Glomerulosa Failure in Congenital Adrenocortical Unresponsiveness to Acth

Davidai, Giora; Kahana, Luna; Hochberg, Zèev

doi:10.1111/j.1365-2265.1984.tb00098.x

Cited by 22 publications

(18 citation statements)

References 10 publications

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“…Hypothyroidism was detected through the national neonatal screening program and showed high blood TSH and low total thyroxine (T4) values. These were confirmed by serum measurements of TSH greater than 100 mU/L (normal range 0.5-6) and free thyroxine (FT4) of 1.2-7.0 pmol/L (normal [11][12][13][14][15][16][17][18][19][20][21][22][23][24] prior to the institution of treatment with levothyroxine (LT4) (Fig. 1).…”

Section: Patientsmentioning

confidence: 88%

“…Characteristically, serum cortisol levels are low or undetectable and ACTH concentrations are high. Cortisol and aldosterone do not respond to exogenous ACTH but aldosterone retains a normal response to activation of the reninangiotensin axis by salt and posture changes (19)(20)(21). The zona fasciculata-reticularis of adrenal cortex is atrophied whil the zona glomerulosa is well preserved (18,19).…”

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confidence: 92%

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The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor

Tiosano

Pannain

Vassart

et al. 1999

Thyroid

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Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.

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Section: Patientsmentioning

confidence: 88%

mentioning

confidence: 92%

The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor

Tiosano

Pannain

Vassart

et al. 1999

Thyroid

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“…Plasma ACTH is increased but the adrenal fasciculata and glomerulosa are unresponsive to ACTH (9). Every single one and the totality of these components may affect the physiological response to stress.…”

mentioning

confidence: 99%

The Importance of Adrenocortical Glucocorticoids for Adrenomedullary and Physiological Response to Stress: A Study in Isolated Glucocorticoid Deficiency

Zuckerman‐Levin

Tiosano

Eisenhofer

et al. 2001

The Journal of Clinical Endocrinology &Amp; Metabolism

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Glucocorticoids are required for the normal functioning of chromaffin cells and their capacity to produce epinephrine. This was modeled in a unique clinical syndrome of isolated glucocorticoid deficiency due to unresponsiveness to ACTH. The working hypotheses were that in patients with isolated glucocorticoid deficiency, adrenomedullary epinephrine would be suppressed despite replacement therapy; that norepinephrine might show a compensatory response; and that the physiological response to stress would reflect these changes. Toward these hypotheses, patients with ACTH unresponsiveness on glucocorticoid replacement were subjected to three levels of acute stress: assumption of upright posture, cold pressor, and exercise. Their catecholamine and physiological response were monitored. Patients with isolated glucocorticoid deficiency of this study had severe adrenomedullary dysfunction, characterized by a minimal resting production of epinephrine (6 +/- 2 pg/ml compared with 64 +/- 22 pg/ml of the controls) and a minimal response to stress. A slight compensatory increase of norepinephrine was found in response to cold pressor test (754 +/- 200 pg/ml compared with 431 +/- 73 pg/ml of the control). The physiological response is characterized by low systolic blood pressure and high pulse rate in rest and mild stress and in a pressor response to exercise (diastolic 87 +/- 5 mm Hg, compared with 73 +/- 2 mm Hg of the control). It is concluded that intra-adrenal glucocorticoids are essential for epinephrine secretion, that norepinephrine may be compensatory, and that these result in a distinct physiological response. The implications of the pressor response to exercise, the declining pulse pressure, and the increased pulse response insinuate a lower physical fitness in patients with adrenal insufficiency.

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“…ACTH levels of above 1,000 pg/ml (normal range <80 pg/ml by RIA; <50 pg/ml by IRMA) are commonly found [8, 23]. Occasionally, children may have minor impairment of the renin-angiotensin-aldosterone axis at the time of initial presentation [8, 24]. The physiological explanation of this observation is unclear.…”

Section: Clinical and Biochemical Features Of Fgdmentioning

confidence: 99%

“…Firstly, there is evidence that ACTH directly activates the production of aldosterone in the zona glomerulosa (ZG). It has been found that MC2R mRNA localizes to the ZG and administration of synthetic ACTH to normal human subjects results in a rise in plasma aldosterone levels [5,24,25,26,27]. The physiological importance of ACTH-dependent regulation of aldosterone in normal physiology and disease is undetermined.…”

Section: Clinical and Biochemical Features Of Fgdmentioning

confidence: 99%

Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

Chan¹,

Clark²,

Metherell³

2007

Horm Res Paediatr

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Familial glucocorticoid deficiency (FGD), otherwise known as hereditary unresponsiveness to ACTH, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Mutations of the ACTH receptor, also known as the melanocortin-2 receptor (MC2R), account for approximately 25% of FGD cases. More recently a second gene, MRAP (melanocortin-2 receptor accessory protein), was identified and found to account for a further 15–20%. MRAP encodes a small single transmembrane domain protein, which is essential in the trafficking of the MC2R to the cell surface. In this review, we will firstly summarize the clinical presentation and genetic aetiology of this condition. Secondly, we will discuss how the discovery of MRAP has enhanced our understanding of the mechanisms of ACTH/MC2R action. Finally, we will explore future developments in this field.

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Glomerulosa Failure in Congenital Adrenocortical Unresponsiveness to Acth

Cited by 22 publications

References 10 publications

The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor

The Hypothyroidism in an Inbred Kindred with Congenital Thyroid Hormone and Glucocorticoid Deficiency is Due to a Mutation Producing a Truncated Thyrotropin Receptor

The Importance of Adrenocortical Glucocorticoids for Adrenomedullary and Physiological Response to Stress: A Study in Isolated Glucocorticoid Deficiency

Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

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