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Families with Autosomal Dominant Brachydactyly Type E, Short Stature, and Severe Hypertension
- Hakan R. Toka, MD;
- Sylvia Bahring, PhD;
- David Chitayat, MD;
- James C. Melby, MD;
- Richard Whitehead, MD;
- Eva Jeschke, BS;
- Thomas F. Wienker, MD;
- Okan Toka, MS;
- Herbert Schuster, MD; and
- Friedrich C. Luft, MD
- From The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Boston University Medical Center, Boston, Massachusetts; and Humboldt University of Berlin, Berlin, Germany. Grant Support: By a grant-in-aid to Friedrich C. Luft from the Bundesministerium fur Bildung und Forschung; a grant-in-aid from the U.S. Air Force; and Perkin-Elmer, Applied Biosystems Division (Foster City, California). Astra Hassle Corp. (Wedel, Germany) supplied the antihypertensive medications. This study partly satisfies the research requirements for the Dr. med. degree of Hakan R. Toka. Requests for Reprints: Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. Current Author Addresses: Drs. Toka, Bahring, Wienker, Schuster, and Luft, Ms. Jeschke, and Mr. Toka: Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany.
Abstract
Background: Rare, monogenic forms of hypertension may give insight into novel mechanisms relevant to essential hypertension. Autosomal dominant hypertension with brachydactyly has been documented in a single Turkish kindred; the gene was mapped to chromosome 12p.
Objective: To describe the molecular genetics of additional families with autosomal dominant hypertension and brachydactyly.
Design: Case series.
Setting: Tertiary care medical centers.
Patients: An 11-member Canadian family and a 7-member U.S. family, neither of Turkish background, with autosomal dominant hypertension and type E brachydactyly.
Measurements: Clinical evaluation, genotyping, and haplotype analyses.
Results: The mode of inheritance, the type E brachydactyly, and the propensity for stroke were consistent with autosomal dominant hypertension with brachydactyly. The same markers on chromosome 12p cosegregated with the phenotype in the families. A haplotype analysis strongly supported the conclusion that these families have a molecular defect in the same gene.
Conclusions: The syndrome of autosomal dominant hypertension and brachydactyly is not confined to patients of Turkish origin. All persons with brachydactyly should have their blood pressure measured, and the syndrome should be considered if hypertension is found.
Monogenic forms of hypertension permit the identification of single genes responsible for elevated blood pressure. Previous research has elucidated the genetics of salt-retaining forms of hypertension and has shed considerable light on the pathogenesis of volume-expansion, salt-sensitive hypertension [1]. We have mapped a gene for hypertension to the short arm of chromosome 12 (12p) in a large Turkish kindred with hypertension and type E brachydactyly. In this family, the phenotypes for hypertension and brachydactyly are always inherited together; they cosegregate 100% [2]. Affected persons are shorter than unaffected persons and do not have volume expansion-induced hypertension, as determined by a volume expansion and contraction protocol; rather, they resemble patients with essential hypertension [3]. The mechanism of the hypertension is unknown. Thus far, this syndrome has been described only in this Turkish kindred and a similar family in Canada [4]. We recently encountered another such family in the United States. In these three families, the hypertension also follows an autosomal dominant mode of inheritance and cosegregates 100% with short stature and type E brachydactyly. By using microsatellite markers on chromosome 12p, we discovered that the Canadian and U.S. families had the same genetic syndrome as the Turkish family. This information has allowed us to narrow the estimated segment on chromosome 12p that harbors the responsible gene.
Methods
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
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).
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
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]. β-Blockers, calcium-channel blockers, α-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.
- Copyright ©2004 by the American College of Physicians
