Three Novel<i>IGSF1</i>Mutations in Four Japanese Patients With X-Linked Congenital Central Hypothyroidism

Nakamura, Akie; Bąk, Beata; Silander, Tanya L; Lam, Jessica; Hotsubo, Tomoyuki; Yorifuji, Tohru; Ishizu, Katsura; Bernard, Daniel J.; Tajima, Toshihiro

doi:10.1210/jc.2013-1224

Cited by 40 publications

(48 citation statements)

References 32 publications

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“…In serum, thyroid function tests showed TSH concentrations between 1.4 and 6.0 mU/l and decreased T 4 of 60-86% of the lower limit of reference. Three Japanese neonates were detected with a TSH between 1.2 and 2.7 mU/l and FT 4 between 0.68 and 0.79 ng/dl, while 2 patients (later identified) escaped neonatal detection with this method [13,14].…”

Section: Igsf1 Gene Defectsmentioning

confidence: 98%

“…Finally, early diagnosis and clinical follow-up of CCH would advance our knowledge of the natural behavior of infantile CH and put forward the identification of novel phenotypes of pituitary-hypothalamic disease, as exemplified by the recently unraveled IGSF1 defects [12][13][14][15], mostly characterized in Dutch and Japanese patients. Genetic investigations in families from other early diagnosed CCH patients may well uncover previously unknown molecular mechanisms for this clinically elusive disease.…”

Section: Neonatal Screening Programs For Central Congential Hypothyromentioning

confidence: 99%

“…Patients can variably show additional pituitary defects in prolactin and GH, which can be partial [12][13][14][15]. Delayed puberty and overweight have also been described in patients.…”

Section: Igsf1 Gene Defectsmentioning

confidence: 99%

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Central Hypothyroidism in Children

García

Fernández

Moreno³

2014

Paediatric Thyroidology

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Central congenital hypothyroidism (CCH) is an underdiagnosed disorder poorly described in childhood and adolescence. Congenital defects in thyroid-stimulating hormone (TSH) synthesis, secretion or bioactivity may lead to a state of 'regulatory' hypothyroidism expressed through aberrantly low or normal TSH levels and low thyroxine (T4), a hormonal pattern undetectable by TSH-based neonatal screening programs for congenital hypothyroidism (CH) implemented in most countries worldwide. CCH is more prevalent than previously thought, reaching 1 in 16,000 neonates in countries consistently identifying CCH through T4-based CH screening strategies. Neonatal detection and early treatment of CCH would prevent the risk of developing mental retardation secondary to late diagnosis of infantile hypothyroidism. CCH is frequently associated with other pituitary defects causing life-threatening situations (like e.g. adrenocorticotropic hormone deficiency) which could benefit from the early detection of CCH, avoiding considerable morbidity and mortality. CCH is not easy to identify clinically, and therefore few children are investigated for the disorder. The current knowledge on the genetic bases of CCH is also scarce. At the hypothalamic level no gene defects causing CCH have yet been identified in humans, but pituitary (thyrotrope)-selective genes encoding the TSH-releasing hormone (TRH) receptor (TRHR), the TSH β-subunit (TSHB) and, recently, the immunoglobulin superfamily factor 1 (IGSF1) are genes involved in isolated central hypothyroidism. Moreover, central hypothyroidism is a complex condition where many regulatory signals are implicated and converge to finely modulate the activity of the hypothalamic-pituitary-thyroid axis. This review focuses on novel pathogenic mechanisms and their implications to understand human CCH and improve the identification and the therapeutic handling of this elusive disease in the pediatric age.

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Section: Igsf1 Gene Defectsmentioning

confidence: 98%

Section: Neonatal Screening Programs For Central Congential Hypothyromentioning

confidence: 99%

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Central Hypothyroidism in Children

García

Fernández

Moreno³

2014

Paediatric Thyroidology

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“…He was born large for gestational age after an obstructed labour. All of the Japanese male IGSF1 mutation carriers reported by Tajima et al [3] and Nakamura et al [4] were born larger than the mean for gestational age. These findings suggest that overgrowth of the foetus could be one element of the phenotype of IGSF1 mutations.…”

Section: Introductionmentioning

confidence: 99%

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

et al. 2015

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Background: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism. Methods: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency. Result: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0). Conclusion: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation.

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“…Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked endocrine syndrome in males, characterized by congenital central hypothyroidism, delayed testosterone rise in puberty despite normal timing of testicular enlargement, adult macroorchidism, variable prolactin deficiency, partial GH deficiency in childhood and mildly increased IGF-1 levels in middle-aged adults, and/or obesity [1,2,3,4]. A small proportion of heterozygous females also show central hypothyroidism, prolactin deficiency, delayed menarche or obesity [2].…”

Section: Introductionmentioning

confidence: 99%

Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome

Joustra

Roelfsema²,

Endert³

et al. 2015

Neuroendocrinology

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Background: Loss-of-function mutations in immunoglobulin superfamily member 1 (IGSF1) cause an X-linked syndrome of central hypothyroidism, macroorchidism, delayed pubertal testosterone rise, variable prolactin deficiency and variable partial GH deficiency in childhood. The clinical features and gene expression pattern suggest a pivotal role for IGSF1 in the pituitary, but detailed knowledge on pituitary hormone secretion in this syndrome is lacking. We therefore aimed to study the 24-hour pituitary hormone secretion in male patients with IGSF1 deficiency. Methods: We collected blood samples every 10 min for 24 h in eight adult male IGSF1-deficient patients and measured circulating TSH, prolactin and gonadotropins. Deconvolution, modified cosinor and approximate entropy analyses were applied to quantify secretion rates, diurnal rhythmicity and regularity of hormone release. Results were compared to healthy controls matched for age and body mass index. Results: Compared to healthy controls, IGSF1-deficient patients showed decreased pulsatile secretion of TSH with decreased disorderliness and reduced diurnal variation. Basal and pulsatile secretion of FSH was increased by over 200%, while LH secretion did not differ from healthy controls. We observed a bimodal distribution of prolactin secretion, i.e. severe deficiency in three and increased basal and total secretion in the other five patients. Conclusion: The altered TSH secretion pattern is consistent with the previously hypothesized defect in thyrotropin-releasing hormone signaling in IGSF1 deficiency. However, the phenotype is more extensive and includes increased FSH secretion without altered LH secretion as well as either undetectable or increased prolactin secretion.

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Three NovelIGSF1Mutations in Four Japanese Patients With X-Linked Congenital Central Hypothyroidism

Abstract: Our findings provide additional genetic evidence that loss-of-function mutations in IGSF1 cause an X-linked form of C-CH and variable prolactin deficiency.

Cited by 40 publications

References 32 publications

Central Hypothyroidism in Children

Central Hypothyroidism in Children

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1

Pituitary Hormone Secretion Profiles in IGSF1 Deficiency Syndrome

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