Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

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BackgroundEpidemiological studies in Kawasaki disease (KD) have suggested infectious aetiology. During the COVID-19 pandemic, measures for mitigating SARS-CoV-2 transmission also suppress the circulation of other contagious microorganisms. The primary objective is to compare the number and incidence of KD before and during the COVID-19 pandemic in Japan, and the secondary objective is to investigate temporal association between the KD epidemiology and activities of SARS-CoV-2 and other viral and bacterial infections.MethodsA retrospective cohort study was conducted between 2016 and 2020 in Kobe, Japan. We collected information of hospitalised KD children in Kobe. Child population was identified through the resident registry system. Activity of COVID-19 and 11 other infectious diseases was derived from a public health monitoring system. Monthly change of KD incidence was analysed using a difference-in-difference regression model.ResultsThroughout the study period, 1027 KD children were identified. KD had begun to decline in April 2020, coinciding with the beginning of the COVID-19 pandemic. The number of KD cases (n=66) between April and December 2020 was 40% of the average in the same period in 2016–2019 (165/year). Annual KD incidence was 315, 300, 353, 347 and 188/100 000 children aged 0–4 years in 2016–2020, respectively. The difference-in-difference value of KD incidence was significantly reduced in the fourth quarter in 2020 (−15.8, 95% CI −28.0 to −3.5), compared with that in 2016–2019. Sentinel surveillance showed a marked decrease of all infectious diseases except exanthema subitum after the beginning of the COVID-19 pandemic. There were 86 COVID-19 cases aged <10 years and no KD children associated with COVID-19.ConclusionThis study showed that the number and incidence of KD was dramatically reduced during the COVID-19 pandemic in Japan. This change was temporally associated with decreased activities of various infectious diseases other than COVID-19, supporting the hypothesis of infection-triggered pathogenesis in KD.

ABSTRACT. We describe 3 infants who were born to mothers with Graves' disease and developed central hypothyroidism that persisted for >6 months after birth. Two were preterm infants, and the other was a term infant who was born to a euthyroid mother who had been treated with an antithyroid drug since week 31 of gestation. These cases suggest that passage of thyroid hormones can occur from a thyrotoxic mother to the fetus and that the gestational period earlier than 32 weeks may be the critical time for development of central hypothyroidism. O nly a minority of newborns from mothers with Graves' disease develop central hypothyroidism. 1 In these cases, free thyroxine (T 4 ) levels at birth were higher than those at 5 days of age, suggesting that the fetal T 4 level was higher than that in the period immediately after birth, probably as a result of passive transfer from the mother during the last trimester. 2 The major negative feedback effect of thyroid hormones on thyrotropin (TSH) secretion is mediated by serum free T 4 , which is monodeiodinated to triiodothyronine (T 3 ) by type II deiodinase in the hypothalamus and pituitary thyrotroph cells. Undetectable TSH in the fetal cord serum in the presence of markedly elevated free T 4 (FT 4 ) suggests pituitary negative feedback at as early as 20 weeks' gestation. 3 The exposure of the fetal hypothalamic-pituitary-thyroid system to a higherthan-normal thyroid hormone concentration might impair its physiologic maturation, because there is a continuous significant decrease in the TSH/FT 4 ratio during development from the midgestational fetus to the young adult. 4 Since 1997, we have experienced 3 cases of central hypothyroidism, as described below, and on the basis of these cases, we conclude that the gestational period earlier than 32 weeks may be the critical time for development of central hypothyroidism in offspring. CASE REPORTS Case 1A male infant was born at 27 weeks of gestation with a birth weight of 1152 g (0.3 SD). His 27-year-old gravida 2, para 0 (G2P0) mother had received a diagnosis of Graves' disease at the age of 13 years. However, she had been noncompliant with medication, and premature rupture of membranes occurred at 27 weeks and 2 days of gestation. A nonstress test revealed fetal tachycardia Ͼ200 beats/min. The mother was transferred to our hospital because of the possibility of preterm labor and abruptio placenta. Her thyroid function was as follows: free T 3 (FT 3 ) 21.1 pg/mL, FT 4 8.1 ng/dL, and TSH Ͻ0.03 IU/mL on the day when premature rupture of membranes occurred. The TSH receptor antibody (TRAb) level was 52% (normal: Ͻ15%), and the thyroid-stimulating antibody (TSAb) level was 294% (normal: Ͻ180%).The infant was born via cesarean section on the day the mother was transferred to our hospital. TRAb in the cord blood was 16%, and the infant showed tachycardia at ϳ200 beats per minute after birth, with the following hyperthyroid function 1 hour after birth: FT 3 7.0 pg/mL, FT 4 4.7 ng/dL, and TSH 0.12 IU/mL. Tachycardia and hyperthyroid fu...