TABLE 1.
| TABLE 1A: Clinical Manifestations and Diagnostic Evaluation of Chrousos Syndrome * | |
|---|---|
| Clinical Presentation | |
| Apparently normal glucocorticoid function in most cases | |
| Asymptomatic | |
| Hypoglycemia, chronic fatigue (glucocorticoid deficiency?) | |
| Mineralocorticoid excess | |
| Hypertension | |
| Hypokalemic alkalosis | |
| Androgen excess | |
|
Children: Ambiguous genitalia at birth**, clitoromegaly, premature adrenarche, gonadotropin- independent precocious puberty |
|
|
Females: Acne, hirsutism, male-pattern hair loss, menstrual irregularities, oligo-anovulation, hypofertility |
|
| Males: Acne, hirsutism, oligospermia, adrenal rests in the testes, hypofertility | |
| Increased HPA axis activity (CRH/AVP and ACTH hypersecretion) | |
| Anxiety | |
| Adrenal rests (oligospermia) | |
| Pituitary corticotropinoma | |
| Diagnostic Evaluation | |
| Absence of clinical features of Cushing syndrome | |
| Normal or elevated plasma ACTH concentrations | |
| Elevated serum or plasma cortisol concentrations | |
| Increased 24-hour urinary free cortisol excretion | |
| Normal circadian and stress-induced pattern of cortisol and ACTH secretion | |
| Resistance of the HPA axis to dexamethasone suppression | |
| Thymidine incorporation assays: Increased resistance to dexamethasone-induced suppression of phytohemaglutinin-stimulated thymidine incorporation compared to control subjects | |
| Dexamethasone-binding assays: Decreased concentration or affinity of the glucocorticoid receptor for the ligand compared to control subjects | |
| Molecular studies: Mutations/deletions of the glucocorticoid receptor; functional studies of mutant receptors | |
| TABLE 1B: Mutations of the Human Glucocorticoid Receptor Gene Causing Chrousos Syndrome * | |||||
|---|---|---|---|---|---|
| Mutation Position | |||||
| Author (Reference) | cDNA | Amino acid | Molecular Mechanisms | Genotype | Phenotype |
| Chrousos et al. (1) Hurley et al. (11) |
1922 (A→T) | 641 (D→V) | Transactivation ↓ Affinity for ligand ↓ (× 3) Nuclear translocation: 22 min Abnormal interaction with GRIP1 |
Homozygous | Hypertension Hypokalemic alkalosis |
| Karl et al. (12) | 4 bp deletion in exon-intron 6 | hGRα number: 50% of control Inactivation of the affected allele |
Heterozygous | Hirsutism Male-pattern hair-loss Menstrual irregularities |
|
| Malchoff et al. (13) | 2185 (G→A) | 729 (V→I) | Transactivation ↓ Affinity for ligand ↓ (× 2) Nuclear translocation: 120 min Abnormal interaction with GRIP1 |
Homozygous | Precocious puberty Hyperandrogenism |
| Karl et al. (10) Kino et al. (14) |
1676 (T→A) | 559 (I→N) | Transactivation ↓ Decrease in hGR binding sites Transdominance (+) Nuclear translocation: 180 Abnormal interaction with GRIP1 |
Heterozygous | Hypertension Oligospermia Infertility |
| Ruiz et al. (15) Charmandari et al. (20) |
1430 (G→A) | 477 (R→H) | Transactivation ↓ No DNA binding Nuclear translocation: 20 min |
Heterozygous | Hirsutism Fatigue Hypertension |
| Ruiz et al. (15) Charmandari et al. (20) |
2035 (G→A) | 679 (G→S) | Transactivation ↓ Affinity for ligand ↓ (× 2) Nuclear translocation: 30 min Abnormal interaction with GRIP1 |
Heterozygous | Hirsutism Fatigue Hypertension |
| Mendonca et al. (16) | 1712 (T→C) | 571 (V→A) | Transactivation ↓ Affinity for ligand ↓ (× 6) Nuclear translocation: 25 min Abnormal interaction with GRIP1 |
Homozygous | Ambiguous genitalia Hypertension Hypokalemia Hyperandrogenism |
| Vottero et al. (17) | 2241 (T→G) | 747 (I→M) | Transactivation ↓ Transdominance (+) Affinity for ligand ↓ (× 2) Nuclear translocation ↓ Abnormal interaction with GRIP1 |
Heterozygous | Cystic acne Hirsutism Oligo-amenorrhea |
| Charmandari et al. (19) | 2318 (T→C) | 773 (L→P) | Transactivation ↓ Transdominance (+) Affinity for ligand ↓ (× 2.6) Nuclear translocation: 30 min Abnormal interaction with GRIP1 |
Heterozygous | Fatigue Anxiety Acne Hirsutism Hypertension |
| Charmandari et al. (21) | 2209 (T→C) | 737 (F→L) | Transactivation ↓ Transdominance (time-dependent) (+) Affinity for ligand ↓ (× 1.5) Nuclear translocation: 180 min |
Heterozygous | Hypertension Hypokalemia |
| McMahon et al. (5) | 2 bp deletion at nt 2318-9 |
773 | Transactivation ↓ Affinity for ligand: absent No suppression of IL-6 |
Homozygous | Hypoglycemia Fatigability with feeding Hypertension |
| Nader et al. (4) | 2141 (G→A) | 714 (R→Q) | Transactivation ↓ Transdominance (+) Affinity for ligand ↓ (× 2) Nuclear translocation ↓ Abnormal interaction with GRIP1 |
Heterozygous | Hypoglycemia Hypokalemia Hypertension Mild clitoromegaly Advanced bone age Precocious pubarche |
*
Modified from Reference 3.
**
This is the only case of ambiguous genitalia documented in a child with 46,XX karyotype who also harbored a heterozygous mutation of the 21-hydroxylase gene.