Clinical and molecular features of idiopathic hypogonadotropic hypogonadism in Taiwan: A single center experience

Cho, Chih-Yi; Tsai, Wen–Yu; Lee, Cheng-Ting; Liu, Shih-Yao; Huang, Shu-Yuan; Chien, Yin‐Hsiu; Hwu, Wuh‐Liang; Lee, Ni‐Chung; Tung, Yung-Liang

doi:10.1016/j.jfma.2021.03.010

Cited by 13 publications

(21 citation statements)

References 28 publications

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“…We confirm that ocular malformations-coloboma, lens abnormalities, and microphthalmia-occur in SOX11 syndrome. [24][25][26][27] These are recapitulated in sox11 null zebrafish, confirming the specificity of the finding. 28 In our cohort, 10% of patients had oculomotor apraxia.…”

Section: Discussionsupporting

confidence: 74%

“…Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada; 4 Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom; 5 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; 6 16 Ambulanzzentrum UKSH, Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany; 17 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India; 18 Medical Genetics Laboratory, Bambino Gesu Children's Hospital, Rome, Italy; 19 Paediatric Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 20 Angers University Hospital Center, Angers, France; 21 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 22 Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; 23 EA7364 RADEME, Institute of Medical Genetics, Lille University Hospital, Lille University, Lille, France; 24 Faculty of Nutritional Science, Sagami Women's University, Sagamihara, Japan; 25 Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan; 26 Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; 27 Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; 28 Department of Orthopedic Surgery, Keio University School of Medicine, Keio University, Tokyo, Japan; 29 Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium; 30…”

Section: Author Informationmentioning

confidence: 99%

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SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Al‐Jawahiri

Kerkhof

McConkey

et al. 2022

Genetics in Medicine

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Section: Discussionsupporting

confidence: 74%

Section: Author Informationmentioning

confidence: 99%

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Al‐Jawahiri

Kerkhof

McConkey

et al. 2022

Genetics in Medicine

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“…There were very few female patients, only 1 case, and indeed no abnormal manifestations of secondary sexual characteristics. This is similar to previous reports [ 26 , 27 ]. After entering puberty, the female patient delayed menarche and was found to have ovarian teratoma, which has since been diagnosed.…”

Section: Resultssupporting

confidence: 94%

“…Among the 6 variants assessed as pathogenic or possibly pathogenic, 5 were CHD7 genes (83.3%), which was significantly different from many study cohorts. CHD7 accounted for 4% [ 33 ], 8.2% [ 34 ], and 26.7% [ 26 , 27 ] of the detected genes in multiple cohorts. CHD7 is a large nucleoprotein containing two N-terminal chromosomal domains, a central Snf2-like ATPASE and helicase domain, a histone/DNA binding SANT domain, and two C-terminal BRK domains.…”

Section: Resultsmentioning

confidence: 99%

The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

Zhang

Yang

Zou

2022

Journal of Oncology

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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.

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“…We compared the clinical phenotypes of our patients with those previously reported (Tsurusaki et al, 2014;Hempel et al, 2016;Khan et al, 2018;Okamoto et al, 2018;Sekiguchi et al, 2019;Diel et al, 2021;Wakim et al, 2021;Al-Jawahiri et al, 2022;Cho et al, 2022), which have been summarized by Al-Jawahiri et al (Al-Jawahiri et al, 2022). Although the clinical features of the three Chinese patients were variable, they still fell within the spectrum of SOX11 syndrome (Table 1).…”

Section: Clinical Description Of the Patientsmentioning

confidence: 85%

Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9

et al. 2022

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SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS.

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Clinical and molecular features of idiopathic hypogonadotropic hypogonadism in Taiwan: A single center experience

Cited by 13 publications

References 28 publications

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9

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