Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β‐subunit of the insulin receptor (<i>INSR</i>) gene

Takasawa, Kei; Tsuji‐Hosokawa, Atsumi; Takishima, Shigeru; Wada, Yasunori; Nagasaki, Keisuke; Dateki, Sumito; Numakura, Chikahiko; Hijikata, Atsushi; Shirai, Tomoyuki; Kashimada, Kenichi; Morio, Tomohiro

doi:10.1111/1753-0407.12797

Cited by 14 publications

(10 citation statements)

References 44 publications

(170 reference statements)

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“…The heterozygous missense mutation c.3601C>T in exon 20 of the INSR gene causes the arginine at amino acid position 1201 in the encoded protein to be mutated to tryptophan. This mutation has been confirmed in previous reports to lead to decreased affinity of INSR for insulin and downregulation of tyrosine kinase activity [9, 10].…”

Section: Discussionsupporting

confidence: 80%

“…Severe IR leads to impaired glucose regulation and eventually to diabetes. After female patients enter puberty, severe hyperinsulinemia stimulates the secretion of ovarian androgen, which causes primary amenorrhea, polycystic ovaries, and other manifestations [10]. Even with the same type of mutation at the same site of the INSR gene, the IR level is usually relatively mild in male patients [13], as was true in the male patients in the family reported in this article.…”

Section: Discussionmentioning

confidence: 93%

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Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

et al. 2019

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BackgroundType A insulin resistance syndrome, one type of the hereditary insulin resistance syndromes, is a rare disorder. Patients with type A insulin resistance syndrome are nonobese and demonstrate severe hyperinsulinemia, hyperandrogenism, and acanthosis nigricans. The clinical features are more severe in affected females than in males, and they mostly become apparent at the age of puberty. In many cases, when severe insulin resistance is covered up by other signs or symptoms of type A insulin resistance syndrome, patients are often easily misdiagnosed with other diseases, such as polycystic ovary syndrome.Case presentationOur patient was a 27-year-old Han Chinese woman who sought treatment because of a menstrual disorder and hirsutism. Tests showed that her levels of insulin and testosterone were elevated, and gynecological color Doppler ultrasound suggested multiple cystic changes in the bilateral ovaries. After a diagnosis of polycystic ovary syndrome was made, pulsatile gonadotropin-releasing hormone therapy and metformin were administered, but the patient’s symptoms did not improve in 1 year of follow-up. Considering that the previous diagnosis might have been incorrect, venous blood samples were collected from the patient and her relatives for genetic analysis. Subsequently, using Illumina sequencing, it was found that the proband, her father, and two brothers all had the c.3601C>T heterozygous missense mutation in exon 20 of the insulin receptor gene. The diagnosis was corrected to type A insulin resistance syndrome, and the patient’s treatment was modified.ConclusionWe report a case of a young woman with type A insulin resistance syndrome that was misdiagnosed as polycystic ovary syndrome. We discuss the causes, clinical features, diagnosis, and treatment of type A insulin resistance syndrome to improve the recognition of the disease and reduce its misdiagnosis. Female patients with high androgen levels and severe hyperinsulinemia should be considered for the possibility of hereditary insulin resistance syndromes (such as type A insulin resistance syndrome). Gene sequencing helps in making an early diagnosis and developing a targeted treatment strategy.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 93%

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

et al. 2019

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“…This receptor binds insulin or other ligands to activate the insulin signaling pathway, and subsequently regulates glucose uptake and release and is involved in lipids synthesis and storage. Loss-of-function mutations in this gene cause severe insulin resistance syndromes manifested by several studies 19 , 20 .…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of the INSR gene as a mediator of the association between prenatal exposure to famine and adulthood waist circumference

Wang

Song

et al. 2020

Sci Rep

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The aims of this study were to explore whether DNA methylation at INSR and IGF2 mediated the association of prenatal exposure to the Chinese great famine with adulthood waist circumference (WC) and BMI. A total of 235 subjects were selected into the present study from severely affected province and a neighbor province with less severely affected famine in China through multi-stage clustered random sampling. DNA methylation at the INSR and IGF2 gene promoter regions was detected by the Sequenom’s MassARRAY system. The “mediation” package of R was used to evaluate the mediation effect of DNA methylation on the association between prenatal exposure to the famine and adult WC and BMI. The results showed that prenatal famine exposure was significantly associated with higher overall methylation level of the INSR gene ( d = 3.6%; 95% CI 1.2–6.0; P = 0.027) and larger adulthood WC ( d = 2.72 cm; 95% CI 0.20–5.24; P = 0.034). Furthermore, famine significantly increased methylation levels at four CpG sites. Methylation of the CpG7 site mediated 32.0% (95% CI 5.0–100.0%, P = 0.029) of the association between prenatal exposure to the Chinese great famine and adulthood WC. In conclusion, Epigenetic changes to the INSR might mediate the adverse effect of prenatal famine exposure on WC in adulthood.

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“…Type A insulin resistance syndrome is also a rare severe insulin resistance syndrome caused by mutations in INSR. Heterozygous and, in some cases, homozygous INSR mutations impair insulin receptor function and signal transduction (43)(44)(45). Individuals with type A insulin resistance syndrome can live beyond middle age (34).…”

Section: Lipodystrophiesmentioning

confidence: 99%

Severe insulin resistance syndromes

Angelidi¹,

Filippaios²,

Mantzoros³

2021

Journal of Clinical Investigation

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Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β‐subunit of the insulin receptor (INSR) gene

Abstract: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.

Cited by 14 publications

References 44 publications

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

Type A insulin resistance syndrome misdiagnosed as polycystic ovary syndrome: a case report

DNA methylation of the INSR gene as a mediator of the association between prenatal exposure to famine and adulthood waist circumference

Severe insulin resistance syndromes

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