A practical GnRH analogue (triptorelin) stimulation test to distinguish constitutional delay of puberty from hypogonadotropic hypogonadism in prepubertal boys.

At present, no established practical and reliable endocrine test exists for differentiating between constitutional delay of puberty (CDP) and hypogonadotropic hypogonadism (HH). The most discriminating results have been reported by measuring LH and testosterone (T) responses to gonadotropin-releasing hormone (GnRH) analogues. In this study, 23 prepubertal boys aged 14 to 16.5 years underwent a modified triptorelin (a GnRH analogue) stimulation test, and they were followed clinically for up 24 to months. Sixteen subjects developed spontaneous puberty during the follow-up period and thus were diagnosed with CDP, and the remaining seven were diagnosed with HH. Retrospective evaluation of their LH, FSH and T responses revealed significant differences without any overlaps in serum LH levels at 4 h (CDP: 33.2 +/- 9.3 vs. HH: 3.3 +/- 2.6 mIU/ml, p < 0.0002) and in serum T levels at 24 h (CDP: 369.3 +/- 128.1 vs. HH: 61.4 +/- 22.6 ng/dl p < 0.0002). We conclude that CDP can be clearly differentiated from HH by the LH response at 4 h and/or T response at 24 h after a single-dose triptorelin administration.

Langerhans' cell histiocytosis: report of an atypical case.

A patient is described with Langerhans' cell histiocytosis and polyneuropathy diagnosed 12 years after the development of diabetes insipidus after head trauma.

A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly.

We examined a family with autosomal-dominant hypertension and brachydactyly from northeastern Turkey. The hypertension was defined as severe, resulting in stroke before age 50 years, featuring normal renin, aldosterone, and catecholamine responses, and did not appear to be salt-sensitive. The responsible gene resides on chromosome 12p. To determine which medications were most effective, we performed a prospective clinical trial. We studied 13 affected individuals in a randomized double-blind, cross-over trial including a beta-blocker (BBL), alpha-blocker (ABL), calcium channel blocker (CCB), converting enzyme inhibitor (CEI), and hydrochlorothiazide (HCT) and placebo (PLA). We then added moxonidine (MOX) and continued the trial for an additional period in a single-blind fashion. Each drug was given for four weeks with an option to double the dose after two weeks; each washout period comprised two weeks. Blood, 24-hour urine, and saliva were studied at the outset, and blood and urine samples were obtained at the end of each phase. Blood pressure (BP) and heart rate measurements were with the patient ambulatory at 24 hours. All regimens required doubled doses at two weeks. Beta blocker, CCB, CEI, and ABL lowered BP (6 to 10 mm Hg) and BP load compared to PLA, while HCT and MOX did not. Converting enzyme inhibitor and HCT increased plasma renin activity (PRA), while BBL lowered PRA. The 24-hour urine analysis indicated a high dietary salt intake with a low potassium and calcium intake. The salivary electrolytes showed similar sodium and potassium concentrations, while chloride values were significantly higher in affected than nonaffected subjects. Thus, this monogenic form of hypertension resembles nonsalt-sensitive essential hypertension in that BBL, CCB, CEI, and ABL were effective, while HCT was not. The BP reduction was similar to other single drug trials in essential hypertension. The high salivary chloride values suggest an additional intermediary phenotype that may be related to electrolyte transport. These results raise the possibility that an as yet unknown hypertensive mechanism is operative in these subjects.

Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly.

BACKGROUND AND PURPOSE: Autosomal dominant hypertension with brachydactyly features severe hypertension that causes stroke usually before the age of 50 years. We recently characterized the hypertension as featuring normal renin, aldosterone, and catecholamine responses and mapped the gene responsible to chromosome 12p. Since angiography in an affected subject had earlier shown tortuous vessels, we performed magnetic resonance tomography (MRT) angiography to look for possible neurovascular anomalies (NVA), which have been previously associated with hypertension. NVA can be caused by a looping posterior inferior cerebellar or vertebral artery. Experimental and clinical evidence suggests that NVA may cause hypertension by a compression of the ventrolateral medulla. METHODS: We performed MRT in 15 hypertensive affected (aged 14 to 57 years) and 12 normotensive nonaffected (aged 12 to 59 years) family members. We then tested for linkage between the hypertension-brachydactyly phenotypes and the presence of NVA. RESULTS: All 15 affected persons had MRT evidence for NVA. All had left-sided posterior inferior cerebellar artery or vertebral artery loops, while 6 had bilateral NVA. None of the nonaffected family members had NVA. The phenotypes were linked with an LOD score of 9.2 given a penetrance of 99%. CONCLUSIONS: Autosomal dominant hypertension and brachydactyly regularly feature NVA, which is frequently bilateral. The early age at which NVA was identified suggests that the condition is primary. We suggest that NVA may be involved in the pathogenesis of this form of hypertension and perhaps essential hypertension as well. Further studies are necessary to address the question of causation.

Leprechaunism in two Turkish patients.

We report two cases of Leprechaunism with the classical features. The first case had hyperglycemia and severe hyperinsulinemia. The postmortem examination of the second child revealed enlargement of both ovaries, islet cell hyperplasia in the pancreas, and cholestasis and paucity of bile ducts in the liver. Cystic changes were noted in the ovaries, and the kidneys contained a few small cortical cysts. Both patients died at early ages.

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

'Treasure your exceptions': what we can learn from autosomal-dominant inherited forms of hypertension.

OBJECTIVE: To discuss the relevance of rare monogenic forms of hypertension to the diagnosis, pathogenesis and treatment of essential hypertension. STUDY SELECTION: Three monogenic forms of hypertension have been identified that are inherited as a simple autosomal-dominant trait. The genetic defects and the pathophysiology of two, namely glucocorticoid-remediable aldosteronism and Liddle's syndrome, have been elucidated in great detail. The third form of monogenic hypertension, which cosegregates with a second phenotype, brachydactyly, is being investigated. RESULTS: Glucocorticoid-remediable aldosteronism is caused by the presence of a chimeric gene, which incorporates the regulatory region of the 11-beta-hydroxylase gene and the structural portion of the aldosterone synthase gene. The enzyme aldosterone synthase is not only expressed in the zona fasiculata but is also regulated by adrenocorticotrophic hormone in this condition. Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel. The mutations result in inappropriate channel patency and increased distal sodium reabsorption. Both of these forms of inherited hypertension are low-renin forms of hypertension. Glucocorticoid-remediable aldosteronism resembles primary aldosteronism, whereas Liddle's syndrome resembles low-renin essential hypertension. An autosomal-dominant genetic form of hypertension has been described in northeastern Turkey. The hypertension cosegregates 100% with brachydactyly. This form resembles essential hypertension, because levels of renin, aldosterone, catecholamines and other regulators are normal. Furthermore, in contrast to glucocorticoid-remediable aldosteronism and Liddle's syndrome, the patients are not salt-sensitive. CONCLUSIONS: Mechanisms of mineralcorticoid hypertension, renally induced salt-sensitive hypertension, and possibly essential hypertension, may be elucidated by studying exceptional families.