Methods

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Patients

The Canadian family, which is of English descent, consists of 11 members over three generations [4]. Six members had the syndrome and 5 did not. The propositus, a 7-year-old child, had a blood pressure of 175/135 mm Hg. Thorough laboratory investigation included examinations of renal function, the renin-angiotensin system, and plasma catecholamine levels. Findings on renal and adrenal arteriography were normal. Echocardiography showed increased septal thickness. The patient's brother, father, paternal uncle, cousin (the son of the paternal uncle), and paternal grandmother all had brachydactyly type E, short stature, and hypertension that was treated with antihypertensive medications. The unaffected family members had neither brachydactyly nor hypertension. The presence of cone-shaped epiphyses was verified on radiography in all affected family members.

The U.S. family, also of English descent, consists of seven currently living persons (four men and three women). We examined all seven family members. Four had brachydactyly, short stature, and hypertension. The three unaffected members were normotensive. The brachydactyly type E in one of the patients had been reported earlier [5].

In the U.S. family, four persons have died of stroke and one, who is alive, has had several strokes (III/2 in the family tree). In the Canadian family, the propositus presented with seizures, probably due to a stroke; this possibility was not documented on computed tomography of the brain, however, and no further investigation was indicated. The rest of the family is asymptomatic except for hypertension that is well controlled with antihypertensive medications.

Genotyping

Genotyping was done by using the ABI PRISM Genotyping System (Perkin-Elmer, Applied Biosystems Division, Foster City, California). Genomic DNA from the participants was prepared from whole blood by using standard methods. Fluorescence-labeled microsatellite markers (AFM338 WH5, D12S363, AFM211ZB2, D12S1595, D12S1027, D12S1650, D12S1682, D12S1654, GATA91H01, D12S1688, AFM267YC9, D12S1606, AFMB351 ZH5, D12S1591, and D12S1057) were amplified by polymerase chain reaction using 50 ng of genomic DNA, 200 µmol of deoxyribonucleotide triphosphate per L, 5 pmol each of forward and reverse primers, 10 mmol of Tris-HCl per L (pH, 8.3), 50 mmol of KCl per L, various concentrations of MgCl₂ (1.5 to 3.5 mmol/L), and 0.6 units of Ampli-Taq-Polymerase (Perkin-Elmer, Norfolk, Virginia) in a total volume of 15 µL. Primer sequences were obtained from the Genome Database (Baltimore, Maryland). Samples were run on a 6% denaturing polyacrylamide (19:1) gel. Allele sizes were automatically calculated by Genescan 1.2 software and analyzed by Genotyper 1.1 software (Perkin-Elmer, Foster City, California).

Results

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Figure 1 shows radiographs of the left hand of a 4.5-year-old child (left) and a 22-year-old woman (right) from the U.S. family. Both have type E brachydactyly, as shown by the shortened metacarpals involving all digits. In the child, cone-shaped epiphyses are evident at several locations. In the adult, typical residua are visible. Figure 2 and Figure 3 shows the family trees of the U.S. family (A) and the Canadian family (B).

View larger version (142K): [in this window] [in a new window]   Figure 1. Radiographs of the left hands of a 4.5-year-old child (left) and a 22-year-old woman (right) with type E brachydactyly (all phalanges and metacarpals are shortened). In the child's hand, cone-shaped epiphyses are apparent at several locations (arrows). Residual of such epiphyses (arrows) are apparent in the adult's hand. Black arrow denotes short metacarpals. Both patients are indicated by arrows in Figure 2 and Figure 3.

View larger version (21K): [in this window] [in a new window]   Figure 2. A. Family tree of 15 U.S. persons. Eight had hypertension, brachydactyly, and short stature, and 7 did not. Seven living persons were examined. The blood pressure status of the deceased persons was discemed by family history. B. Family tree of 11 Canadian persons over three generations. Six persons had hypertension, brachydactyly, and short stature (black symbols), and 5 did not (white symbols). In both families, all affected persons were, on average, 10 cm shorter than unaffected family members. The blood pressures (mm Hg) of persons not yet treated are given. The haplotype analysis of the respective microsatellite markers is given under each symbol.

View larger version (29K): [in this window] [in a new window]   Figure 3. Figure 2 Continued.

Within each family, all affected members had an identical haplotype for the microsatellite markers between and including D12S1650 and D12S1057. The information from these two families has allowed us to narrow the segment on chromosome 12p in which the gene must lie between microsatellite markers D12S1650 and D12S1057.

Discussion

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On the basis of these molecular genetic findings and clinical observations, we are confident that the families from Turkey, Canada, and the United States have the same autosomal dominant syndrome. The cause of the hypertension in these patients is unknown. Unlike in patients with salt-retaining, monogenic forms of hypertension [1], plasma renin activity, aldosterone, and circulating catecholamines in these patients respond normally to provocative maneuvers [3]. We found no evidence of renovascular hypertension in the Turkish family [3]. Chitayat and colleagues [4] found normal renal arteries in the 7-year-old propositus from the Canadian family described here. They also observed a 38-year-old Hispanic man who probably also had autosomal dominant hypertension with brachydactyly. That patient had narrowed renal arteries, a narrowed superior mesenteric artery, left carotid artery stenosis, and middle left cerebral artery occlusion [4]. Because the patient was lost to follow-up, we could not include his family in the analysis.

Because neurovascular contact from an aberrant posterior-inferior cerebellar artery loop at the level of the ventrolateral medulla has been reported to be common in essential hypertension and may be of pathogenic significance [6, 7], we performed magnetic resonance angiography in 15 affected and 11 unaffected members of the Turkish kindred [8]. All 15 affected family members and 0 of 11 unaffected members had these neurovascular anomalies. The two families described here have not yet been studied completely for these anomalies. A neurogenic origin of the hypertension remains possible.

We conducted a randomized, double-blind, cross-over trial of six different medication classes in patients with autosomal dominant hypertension and brachydactyly [9]. ß-Blockers, calcium-channel blockers, -blockers, and angiotensin-converting enzyme inhibitors all decreased blood pressure by about 8 mm Hg; hydrochlorothiazide and moxonidine were less effective. Generally two and, often, three or more medications were necessary for adequate blood pressure control, depending on the patients' ages.

The syndrome described here is not the only reported genetic association between brachydactyly and hypertension. Pseudohypoparathyroidism also features brachydactyly and, commonly, hypertension [10]. However, patients with pseudohypoparathyroidism are generally mentally retarded, whereas patients with autosomal dominant hypertension and brachydactyly are not. The gene for pseudohypoparathyroidism has been cloned and resides on chromosome 20q [11].

The similarities between essential hypertension and hypertension associated with brachydactyly type E plus short stature make the gene causing this rare disorder (brachydactyly-hypertension-short stature) highly relevant to the search for the cause of essential hypertension. In this syndrome, a single gene causes a 50-mm Hg increase in mean arterial blood pressure by the time the patient is 50 years of age [2]. If a neurogenic mechanism is responsible and if such a mechanism is confirmed to be relevant to essential hypertension, a new avenue of diagnosis and potential treatment could result. We have thus far assumed that only one gene is responsible for this autosomal dominant syndrome. However, the existence of mutations in two closely located genes or the presence of a contiguous gene syndrome has not been excluded.

Our observations are not only of genetic interest; they also have general clinical implications. Members of one family were described in an earlier report because of their brachydactyly [5], but the presence of genetic hypertension was not appreciated at that time. Brachydactyly, including type E brachydactyly, is not uncommon. We believe that this genetic syndrome may be more common than previously believed, and we recommend that all patients with brachydactyly have their blood pressure measured. Identification of additional families with autosomal dominant hypertension and brachydactyly will also facilitate identification, cloning, and characterization of the responsible gene.

Dr. Chitayat: Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.

Drs. Melby and Whitehead: Endocrine Section, Boston Medical Center, 720 Harrison Avenue, Boston, MA 02118.