American Journal of Medical Genetics 73:279–285 (1997)

Brachydactyly-Short Stature-Hypertension
(Bilginturan) Syndrome: Report on Two Families
David Chitayat,1* Art Grix,2 J. Williamson Balfe,1 Jacques S. Abramowicz,3 Judy Garza,3
Chin-To Fong,3 Meredith M. Silver,1 Devereux N. Saller Jr.,3 George H. Bresnick,3 Andres Giedion,4
Ralph S. Lachman,5 and David L. Rimoin5
1
Hospital for Sick Children, Toronto, Ontario, Canada
2
The Permanente Medical Group, Sacramento, California
3
Strong Memorial Hospital, Rochester, New York
4
Kinderspital Zurich, Zurich, Switzerland
5
Cedars-Sinai Medical Center, Los Angeles, California

We report on two families with autosomal INTRODUCTION

dominant brachydactyly of hands and feet
and hypertension. All affected members of
the first family had proportionate short
stature. However, the propositus and the af-
fected relatives in the second family were
only short compared to unaffected relatives.
The hypertension was medically responsive
in all cases. The propositus in the second
family had poor compliance and a striking
generalized vasculopathy. All patients were
of normal intelligence and had a normal fa-
cial appearance. The brachydactyly-short
stature-hypertension syndrome was first re-
ported by Bilginturan et al. [1973] in a Turk-
ish family and the families reported by us
are Caucasian and Hispanic. The gene caus-
ing this condition in the original Turkish
family was recently mapped to 12p. Our re-
port expands our existing knowledge and
the ethnic diversity of this syndrome. Am. J.
Med. Genet. 73:279–285, 1997.
© 1997 Wiley-Liss, Inc.
KEY WORDS: hypertension; short stature;
brachydactyly; vasculopa-
thy; intracerebral hemor-
rhage; autosomal dominant
Contract grant sponsor: NIH Program Project Grant; Contract
grant number: HD 22657; Contract grant sponsor: The Interna-
tional Skeletal Dysplasia Registry; Contract grant sponsor:
Steven Spielberg Pediatric Research Center at Cedars-Sinai
Medical Center.
*Correspondence to: Dr. D. Chitayat, The Hospital for Sick
Children, 555 University Avenue, Toronto, Ontario, Canada,
M5G 1X8.
Received 2 April 1997; Accepted 12 April 1997
Hypertension is a heterogeneous condition affecting
about 20% of the world population [Lifton, 1996]. In
spite of intensive research, the vast knowledge ac-
quired about the pathophysiology of this common con-
dition and the advances in the treatment of hyperten-
sion, the genetic basis of most forms of hypertension
has not been delineated. In 1973, Bilginturan et al.
[1973] reported on a large Turkish family with hyper-
tension, brachydactyly, and short stature with autoso-
mal dominant inheritance and full penetrance. Com-
parison of affected with unaffected relatives in this kin-
dred demonstrated a 50 mm Hg higher median blood
pressure in the affected persons by age 50 years.
We report on two families with autosomal dominant
brachydactyly-short stature-hypertension (BSH) syn-
drome. One family was of English and the other of His-
panic origin. The propositus in the first family was ad-
mitted to the hospital for investigation of seizures as-
sociated with hypertension and the propositus in the
second family was investigated for hypertension and
chest pain.
The two families reported by us show the ethnic di-
versity of this autosomal dominant disorder and em-
phasize the importance of screening all cases with
brachydactyly for hypertension. Treatment with anti-
hypertensive medications resulted in a good prognosis
and the prevention of complications in the affected
members of the English family. The propositus in fam-
ily B had severe stenosing vasculopathy, which most
probably caused his high blood pressure, although his
poor compliance may have increased the severity of
this condition. Further reports are needed to find if the
vasculopathy is part of the genetic condition in this
family.
CLINICAL REPORTS
Family A (Fig. 1)
The propositus (III-2) (Fig. 2) presented at age 7
years age with headaches and 3 days later developed

© 1997 Wiley-Liss, Inc.

280 Chitayat et al.
Fig. 1. Family A: pedigree.
seizures. On examination, he was short [111 cm (−3.5
SD)], his OFC was 51 cm (−1 SD), and weight was 20.2
kg (5th centile). His armspan minus height and U/L
segment ratio were normal. He had brachydactyly of
hands (Fig. 3) and feet (Fig. 4) (total hands, palms, and
3rd fingers measured <3rd centile). His blood pressure
was 175/135 mm Hg and ophthalmologic findings were
normal. An echocardiogram showed thickening of the
Fig. 2. The propositus. Note normal facial appearance.
Fig. 3. The propositus’s hands showing brachydactyly.
interventricular septum. Results of coagulation stud-
ies, plasma electrolytes, creatinine, and urinalysis
were normal. Captopril DTPA scan, 24 hour urine for
VMA, and cathecholamines were normal. An abdomi-
nal CT scan demonstrated normal kidneys and adre-
nals. Renal and adrenal arteriography findings were
normal and renal vein renin activity showed no later-
alization [left renal vein, 17.7; right renal vein, 19.7;
IVC above the kidneys, 18; and IVC below the kidneys,
16.1 ng/ml/hour]. Brain CT scan and EEG were also
normal. A complete skeletal survey showed generalized
brachymetacarpalia but more marked shortness of the
4th and 5th metacarpals, brachyphalangy, and un-
usual cone-shaped epiphyses of the phalanges (Fig. 5).
The feet showed generalized brachymetatarsalia and
Fig. 4. Radiograms of the propositus’s hands showing brachymetacar-
palia more marked of the 4th and 5th metacarpals, as well as brachypha-
langy and cone shaped epiphyses in the phalanges.

Fig. 5. Radiograms of the propositus’ feet showing generalized
brachymetatarsalia and brachyphalangy with cone shaped epiphyses and
premature closure of the epiphyses.
brachyphalangy, mainly of the basal phalanges with
premature closure or absence of the epiphyses (Fig. 6).
There was also mild scoliosis of the thoracic spine with
flattening of the posterior parts of the vertebral bodies
T10-12.
Detailed family history (Fig. 1) showed that the pro-
positus’ brother, his father (II-1), a paternal uncle and
his son, and the paternal grandmother all had short
stature, brachydactyly (Fig. 7) and high blood pressure,
well controlled with medication. Their skeletal changes
were confined to hands and feet. The grandmother (I-2)
showed more pronounced brachymetacarpalia com-
pared to the propositus but her brachymetatarsalia
and brachyphalangy were similar to that of the pro-
Fig. 6. The propositus’ father’s hands showing brachydactyly.
Brachydactyly-Hypertension 281
Fig. 7. Radiograms of the propositus’ paternal grandmother showing
similar brachymetacarpalia and brachyphalangy.
positus, except for more cone epiphyses residua in the
proximal phalanges (Fig. 8). Her lumbar spine showed
ventral osteophytes on the vertebral bodies most
marked between L4/L5 with narrowing of the disc. The
pelvic bones and acetabula were normal. Ophthalmo-
logic findings including ERG’s on the propositus’s
brother, grandmother, and affected uncle were normal.
Chromosomes of the affected uncle (II-3) were normal.
Family B (Fig. 9): This propositus (II-2) was a 38-
year-old Hispanic male who was hospitalized for
chronic severe hypertension. He was initially found to
be hypertensive at age 26 years in Mexico and re-
mained untreated until 4 months before hospitaliza-
tion. He was 167.5 cm tall (5–10th centile), weighed
55.2 kg (5th centile), and his blood pressure was 250/
170 mm Hg before treatment and 174/110 mm Hg after
therapy. He had brachydactyly of hands and feet, his
palm length was 9.3 cm, and the 3rd finger length was
6.3 cm, both below the 3rd centile. Ophthalmologic ex-
amination showed retinal hard exudates. Radiographs
showed shortness of the metacarpals (Fig. 9), metatar-
sals, and phalanges, and scalloping of the vertebral
bodies. Echocardiography showed severe concentric left
ventricular hypertrophy with global hypokinesia and
thickened aortic valve annulus and leaflets. Cardiac
catheterization showed narrowing of the coronary ar-
teries and a dilated aortic root. Renal ultrasound ex-
Fig. 8. Family B: pedigree.
282 Chitayat et al.
Fig. 9. X-rays films of the propositus’ (family B) hands showing brachymetacarpalia and brachyphalangy.
amination showed normal renal size [right 9.5 and left
10 cm (normal 4 10–12 cm)]. There was an area of
parenchymal loss in the lower pole of the right kidney
in a wedge distribution and arteriogram showed nar-
row renal and mesenteric arteries [renal artery diam-
eter was 4 mm (normal 4 10 mm)]. His BUN was 19
[normal 4 11–23] and his creatinine was 1.0 [normal
4 0.6–1.2]. His plasma electrolyte levels were normal
and his urinalysis showed normal specific gravity and
+1 protein. Renal vein renin levels were 18.6 ng/ml/
hour on the left and 24.4 ng/ml/hour on the right (nor-
mal41–7.7 ng/ml/hour). Thyroid and adrenal functions
were normal as were urinary VMA and metanephrine
and salt-loaded aldosterone levels in supine and stand-
ing position.
The propositus’ blood pressure was stabilized and he
was discharged on antihypertensive medication. He
was re-admitted 10 months later for evaluation of chest
pain and shortness of breath. His blood pressure on
admission was 260/135 mm Hg. Angiography demon-
strated stenosis of the renal and mesenteric arteries
(Fig. 10), a 1 cm right proximal subclavian artery an-
eurysm with two long irregular stenotic foci in the left
subclavian artery distal to the left vertebral artery, 20–
30% stenosis of the distal left common carotid artery, a
long segment of less than 50% stenosis of the proximal
left internal carotid artery, and complete occlusion of
the left middle cerebral artery with a well developed
collateral from the anterior cerebral artery and exter-
nal carotid artery. The right internal carotid artery
was 90% stenotic at its origin and the left vertebral
artery was 70–90% stenotic at its origin.
Biopsy of the left temporal artery showed severe ste-
nosis due to marked intimal fibroplasia, with no in-
flammatory or atherosclerotic changes (Fig. 11). Fo-
cally, the thickened intima encroached on the media
with local loss and/or reduplication of the internal elas-
tic lamina. Occasional foci of dystrophic calcification
were present in the outer zone of the intima. The media
and adventitia showed no inflammation, either chronic
or granulomatous, nor scarring that could have marked
healed inflammation. The changes were consistent
with the intimal fibroplastic subtype of fibromuscular
dysplasia.
The patient reported that his sister also had brachy-
dactyly involving her hands and feet, and short stat-
ure, with hypertension, and that she died in her 30’s or
40’s of a stroke. His father, as well as one of his pater-
nal half sisters, also had brachydactyly of the hands
and feet as well as short stature but their blood pres-
sure was not known. All unaffected members of his
family were 180 cm tall and our patient was also ex-

Fig. 10. Angiography of the renal artery (arrow) showing narrowing of the arteries.
ceptionally short. The patient was treated with antihy-
pertensive medication and was subsequently lost to fol-
low-up.
DISCUSSION
Hypertension is a heterogeneous condition affecting
about 15–20% of adults in developed countries and con-
tributing to over 200,000 deaths from stroke, myocar-
dial infarction, and end-stage renal disease each year
[Lifton, 1966]. The cause of essential hypertension is
the subject of ongoing debate. The Pickering school
[Pickering, 1978] advocates that blood pressure has a
continuous distribution and high blood pressure is the
upper end of the distribution. Thus, essential hyper-
tension is a multifactorial trait with multiple genes as
well as environmental factors determining blood pres-
sure elevation. On the other hand, the Platt school
[1963] states that essential hypertension is an autoso-
mal dominant single gene disorder. These theories are
not necessarily contradictory in that many genes are
involved in controlling blood pressure and mutations in
certain of these genes could result in high blood pres-
sure, inherited as a single gene disorder. Recently,
much of the research aimed at deciphering the cause of
hypertension has concentrated on single gene disorders
associated with high blood pressure [Lifton, 1996].
These conditions may simplify the genetic analysis,
Brachydactyly-Hypertension 283
mapping, and eventually the detection of the genes in-
volved in regulating blood pressure.
Two autosomal dominant conditions associated with
hypertension have been delineated. Glucocorticoid-
remediable aldosteronism is caused by a chimeric gene
arising from unequal crossing-over between the aldo-
sterone synthase and 11b-hydroxylase genes. This
fuses the 58 regulatory sequences from the latter onto
the coding sequences of the former. As a result, the
expression of the aldosterone synthase gene is brought
under the control of ACTH [Ulick et al., 1990].
Another autosomal dominant condition associated
with high blood pressure is Liddle’s syndrome or pseu-
dohypoaldosteronism. This syndrome is the result of a
mutation in genes encoding either the b or g subunits
of the amiloride-sensitive distal renal epithelial sodium
channel [Shimkets et al., 1994]. Neither of these two
syndromes is associated with skeletal abnormalities.
The association of brachydactyly, cone-shaped epiph-
yses, and hypertension was reported in Saldino-
Mainzer dysplasia [Saldino and Mainzer, 1971; Ellis et
al., 1984]. However, unlike the two families discussed
in this report, Saldino-Mainzer dysplasia is an autoso-
mal recessive disorder associated with nephronophthi-
sis and chronic renal failure, Leber’s optic atrophy, cer-
ebellar ataxia, and hepatic fibrosis.
In 1973, Bilginturan et al. reported a six-generation
Turkish family from the eastern Black Sea coast, with
284 Chitayat et al.
Fig. 11. The temporal artery biopsy (propositus, family B) showing a marked intimal fibrous thickening and lumenal lies at the bar of the ‘‘H’’ caused
by folds in the paraffin section. Three foci of dystrophic calcification, the largest marked by an arrow, are present in the outer layers of the intima adjacent
to a faint wavy line, the internal elastic lamina. To the left of the arrow, the thinnest part of the media is marked by opposing arrowheads. (Hematoxylin
and eosin ×10 [original magnification]).
autosomal dominant brachydactyly, short stature, and
hypertension. The hypertension increased in severity
with age and many of the affected relatives died at a
relatively young age of stroke. Intensive investigations
failed to delineate the etiology of this condition. Recent
linkage analysis has mapped the gene causing the con-
dition in this family to 12p [Schuster et al., 1996].
The clinical findings in the two families reported by
us have many similarities to the family reported by
Bilginturan et al. [1973] and later by Schuster et al.
[1996]. In our family A, the propositus presented with
high blood pressure and seizures. He also had brachy-
dactyly of both hands and feet and short stature. His
short stature was proportionate and a skeletal survey
showed brachydactyly of the hands and feet with
brachymetacarpalia and brachyphalangy, brachymeta-
tarsalia, and cone-shaped epiphyses. Renal function
was normal and his ophthalmological findings were
normal.
The other affected members of this family had hy-
pertension, detected in childhood and diagnosed as es-
sential hypertension, after a thorough investigation
failed to delineate the etiology. Unlike the family re-
ported by Bilginturan et al. [1973] none of the affected
members of this family had strokes (apart from the
propositus whose hypertension was detected only after
he developed seizures which may have been the sequeli
of vascular occlusion). Moreover, some unaffected rela-
tives were short (patient II-5 and II-2) and none of the
affected members had a stocky build and a round face.
Also, none of the affected patients had hypertensive
retinopathy. Most of the dissimilarities and the milder
manifestations in family A might be attributed to the
monitoring and early treatment with antihypertensive
medications.
The propositus in family B (the only member of this
family examined by us) had severe hypertension de-
tected at the age of 26. He was not treated for the next
12 years until he was seen by us and had poor compli-
ance thereafter. Unlike family A in our report, he had
extensive vasculopathy affecting the large vessels in all
organs investigated. The histopathological findings on
the temporal artery biopsied was characteristic of the
intimal fibroplastic type of fibromuscular dysplasia,
and, angiographically, the distribution of arterial ste-
noses in major systemic arteries, together with a single
aneurysm in a subclavian artery, resembles the pat-
tern described in previously reported cases with this
disorder [Fleisher et al., 1978; Siegal and Dunton,
1991]. Arteritides such as Takayasu disease, temporal
(giant-cell) arteritis, and polyarteritis nodosa were
clearly absent and the artery showed no scarring that
may have represented healed inflammation. Since only
the propositus in family A had arteriography (which
was normal), the vascular changes in this patient were
most probably the cause and not the result of the un-
treated hypertension. However, the lack of compliance
with treatment with antihypertensive medication may

have contributed to the severity of the stenosing vas-
culopathy. Schuster et al. [1996a,b] reported an in-
crease in the rate of fibroblast growth in patients from
the family reported by Bilginturan et al. [1973]. Simi-
lar increased growth of fibroblast and smooth muscle
cells was reported in spontaneously hypertensive rats
[Haller et al., 1995]. These observations might provide
a clue to the cause of the vasculopathy detected in the
propositus in family B.
Short stature was present in the family of Bilgin-
turan et al. [1973] and both families reported herein. In
our family A, all affected members were below −2 SD in
height and in our family B the propositus, and the
other affected members of his family were much
shorter than the unaffected sibs. However, Bilginturan
et al. [1973] did not mention the normal height of un-
affected patients in the Turkish family. Since short
people, especially men, tend to choose short spouses,
we can expect that the spouses as well as the unaf-
fected members of the family will be short and thus this
finding may not serve as a characteristic finding of this
syndrome. The families reported by us were of English
and Hispanic descent, which extends the ethnic diver-
sity of this condition. The propositus in family B was
lost to follow-up and cannot be investigated further.
However, attempts are ongoing to demonstrate linkage
of the condition in family A to markers at 12p11.2-12.1
[Schuster et al., 1996a,b].
Recent research has demonstrated that cases with
essential hypertension have an increased incidence of
neurovascular compression at the ventrolateral me-
dulla [Naraghi et al., 1994] and similar findings
[Naraghi et al., in press] were detected in members of
the Turkish family reported by Bilginturan et al.
[1973]. Further studies are ongoing to determine if the
affected members in our family A have similar neuro-
vascular compression.
Although most cases with essential hypertension
have a multifactorial condition, it is by studying the
rare single gene disorders, associated with hyperten-
sion, that the major genes involved in the pathogenesis
of this common condition will be identified and their
role delineated.
Brachydactyly-Hypertension 285
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