Candidate gene analysis in a case of congenital absence of the endometrium.

BACKGROUND: Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea. CASE PRESENTATION: A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus. CONCLUSIONS: Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case.

Succinate dehydrogenase gene mutations in cardiac paragangliomas.

Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9 years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx germline mutations, suggesting a need for genetic testing of all patients with this rare tumor.

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).

CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.

Glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism and the most common monogenic cause of hypertension. A chimeric gene duplication leads to ectopic aldosterone synthase activity in the cortisol-producing zona fasciculata of the adrenal cortex, under the regulation of adrenocorticotropin (ACTH). Hypertension typically develops in childhood, and may be refractory to standard therapies. Hypokalemia is uncommon in the absence of treatment with diuretics. The discovery of the genetic basis of the disorder has permitted the development of accurate diagnostic testing. Glucocorticoid suppression of ACTH is the mainstay of treatment; alternative treatments include mineralocorticoid receptor antagonists.

A patient with ectopic cortisol production derived from malignant testicular masses.

BACKGROUND: A 65-year-old man presented to an oncology clinic with bilateral testicular masses, lower extremity edema, and cushingoid appearance. INVESTIGATIONS: Measurements of serum cortisol and adrenocorticotropic hormone levels, testicular ultrasound and abdominal CT scans, and review of histopathology to identify the cellular origin of the ectopic cortisol production. DIAGNOSIS: Cushing syndrome was diagnosed on the basis of a markedly elevated 24-hour urine free cortisol level and classic cushingoid features. The etiology of Cushing syndrome was determined to be an adrenocortical carcinoma arising from testicular adrenal rest cells. Nevertheless, the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be excluded. MANAGEMENT: Mitotane and metyrapone were used to decrease cortisol production. Excess mineralocorticoid activity was blocked with spironolactone; sodium retention was also managed with sodium restriction and diuretics. Despite initial success with this regimen, the patient died as a result of tumor progression and complications of poorly controlled hypercortisolism.

Diagnosis of primary aldosteronism: from screening to subtype differentiation.

Numerous studies conducted in recent years have reported an increase in the prevalence of primary aldosteronism (PA). This increase has arisen because of changes in our screening methods used to detect PA, notably the widespread use of the ratio of plasma aldosterone concentration to plasma renin activity. A positive screening result, however, is not diagnostic and requires a confirmatory test. Strategies for screening and confirmation of PA and the techniques to identify the two main subtypes of PA--aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH)--are particularly important because hypertension in APA can be cured by adrenalectomy, whereas individuals affected with BAH can receive targeted medical treatment with mineralocorticoid receptor antagonists.

Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is a monogenic form of human hypertension that predisposes to cerebral hemorrhage. As a result of a chimeric gene duplication, aldosterone is ectopically synthesized in the cortisol-secreting zona fasciculata of the adrenal gland under the control of adrenocorticotropin (ACTH). Hypertension frequently has its onset during childhood and is usually refractory to standard anti-hypertensives such as ACE inhibitors and beta-blockers. Hypokalemia can develop in those treated with a potassium-wasting diuretic, but random potassium levels are usually normal. Diagnosis has been facilitated by the availability of a genetic test. Suppression of ACTH release with exogenous dexamethasone is a useful diagnostic and therapeutic strategy. Treatment with the mineralocorticoid receptor antagonists spironolactone and epleronone is also efficacious. The diagnosis of GRA facilitates directed therapies and screening of at-risk individuals and kindreds.