Two siblings with congenital central hypothyroidism caused by a novel mutation in the &lt;i&gt;IGSF1&lt;/i&gt; gene

Oguma, Makiko; Kobayashi, Mizuki; Yamazaki, Masayo; Yokoyama, Koji; Morikawa, Shuntaro; Yamaguchi, Takeshi; Yamagata, Takanori; Tajima, Toshihiro

doi:10.1297/cpe.27.95

Cited by 6 publications

(8 citation statements)

References 16 publications

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“…We present a male index case with CeH, premature testicular growth, and severe, early-onset obesity, associated with a hemizygous nonsense variant in IGSF1 [c.3411_3412del, p.(Tyr1137*)], as well as variable phenotypes observed in four male relatives carrying the variant, including normal fT4 concentrations. The large variation in clinical and biochemical findings in affected males in this pedigree shows that the phenotype of IGSF1 deficiency is even broader than has so far been reported ( 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ), and may include a serum fT4 concentration above the lower limit of the reference range, premature testicular growth and severe early-onset obesity.…”

Section: Introductionmentioning

confidence: 75%

“…In this family, there are three clinical observations that are unusual when compared to previously reported families. First, in virtually all patients with IGSF1 deficiency reported to date, the serum fT4 concentration is decreased in combination with a normal or low serum TSH, while the occurrence of other clinical and laboratory features is more variable ( 4 , 7 , 8 , 9 , 10 , 11 , 12 , 14 , 16 , 17 , 18 ). Serum fT4 levels have been reported to be just above the lower limit of reference range ( 13 , 15 ) or fluctuating around it ( 19 ) in only two and one male patients, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of this protein in the human male causes X-linked CeH, disharmonious pubertal development (normal timing of testicular growth, but delayed rise of testosterone) and macroorchidism. In a variable proportion of affected males other features are observed, including prolactin deficiency, partial and transient growth hormone (GH) deficiency in childhood, increased body mass index (BMI), and decreased attentional control ( 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ). Mean follicle stimulating hormone (FSH) and GH secretion are increased in some affected males ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

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The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Ghanny

Zidell

Pedro

et al. 2021

Jcrpe

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Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband’s brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Ghanny

Zidell

Pedro

et al. 2021

Jcrpe

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“…To date, in Japan, 10 patients described in six publications within the medical literature have been identified (28,29,30, 32, 38, 39). Clinical features and endocrine findings are summarized in Table 3…”

Section: Igsf1 Deficiencymentioning

confidence: 99%

Recent advances in research on isolated congenital central hypothyroidism

Tajima

Nakamura

Oguma

et al. 2019

Clin Pediatr Endocrinol

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. Congenital central hypothyroidism (C-CH) is caused by defects in the secretion of thyrotropin-releasing hormone (TRH) and/or TSH, leading to an impairment in the release of hormones from the thyroid. The causes of C-CH include congenital anomalies of the hypothalamic-pituitary regions and several genetic defects. In terms of endocrinology, C-CH is divided into two categories: ( 1 ) accompanied by another pituitary hormone deficiency and called combined pituitary hormone deficiency, and ( 2 ) isolated C-CH, showing mainly TSH deficiency. For isolated C-CH, a mutation in the TSH gene ( TSHB ) encoding the β-subunit of the protein was first found in 1990 by Japanese researchers, and thereafter several mutations in TSHB have been reported. Mutations in the thyrotropin-releasing hormone receptor gene ( TRHR ), as well as genetic defects in immunoglobulin superfamily 1 ( IGSF1 ), have also been identified. It was recently found that isolated C-CH is caused by mutations in transducin β-like 1 X-linked and insulin receptor substrate 4. It is noted that all patients with TSHB deficiency and some with IGSF1 deficiency show severe hypothyroidism soon after birth. Among the causes of C-CH, high frequency of mutations in IGSF1 is the most prevalent. This review focuses on recent findings on isolated C-CH.

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“…The risk factors for neonatal hypothyroidism vary and have been reported to include increased gestational age at birth and birth weight. Neonates who had a premature birth, low birth weight, post-term birth and fetal macrosomia are at a higher risk of hypothyroidism compared with neonates born at term (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Combined use of thyroid stimulating hormone plus free thyroxine levels and gestational age at birth for the prediction of neonatal hypothyroidism and associated risk factors

Cheng

2020

Exp Ther Med

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The present study aimed to explore the effectiveness of the combined use of thyroid-stimulating hormone (TSH) and free thyroxine [(FT4); TSH+FT4] levels and gestational age at birth to predict neonatal hypothyroidism and to identify the risk factors associated with the disease. The clinical data of 686 neonates with suspected hypothyroidism (TSH >10 mIU/l) who were admitted to The First Affiliated Hospital of Chongqing Medical University were retrospectively analyzed. From these, 70 neonates with confirmed hypothyroidism were assigned to the patient group and another 70 neonates with normal thyroid function to the normal (control) group. Sex, gestational age at birth, Apgar score, birth weight, body length, head circumference and heart rate data were collected. TSH and FT4 levels were measured by electrochemiluminescence immunoassay, and the predictive value of combined use of TSH+FT4 and gestational age at birth on neonatal hypothyroidism was analyzed. The prespecified secondary outcomes were the risk factors for neonatal hypothyroidism determined using univariate and logistic regression analyses. TSH levels were significantly higher, whereas FT4 levels were lower in the patient group at 3 days of age compared with the control group (P<0.05). After 8-week treatment with thyroxine, these levels were not significantly different between the patient and control groups (P<0.05). The combined use of TSH+FT4 levels and gestational age at birth to predict neonatal hypothyroidism demonstrated a significantly improved sensitivity, specificity, accuracy, positive predictive value and negative predictive value (92.86, 97.26, 96.76, 81.25 and 99.07%, respectively) compared with the use of only TSH+FT4 levels (P<0.05). Logistic regression analysis revealed a low gestational age at birth, maternal thyroid dysfunction and low birth weight were risk factors for neonatal hypothyroidism (P<0.05). The combined use of TSH+FT4 levels and gestational age at birth resulted in an improved prediction of neonatal hypothyroidism and contributed to early therapeutic intervention. Thus, special intervention is necessary for pregnant women with thyroid dysfunction to reduce the incidence of neonatal hypothyroidism.

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Two siblings with congenital central hypothyroidism caused by a novel mutation in the <i>IGSF1</i> gene

Cited by 6 publications

References 16 publications

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Recent advances in research on isolated congenital central hypothyroidism

Combined use of thyroid stimulating hormone plus free thyroxine levels and gestational age at birth for the prediction of neonatal hypothyroidism and associated risk factors

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