The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism.

Background: Idiopathic hypogonadotropin hypogonadism (IHH) is caused by hypothalamic-pituitary-gonadal axis dysfunction. This is divided into Kallmann syndrome which has an impaired sense of smell and hypogonadotropin hypogonadism with normal olfactory (nIHH sense. Approximately 60% of patients are associated with Kallmann syndrome, whereas there are approximately 40% with hypogonadotropin hypogonadism (nIHH). This disease is associated with various variants in genes along with different phenotypic characteristics, and even those gene variations could also lead to the cancer formation in patients. So, current study has been designed to investigate and to better understand the characteristics of various IHH-associated genes and the correlation between IHH genes and phenotype. Methods: The cohort included 14 children with IHH (6 patients of KS and 8 patients of IHH), including 13 boys and 1 girl. Exclusion criteria are as follows: diagnosis of secondary hypogonadotropin hypogonadism due to tumor, trauma, drugs, or other systemic diseases. Clinical data and genetic results were analyzed. Results: Almost all male patients showed micropenis (12/13, 92.3%), and few of them had cryptorchidism (5/13, 41.7%). A total of 6 genes, CHD7, PROKR2, ANOS1, FGFR1, SEMA3A, and NDNF, were detected. CHD7 was the most common (11/17, 64.7%), and the main mutation type was missense mutation (14/16, 87.5%). Six reported variants and 10 new variants (5 genes, including entire ANSO1 duplicates) were found. Neonatal variation was detected in 3 patients with IHH. Eight patients inherited the variation from their father, while five patients inherited it from their mother. One patient had both FGFR1 and SEMA3A gene variants, while the other had two different CHD7 gene variants and entire ANSO1 repeats. According to ACMG criteria, 4 variants were pathogenic (P), 2 were possibly pathogenic (LP), and 8 had uncertain significance (US). In patients with P or LP (5/6, 83.3%), we found that extragonadal symptoms were more common. Conclusions: It was concluded that variations in the studied genes could lead to the IHH. Ten new variants have been reported which may lead to different symptoms of IHH. For CHD7 variants, the rare sequencing variants (RSVs) of P or LP showed commonly associated with CHARGE syndrome. Findings of the current study may help for the better diagnosis and treatment of IHH.

A patient with pseudohypoparathyroidism type 1A previously misdiagnosed as hereditary multiple exostosis: A case report.

Pseudohypoparathyroidism type 1A (PHP1A), a rare hereditary disorder, is featured by end-organ resistance to parathyroid hormone and Albright's hereditary osteodystrophy. Heterozygous mutation of guanine nucleotide-binding protein α stimulating (GNAS) gene causes the half decreased bioactivity of the Gsα protein levels. Due to the diverse early clinical manifestations of PHP1A, a diagnosis of PHP1A is often easily overlooked and misdiagnosis or missed diagnosis is common. The present study described a girl who was initially diagnosed with hereditary multiple exostoses, but was afterwards confirmed with PHP1A. Moreover, genetic analysis indicated a new mutation (c2277deIC) of the gene.

Combination of C-reactive protein, procalcitonin, IL-6, IL-8, and IL-10 for early diagnosis of hyperinflammatory state and organ dysfunction in pediatric sepsis.

BACKGROUND: Although early diagnosis and management are critical for prognosis of pediatric sepsis, there are no specific diagnostic biomarkers for the hyperinflammatory state and organ dysfunction, important stages of sepsis. METHODS: We enrolled 129 children with infection into three groups: non-sepsis infection (33), Sepsis 1.0 (hyperinflammatory state, 67), and Sepsis 3.0 (organ dysfunction, 29). Another 32 children with no infections were included as controls. Serum C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-α, and IFN-γ were assessed to diagnose the two stages, and their diagnostic capacities were evaluated using receiver operating characteristic (ROC) curves. We also examined whether combining biomarkers improved diagnostic efficiency. RESULTS: Significantly higher CRP, PCT, and IL-6 levels were detected in the Sepsis 1.0 than the non-sepsis infection group (p < 0.001). The areas under the curve (AUCs) for diagnosing Sepsis 1.0 were 0.974 (CRP), 0.913 (PCT) and 0.919 (IL-6). A combination of any two biomarkers increased diagnostic sensitivity to ≥92.54% and specificity to 100.00%. Significantly higher PCT, IL-8, and IL-10 levels were found in the Sepsis 3.0 than the Sepsis 1.0 group (p ≤ 0.01), with AUCs for diagnosing Sepsis 3.0 0.807 (PCT), 0.711 (IL-8), and 0.860 (IL-10). Combining these three biomarkers increased diagnostic sensitivity to 96.55% and specificity to 94.03%. CONCLUSION: In pediatric sepsis, combining any two of CRP, PCT, and IL-6 can accurately diagnose the hyperinflammatory state and increase diagnostic specificity. Early diagnosis of organ dysfunction requires a combination of PCT, IL-8, and IL-10.