A boy with overgrowth caused by multi-locus imprinting disturbance including hypomethylation of MEST:alt-TSS-DMR.

Most imprinting disorders (IDs) entail growth abnormalities. Some patients with IDs caused by epimutation have multi-locus imprinting disturbance (MLID) showing aberrant methylation patterns in multiple differentially methylated regions (DMRs). Patients with MLID often have typical ID-specific symptoms. However, certain MLID cases have only non-specific symptoms, and it is necessary to clarify the association between their clinical features and the affected DMRs. We report a case of MLID presenting with overgrowth and temporarily impaired glucose tolerance. Genome-wide methylation analysis for the DMRs revealed hypomethylation of PLAGL1:alt-TSS-DMR, MEST:alt-TSS-DMR, and other DMRs. Because no MEST expression and increased PLAGL1 expression cause growth failure and transient neonatal diabetes mellitus, hypomethylation of MEST:alt-TSS-DMR and PLAGL1:alt-TSS-DMR may have caused overgrowth and temporary impaired glucose tolerance in our case. In cases with multiple non-specific ID-related symptoms, such as growth abnormalities, psychomotor developmental delay, and mild glucose metabolic disorders, multi-locus methylation analysis needs to be considered.

Peripheral precocious puberty in a girl with an intracranial hCG-producing tumor: case report and literature review.

Human chorionic gonadotropin (hCG)-producing tumors cause peripheral precocious puberty (PP) in boys, but generally not in girls. Homology between LH and hCG activates the LH receptor in testicular Leydig cells, increases testosterone production, and causes virilization. However, since FSH action is required for follicle development, hCG action alone does not increase estradiol (E2) production and does not cause feminization. Only a few cases of peripheral PP with hCG tumors in girls have been reported. We describe the case of a 7-year-old Japanese girl with peripheral PP associated with an hCG-producing tumor. She had prolonged vomiting, loss of appetite, and Tanner stage III breast development. Although no apparent increase in growth rate, bone age was advanced at 9.8 years. Serum E2 was slightly elevated and LH and FSH were below the measurement sensitivity, and abdominal ultrasonography and computed tomography images showed no abnormal findings in the uterus or ovaries. Subsequently, she developed visual field disturbance and loss of consciousness, and brain magnetic resonance imaging revealed an intracranial tumor. Based on pathological findings and abnormally high serum hCG-ß level (48,800 IU/L), intracranial choriocarcinoma was diagnosed. 2.5 months after the start of chemotherapy, the hCG-ß level became almost negative and the breast development disappeared synchronously. Tissue immunostaining of the tumor showed strong positivity for aromatase and hCG, indicating that the choriocarcinoma cells themselves may have produced estrogen via aromatase. This unique case highlights the possibility that hCG-producing tumors can cause peripheral PP in girls as well as boys.

Re-Evaluation of the Prevalence of Permanent Congenital Hypothyroidism in Niigata, Japan: A Retrospective Study.

Although newborn screening (NBS) for congenital hypothyroidism (CH) in Japan started more than 40 years ago, the prevalence of CH remains unclear. Prevalence estimations among NBS-positive CH individuals include those with transient hypothyroidism and transient hyperthyrotropinemia, and re-evaluation with increasing age is necessary to clarify the actual incidence. Thus, we re-evaluated the incidence of permanent CH. Of the 106,114 patients who underwent NBS in the Niigata Prefecture, Japan, between April 2002 and March 2006, 116 were examined further due to high thyroid-stimulating hormone levels (>8 mIU/L) and were included in the study. We retrospectively evaluated their levothyroxine sodium (LT4) replacement therapy status from the first visit to 15 years of age. Of the 116 NBS-positive patients, 105 (91%) were initially examined in our department. Of these, 72 (69%) started LT4 replacement therapy on the first visit. Subsequently, 27 patients continued LT4 replacement until 15 years of age after multiple re-evaluations. The prevalence of permanent CH in the Niigata Prefecture during this period was 1 in 2500-3500 children. Ultimately, 62.5% of patients on LT4 replacement discontinued treatment by 15 years of age. This is the first study to clarify the true prevalence of permanent CH in Japan.

Regulation of Serum Sodium Levels during Chemotherapy Using Selective Arginine Vasopressin V2-Receptor Antagonist Tolvaptan in a Four-Year-Old Girl with a Suprasellar Germ Cell Tumor.

There are limited reports on the use of tolvaptan for syndrome of inappropriate antidiuretic hormone secretion (SIADH) in children. Managing serum sodium levels in SIADH patients during chemotherapy is often difficult because of the need for massive fluid infusions. We report the course of the use of tolvaptan for the treatment of hyponatremia during chemotherapy in a four-year-old girl with a suprasellar germ cell tumor. The patient was a Japanese girl who presented with left ptosis with a mass in the pituitary gland and cavernous sinus. She was diagnosed with an intermediate-grade germ cell tumor and was treated with carboplatin and etoposide combination chemotherapy. She developed hyponatremia due to SIADH caused by intravenous infusion therapy before chemotherapy. Subsequently, tolvaptan (3.25 mg; 0.20 mg/kg/dose) was administered orally to control serum sodium levels. After 4 h of administration, a marked increase in urine volume of up to 15 mL/kg/h was observed, and serum sodium level increased from 126 to 138 mEq/L after 10 h of tolvaptan administration, followed by a decrease in urine volume. The use of tolvaptan in pediatric patients with SIADH who require intravenous hydration during chemotherapy can be useful for the management of serum sodium balance.

A Japanese Family with DICER1 Syndrome Found in Childhood-Onset Multinodular Goitre.

INTRODUCTION: Germline DICER1 mutations have recently been identified in familial multinodular goitre (MNG). The natural history of thyroid nodules in DICER1 carriers in children is unclear. The purpose of this study was to describe the clinical and genetic findings of childhood-onset MNG with DICER1 carrier in a patient who underwent total thyroidectomy. CASE PRESENTATION: The 6-year-old proband had a thyroid nodule, and the number and size of nodules increased over 3 years. A total thyroidectomy was chosen because of the rapid rise in thyroglobulin levels, discomfort when swallowing, and the mother's history of poorly differentiated thyroid cancer (PDTC). Histopathology revealed adenomatous goitre without malignant cells. Her mother, maternal aunt, and maternal grandmother also had thyroid nodules removed during adolescence. Also, her mother had PDTC with lung metastases, and her maternal aunt had an ovarian germ cell tumour. DICER1 mutation analysis identified a heterozygous novel nonsense mutation (c.4509C>G, p.Y1503X) for the patient, her mother, her maternal grandmother, and her asymptomatic elder brother. Y1503X was identified in all resected thyroid tissues, while heterozygous D1709G, D1810V, and E1813K mutations were identified in individual nodules. DISCUSSION/CONCLUSION: A thyroid nodule was detected in chemotherapy- or radiotherapy-naïve patient with DICER1 carrier aged 6 years, and MNG developed over 3 years. This pedigree highlights the natural history of nodular disease in DICER1 carriers and identifies a possible association between DICER1 and more aggressive malignancies.

Timing of hyponatremia development in patients with salt-wasting-type 21-hydroxylase deficiency.

Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10-14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.

Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.

Omodysplasia-2 (OMOD2; OMIM%16475) is a rare autosomal dominant (AD) skeletal dysplasia characterized by shortened humeri, short first metacarpal, craniofacial dysmorphism (frontal bossing, depressed nasal bridge, bifid nasal tip, and long philtrum), and variable degrees of genitourinary anomalies. This clinical phenotype overlaps with that of AD type Robinow syndrome. Recently, a mutation in FZD2 encoding a Frizzled Class Receptor 2 has been identified in a family with AD omodysplasia (an affected girl and her affected mother). Here, we present the second report on a heterozygous novel nonsense FZD2 mutation in OMOD2 or Robinow syndrome-like phenotype. The proband was a 16-year-old boy, who has been followed from infancy to adolescence. He presented with rhizomelic short stature with elbow restriction, mild facial dysmorphism (depressed broad bridge, short nose, anteverted nostrils, long philtrum, and low-set ears), and genital hypoplasia. Radiological examination in infancy showed short, broad humeri with relatively narrow distal ends, mildly broad femora, thick proximal ulnae with hypoplastic, dislocated proximal radii, and short first metacarpals. The abnormal skeletal pattern was persistent in adolescence; however, the humeri and femora became less undermodeled, while the humeri and radii became mildly bowed. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2. The affected codon was next to the previously reported mutation (p.Trp548*). The results indicate that OMOD2 or Robinow syndome-like phenotype can be caused by a heterozygous nonsense FZD2 mutation impairing Wnt signaling. Further molecular studies will permit better clarification of the phenotypic spectrum in patients with OMOD2.

Predicting factors of plural hospitalization with pneumonia in low-birthweight infants.

BACKGROUND: Children with a history of low birthweight (LBW) are often hospitalized with plural episodes of pneumonia after discharge from the neonatal intensive care unit. The aim of this study was to clarify the multiple factors predisposing them to developing three or more hospitalizations with pneumonia and whether the factors are related to their own prematurity. We also aimed to determine a predictable numerical formula for three or more episodes. METHODS: Fourteen patients with two hospitalizations with pneumonia were grouped into group A. Fourteen patients with at least three episodes during the same investigation period were grouped into group B. The quantification theory type III was employed to investigate the similarities among the items and the gravity of each attribution in the two groups. To evaluate the items of discrimination of both groups, six items were analyzed by the quantification theory type II. RESULTS: The dominant order of items contributing to the grouping was as follows: methicillin-resistant staphylococcus aureus detection (partial correlation coefficient = 0.5284), asthmatic attack (partial correlation coefficient = 0.4138), severe motor and intellectual disability, Haemophilus influenzae, accompanying diseases and chronic lung disease. A predicting numerical formula was attained from these results. The success rate of discrimination was 85.7%. The six items seemed to be related to the patients' own prematurity. CONCLUSIONS: The authors emphasize that plural hospitalizations with pneumonia in the patients with LBW might be caused by the combined influence of six clinical factors as well as their own prematurity.