Isolated Central Hypothyroidism in Short Stature

Rose, Susan R.

doi:10.1203/00006450-199512000-00023

Cited by 55 publications

(23 citation statements)

References 12 publications

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“…The clinical manifestations of central hypothyroidism are usually mild, especially when it is isolated (1). Indeed, in our patient, the only presenting symptoms were short stature with markedly delayed bone maturation, which shows the exquisite sensitivity of these markers of hypothyroidism in children (18). It is uncertain whether the TRH-R gene defect is causally related to our patient's cognitive deficiencies, as his two unaffected brothers had similar learning difficulties and subnormal I.Q.…”

Section: Discussionmentioning

confidence: 90%

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

Collu¹,

Tang²,

Castagné³

et al. 1997

The Journal of Clinical Endocrinology & Metabolism

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Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients' genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5Ј-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established. (J Clin Endocrinol Metab 82: 1361-1365, 1997) C ENTRAL hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder with an estimated frequency of 0.005% in the general population; most cases are associated with other pituitary deficiencies and are due to tumors or infiltrative diseases of the hypothalamic-pituitary area or to pituitary atrophy (1). Isolated central hypothyroidism due to mutations of the TSH ␤-subunit has been described (2, 3). On the other hand, inactivating mutations of receptors for hypothalamic hormones can also lead to pituitary hormone deficiencies, as recently reported for the GHRH receptor (4).We report a patient with central hypothyroidism whose plasma TSH and PRL levels did not rise after the administration of TRH. He was found to be a compound heterozygote, having inherited from each parent a different mutation in the TRH receptor gene. Both mutations resulted in a receptor with reduced or absent biological activity. Case ReportThe propositus, the second of three sons born to nonconsanguineous Caucasian parents, was referred for evaluation of short stature at 8.9 yr of age. His clinical history was unremarkable except for poor school performance. On examination, his height was 115.2 cm (Ϫ2.6 sd), his weight was 23.0 kg (Ϫ0.4 sd), and his heart rate was 64 beats/min without other signs of hypothyroidism. The bone age was 4 yr (Ϫ4.1 sd). Plasma T 4 was 4.0 g/dL (52 nmol/L; normal, 4.5-11.5 g/dL), and TSH was 1.3 mU/L (normal, 0.1-5.0). A retrospective verification of T 4 and TSH values obtained at neonatal screening revealed that the T 4 value, at 4.9 g/dL...

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Section: Discussionmentioning

confidence: 90%

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

Collu¹,

Tang²,

Castagné³

et al. 1997

The Journal of Clinical Endocrinology & Metabolism

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“…In children with documented mild CH and short stature, increasing serum FT 4 from the lower third to near the upper third of the normal reference interval during 6 months significantly increases growth velocity (108 4 to be in the mid-normal or in the upper part of the reference range, which was supported in another study (111). In this study, it was observed that CH patients on empirical T 4 doses (1G0.05 mg/kg per day) had worse outcome in terms of BMI, total-, LDL-, and HDL-cholesterol than patients on a body weight-guided dosing (1.6 mg/kg per day) (111).…”

Section: Central Hypothyroidismmentioning

confidence: 99%

GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies

Filipsson

Johannsson

2009

European Journal of Endocrinology

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Severe GH deficiency (GHD) in adults has been described as a clinical entity. However, some of the features associated with GHD could be due to unphysiological and inadequate replacement of other pituitary hormone deficiencies. This may be true for glucocorticoid replacement that lacks a biomarker making dose titration and monitoring difficult. Moreover, oral estrogen replacement therapy decreases IGF1 levels compared with the transdermal route, which attenuates the responsiveness to GH replacement therapy in women. In addition, in untreated female hypogonadism, oral estrogen may augment the features associated with GHD in adult women. Important interactions between the hormones used for replacing pituitary hormone deficiency occur. Introducing GH replacement may unmask both an incipient adrenal insufficiency and central hypothyroidism. Therefore, awareness and proper monitoring of these hormonal interactions are important in order to reach an optimal replacement therapy. This review will focus on the complex hormonal interactions between GH and other pituitary hormones in GHD and in GH replacement. European Journal of Endocrinology 161 S85-S95

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“…[10][11][12]15 Finally, the low-dose ACTH test also has good normative data and has been validated in metanalysis. 13,14 In our study, growth velocity data were not available.…”

Section: Discussionmentioning

confidence: 99%

“…Patients who had low GH screening later underwent GH stimulation tests. Children weighing 15 kg or more had the following samples obtained for hormone profile evaluation: serum GH every 20 min from 10:00 pm to 4:00 am 9 ; nocturnal thyrotropin (TSH) surge with serum TSH hourly from 2:00 pm to 6:00 pm and 10:00 pm to 4:00 am [10][11][12] ; firstmorning and low-dose ACTH-stimulated cortisol 13,14 ; insulin-like growth factor 1 (IGF-1); IGF-binding protein 3 (IGFBP3); free thyroxine (FT4); prolactin (PRL); and 12-h fasting serum and urine osmolality (total blood volume, 39 mL, 2.6 mL/kg or less). IGF-1 was not performed in younger children because the normal range for IGF-1 in children younger than 4 years overlaps with the ranges observed in GH deficiency (GHD).…”

Section: Methodsmentioning

confidence: 99%

Hypopituitarism in Pediatric Survivors of Inflicted Traumatic Brain Injury

Auble

Bollepalli

Makoroff

et al. 2014

Journal of Neurotrauma

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Endocrine dysfunction is common after accidental traumatic brain injury (TBI). Prevalence of endocrine dysfunction after inflicted traumatic brain injury (iTBI) is not known. The aim of this study was to examine endocrinopathy in children after moderate-to-severe iTBI. Children with previous iTBI (n = 14) were evaluated for growth/endocrine dysfunction, including anthropometric measurements and hormonal evaluation (nocturnal growth hormone [GH], thyrotropin surge, morning and low-dose adrenocorticotropin stimulated cortisol, insulin-like growth factor 1, IGF-binding protein 3, free thyroxine, prolactin [PRL], and serum/urine osmolality). Analysis used Fisher's exact test and Wilcoxon's rank-sum test, as appropriate. Eighty-six percent of subjects had endocrine dysfunction with at least one abnormality, whereas 50% had two or more abnormalities, significantly increased compared to an estimated 2.5% with endocrine abnormality in the general population ( p < 0.001). Elevated prolactin was common (64%), followed by abnormal thyroid function (33%), short stature (29%), and low GH peak (17%). High prolactin was common in subjects with other endocrine abnormalities. Two were treated with thyroid hormone and 2 may require GH therapy. In conclusion, children with a history of iTBI show high risk for endocrine dysfunction, including elevated PRL and growth abnormalities. This effect of iTBI has not been well described in the literature. Larger, multi-center, prospective studies would provide more data to determine the extent of endocrine dysfunction in iTBI. We recommend that any child with a history of iTBI be followed closely for growth velocity and pubertal changes. If growth velocity is slow, PRL level and a full endocrine evaluation should be performed.

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Isolated Central Hypothyroidism in Short Stature

Cited by 55 publications

References 12 publications

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies

Hypopituitarism in Pediatric Survivors of Inflicted Traumatic Brain Injury

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Isolated Central Hypothyroidism in Short Stature

Cited by 55 publications

References 12 publications

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene1

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene1

GH replacement in adults: interactions with other pituitary hormone deficiencies and replacement therapies

Hypopituitarism in Pediatric Survivors of Inflicted Traumatic Brain Injury

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Product

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A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹