-κB reporter gene assay, to evaluate the pathogenicity ofTNFAIP3missense variants for the accurate diagnosis of HA20.

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.787TC, 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.787TC variant, suggesting clinical implications regarding the controversial pathogenicity of c.787TC. First, despite the lack of obvious clinical phenotypes, homozygous c.787TC would decrease the serum level of ALP activity. Second, c.787TC might deteriorate phenotypes of a patient harboring another ALPL variant, especially one that has thus far presumed to be benign, e.g., the c.1144GA 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.

Aim In Japan, most of the patients with primary amenorrhea or related conditions, such as delayed menarche, are diagnosed by pediatricians or gynecologists; accordingly, the number of the patients and the ratio of the causes were unclear. To clarify them, we conducted a nationwide survey in both the departments for the first time. Methods We sent a questionnaire about the patients with chief complaint of no menarche whose first visit was from January 2015 to December 2017, to 596 training institutions for specialist physicians of the Japan Society of Obstetrics and Gynecology and 152 facilities to which councilors of the Japanese Society for Pediatric Endocrinology belong. Results We received replies from 283 (37.8%) institutions. During the 3 years, 1043 patients first visited pediatrics or gynecology for no menarche. In 303 patients under 16 years old at the first visit, 177 (58.4%) patients had menarche by the age of 16. Of them, 41 (13.5%) patients had menarche spontaneously. Among 308 patients aged 16 to 17 at the first visit, 216 patients were 18 years or older at the survey. Of them, 124 (57.4%) patients had menarche by the age of 18, and 21 (9.7%) of them had menarche spontaneously. The causes of amenorrhea were detected in 462 patients. Abnormal karyotype including Turner syndrome was the most common at 122 (26.4%), followed by Mullerian agenesis at 73 (15.8%). Conclusions The first national survey revealed the number and causes of primary amenorrhea and related conditions. This report will provide better information for clinicians.

Context Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. Classic (CLCAH) and nonclassic (NCLCAH) forms were reported as total and partial deficiencies, respectively, of adrenal and gonadal steroid hormones. The rarity of LCAH has precluded large-scale epidemiological and clinical investigations. Objective To determine the epidemiological and clinical characteristics of 2 forms of LCAH. Design A multicenter cross-sectional cohort study in Japan on December 1, 2017. Participants Fifty-seven patients with LCAH (median age, 23.7 years; range, 0.0–47.5 years). Main Outcome Measures Patient demographics, STAR genotype, Quigley grade, endocrinological and imaging data, treatment, and prognosis. Results Fifty-three and 4 patients fulfilled definite and probable diagnostic criteria for LCAH, respectively. When NCLCAH was defined as either Quigley grade 1 in XY karyotype, no episode of salt losing or requirement of fludrocortisone, or onset of primary adrenal insufficiency (PAI) at 1 year or older, patients were divided into groups of 43 patients with CLCAH (75.4%), 11 with NCLCAH (19.3%), and 3 with unclassified LCAH (5.3%). All of the patients with CLCAH and 7/11 NCLCAH (63.6%) were treated with fludrocortisone. CLCAH was diagnosed at a significantly younger age than NCLCAH (median, 0.0 vs 4.0 years). STAR-Arg272Cys or -Met225Thr was identified only in NCLCAH (8/11, 72.7%). Conclusions We demonstrated the relative proportions and clinical and molecular characteristics of NCLCAH and CLCAH in Japan. These criteria for NCLCAH correspond to all previously published cases and our cases whose masculinization of the external genitalia, ability of mineralocorticoid production, and onset of PAI were described.

In addition to malignant diseases, hematopoietic stem cell transplantation (HSCT) is also a vital option as a curative therapy for non-malignant diseases, such as immunodeficiency, and other hematological disorders. Not only for malignant diseases, but for non-malignant diseases, cytotoxic therapy of conditioning regimens are associated with high risks of adverse effects; however, clinical details regarding the long term outcomes of cytotoxic therapy for non-malignant diseases are not documented yet. To clarify the endocrinological consequences of pediatric HSCT for non-malignant disease patients, we conducted a retrospective analysis. From 1983 to 2014, 75 patients that underwent HSCT for non-malignant diseases were selected for this study. Of these, 23 patients (19 men, 4 women) were continuously followed up in our institute, with regular health check-ups for late effects. Based on a multiple linear regression analysis, the glucocorticoid treatment duration for chronic graft-versus-host disease (cGVHD) and the conditioning regimen were found to be independent predictors of growth retardation. All four female patients developed hypogonadism, and required hormone replacement therapy. The conditioning regimen for the four female patients with hypogonadism was based on the use of alkylating agents, and two female patients were treated with a reduced-intensity conditioning (RIC) regimen. Our study revealed that even the RIC regimen was toxic for the gonads in female patients, and that the survivors of both non-malignant and malignant diseases should be followed up carefully after pediatric HSCT.

Introduction: Thoracic aortic aneurysms and dissections (TAAD) are rare in children and often associated with underlying genetic disorders accompanied with other systemic manifestations, including connective or osteo-articular tissue diseases. Case Presentation: We report the case of a 10-year-old girl with a novel nonsense SMAD3 mutation, p.Glu102X, who presented with familial TAAD without any signs of osteoarthritis. Histological analysis of aorta fragments from the patient with TAAD obtained during surgery revealed elastin degradation and inflammatory infiltration of T cells with dense CD31 + microvessels, which is consistent with previous findings. Interestingly, the family members with the SMAD3 mutation developed IgA nephropathy. Conclusion: Because the TGF-β/Smad signalling pathway plays an important role in the primary pathogenesis of IgA nephropathy and TAAD, we presume that IgA nephropathy could be a novel clinical phenotype of SMAD3 deficiency. Further accumulation of genetically proven cases with SMAD3 deficiency is needed to more accurately characterize phenotypic variability and elucidate a wide spectrum of TGF-β-associated disorders.

Context Inactivating variants of thyrotropin (thyroid-stimulating hormone; TSH) receptor (TSHR) cause congenital hypothyroidism. More than 60 such variants have been reported so far, most of which were located in the extracellular or transmembrane domain. Objective We report the identification and characterization of a frameshift TSHR variant in the intracytoplasmic C-tail region. Methods Sequencing of TSHR was performed in a patient with congenital hypothyroidism. The functionality of the identified variants was assessed by expressing TSHR in HEK293 cells and measuring TSH-dependent activation of the cAMP–response element-luciferase reporter. A series of systematic mutagenesis experiments were performed to characterize the frameshifted amino acid sequence. Results The proband was heterozygous for a known TSHR variant (p.Arg519His) and a novel frameshift TSHR variant (p.Val711Phefs*18), which removed 54 C-terminal residues and added a 17–amino acid frameshifted sequence. The loss of function of Val711Phefs*18-TSHR was confirmed in vitro, but the function of Val711*-TSHR was found to be normal. Western blotting showed the low protein expression of Val711Phefs*18-TSHR. Fusion of the frameshift sequence to green fluorescent protein or luciferase induced inactivation of them, indicating that the sequence acted as a degron. A systematic mutagenesis study revealed that the density of hydrophobic residues in the frameshift sequence determined the stability. Eight additional frameshift TSHR variants that covered all possible shifted frames in C-tail were created, and another frameshift variant (Thr748Profs*27) with similar effect was found. Conclusions We characterized a naturally occurring frameshift TSHR variant located in C-tail, and provided a unique evidence that hydrophobicity in the C-terminal region of the receptor affects protein stability.