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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
Hypertension is a heterogeneous condition affecting
and hypertension. All affected members of about 20% of the world population [Lifton, 1996]. In
the first family had proportionate short
spite of intensive research, the vast knowledge ac-
stature. However, the propositus and the af-
quired about the pathophysiology of this common con-
fected relatives in the second family were dition and the advances in the treatment of hyperten-
only short compared to unaffected relatives. sion, the genetic basis of most forms of hypertension
The hypertension was medically responsive
has not been delineated. In 1973, Bilginturan et al.
in all cases. The propositus in the second [1973] reported on a large Turkish family with hyper-
family had poor compliance and a striking
tension, brachydactyly, and short stature with autoso-
generalized vasculopathy. All patients were
mal dominant inheritance and full penetrance. Com-
of normal intelligence and had a normal fa- parison of affected with unaffected relatives in this kin-
cial appearance. The brachydactyly-short
dred demonstrated a 50 mm Hg higher median blood
stature-hypertension syndrome was first re- pressure in the affected persons by age 50 years.
ported by Bilginturan et al. [1973] in a Turk-
We report on two families with autosomal dominant
ish family and the families reported by us
brachydactyly-short stature-hypertension (BSH) syn-
are Caucasian and Hispanic. The gene caus-
drome. One family was of English and the other of His-
ing this condition in the original Turkish panic origin. The propositus in the first family was ad-
family was recently mapped to 12p. Our re-
mitted to the hospital for investigation of seizures as-
port expands our existing knowledge and sociated with hypertension and the propositus in the
the ethnic diversity of this syndrome. Am. J.
second family was investigated for hypertension and
Med. Genet. 73:279–285, 1997.
chest pain.
© 1997 Wiley-Liss, Inc.
The two families reported by us show the ethnic di-
versity of this autosomal dominant disorder and em-
KEY WORDS: hypertension; short stature; phasize the importance of screening all cases with
brachydactyly; vasculopa- brachydactyly for hypertension. Treatment with anti-
thy; intracerebral hemor- hypertensive medications resulted in a good prognosis
rhage; autosomal dominant 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
Contract grant sponsor: NIH Program Project Grant; Contract
grant number: HD 22657; Contract grant sponsor: The Interna- vasculopathy is part of the genetic condition in this
tional Skeletal Dysplasia Registry; Contract grant sponsor: family.
Steven Spielberg Pediatric Research Center at Cedars-Sinai
Medical Center. CLINICAL REPORTS
*Correspondence to: Dr. D. Chitayat, The Hospital for Sick Family A (Fig. 1)
Children, 555 University Avenue, Toronto, Ontario, Canada,
M5G 1X8. The propositus (III-2) (Fig. 2) presented at age 7
Received 2 April 1997; Accepted 12 April 1997 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
Fig. 3. The propositus’s hands showing brachydactyly.
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 interventricular septum. Results of coagulation stud-
was 175/135 mm Hg and ophthalmologic findings were ies, plasma electrolytes, creatinine, and urinalysis
normal. An echocardiogram showed thickening of the 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-
Fig. 2. The propositus. Note normal facial appearance. langy and cone shaped epiphyses in the phalanges.
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
Fig. 5. Radiograms of the propositus’ feet showing generalized ventral osteophytes on the vertebral bodies most
brachymetatarsalia and brachyphalangy with cone shaped epiphyses and marked between L4/L5 with narrowing of the disc. The
premature closure of the epiphyses. pelvic bones and acetabula were normal. Ophthalmo-
logic findings including ERG’s on the propositus’s
brachyphalangy, mainly of the basal phalanges with brother, grandmother, and affected uncle were normal.
premature closure or absence of the epiphyses (Fig. 6). Chromosomes of the affected uncle (II-3) were normal.
There was also mild scoliosis of the thoracic spine with Family B (Fig. 9): This propositus (II-2) was a 38-
flattening of the posterior parts of the vertebral bodies year-old Hispanic male who was hospitalized for
T10-12. chronic severe hypertension. He was initially found to
Detailed family history (Fig. 1) showed that the pro- be hypertensive at age 26 years in Mexico and re-
positus’ brother, his father (II-1), a paternal uncle and mained untreated until 4 months before hospitaliza-
his son, and the paternal grandmother all had short tion. He was 167.5 cm tall (5–10th centile), weighed
stature, brachydactyly (Fig. 7) and high blood pressure, 55.2 kg (5th centile), and his blood pressure was 250/
well controlled with medication. Their skeletal changes 170 mm Hg before treatment and 174/110 mm Hg after
were confined to hands and feet. The grandmother (I-2) therapy. He had brachydactyly of hands and feet, his
showed more pronounced brachymetacarpalia com- palm length was 9.3 cm, and the 3rd finger length was
pared to the propositus but her brachymetatarsalia 6.3 cm, both below the 3rd centile. Ophthalmologic ex-
and brachyphalangy were similar to that of the pro- 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. 6. The propositus’ father’s hands showing brachydactyly. 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 left internal carotid artery, and complete occlusion of
10 cm (normal 4 10–12 cm)]. There was an area of the left middle cerebral artery with a well developed
parenchymal loss in the lower pole of the right kidney collateral from the anterior cerebral artery and exter-
in a wedge distribution and arteriogram showed nar- nal carotid artery. The right internal carotid artery
row renal and mesenteric arteries [renal artery diam- was 90% stenotic at its origin and the left vertebral
eter was 4 mm (normal 4 10 mm)]. His BUN was 19 artery was 70–90% stenotic at its origin.
[normal 4 11–23] and his creatinine was 1.0 [normal Biopsy of the left temporal artery showed severe ste-
4 0.6–1.2]. His plasma electrolyte levels were normal nosis due to marked intimal fibroplasia, with no in-
and his urinalysis showed normal specific gravity and flammatory or atherosclerotic changes (Fig. 11). Fo-
+1 protein. Renal vein renin levels were 18.6 ng/ml/ cally, the thickened intima encroached on the media
hour on the left and 24.4 ng/ml/hour on the right (nor- with local loss and/or reduplication of the internal elas-
mal41–7.7 ng/ml/hour). Thyroid and adrenal functions tic lamina. Occasional foci of dystrophic calcification
were normal as were urinary VMA and metanephrine were present in the outer zone of the intima. The media
and salt-loaded aldosterone levels in supine and stand- and adventitia showed no inflammation, either chronic
ing position. or granulomatous, nor scarring that could have marked
The propositus’ blood pressure was stabilized and he healed inflammation. The changes were consistent
was discharged on antihypertensive medication. He with the intimal fibroplastic subtype of fibromuscular
was re-admitted 10 months later for evaluation of chest dysplasia.
pain and shortness of breath. His blood pressure on The patient reported that his sister also had brachy-
admission was 260/135 mm Hg. Angiography demon- dactyly involving her hands and feet, and short stat-
strated stenosis of the renal and mesenteric arteries ure, with hypertension, and that she died in her 30’s or
(Fig. 10), a 1 cm right proximal subclavian artery an- 40’s of a stroke. His father, as well as one of his pater-
eurysm with two long irregular stenotic foci in the left nal half sisters, also had brachydactyly of the hands
subclavian artery distal to the left vertebral artery, 20– and feet as well as short stature but their blood pres-
30% stenosis of the distal left common carotid artery, a sure was not known. All unaffected members of his
long segment of less than 50% stenosis of the proximal family were 180 cm tall and our patient was also ex-
Brachydactyly-Hypertension 283

Fig. 10. Angiography of the renal artery (arrow) showing narrowing of the arteries.

ceptionally short. The patient was treated with antihy- mapping, and eventually the detection of the genes in-
pertensive medication and was subsequently lost to fol- volved in regulating blood pressure.
low-up. Two autosomal dominant conditions associated with
hypertension have been delineated. Glucocorticoid-
remediable aldosteronism is caused by a chimeric gene
DISCUSSION
arising from unequal crossing-over between the aldo-
sterone synthase and 11b-hydroxylase genes. This
Hypertension is a heterogeneous condition affecting
about 15–20% of adults in developed countries and con- fuses the 58 regulatory sequences from the latter onto
tributing to over 200,000 deaths from stroke, myocar- the coding sequences of the former. As a result, the
dial infarction, and end-stage renal disease each year expression of the aldosterone synthase gene is brought
[Lifton, 1966]. The cause of essential hypertension is under the control of ACTH [Ulick et al., 1990].
the subject of ongoing debate. The Pickering school Another autosomal dominant condition associated
[Pickering, 1978] advocates that blood pressure has a with high blood pressure is Liddle’s syndrome or pseu-
continuous distribution and high blood pressure is the dohypoaldosteronism. This syndrome is the result of a
upper end of the distribution. Thus, essential hyper- mutation in genes encoding either the b or g subunits
tension is a multifactorial trait with multiple genes as of the amiloride-sensitive distal renal epithelial sodium
well as environmental factors determining blood pres- channel [Shimkets et al., 1994]. Neither of these two
sure elevation. On the other hand, the Platt school syndromes is associated with skeletal abnormalities.
[1963] states that essential hypertension is an autoso- The association of brachydactyly, cone-shaped epiph-
mal dominant single gene disorder. These theories are yses, and hypertension was reported in Saldino-
not necessarily contradictory in that many genes are Mainzer dysplasia [Saldino and Mainzer, 1971; Ellis et
involved in controlling blood pressure and mutations in al., 1984]. However, unlike the two families discussed
certain of these genes could result in high blood pres- in this report, Saldino-Mainzer dysplasia is an autoso-
sure, inherited as a single gene disorder. Recently, mal recessive disorder associated with nephronophthi-
much of the research aimed at deciphering the cause of sis and chronic renal failure, Leber’s optic atrophy, cer-
hypertension has concentrated on single gene disorders ebellar ataxia, and hepatic fibrosis.
associated with high blood pressure [Lifton, 1996]. In 1973, Bilginturan et al. reported a six-generation
These conditions may simplify the genetic analysis, 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 affected members had a stocky build and a round face.
hypertension. The hypertension increased in severity Also, none of the affected patients had hypertensive
with age and many of the affected relatives died at a retinopathy. Most of the dissimilarities and the milder
relatively young age of stroke. Intensive investigations manifestations in family A might be attributed to the
failed to delineate the etiology of this condition. Recent monitoring and early treatment with antihypertensive
linkage analysis has mapped the gene causing the con- medications.
dition in this family to 12p [Schuster et al., 1996]. The propositus in family B (the only member of this
The clinical findings in the two families reported by family examined by us) had severe hypertension de-
us have many similarities to the family reported by tected at the age of 26. He was not treated for the next
Bilginturan et al. [1973] and later by Schuster et al. 12 years until he was seen by us and had poor compli-
[1996]. In our family A, the propositus presented with ance thereafter. Unlike family A in our report, he had
high blood pressure and seizures. He also had brachy- extensive vasculopathy affecting the large vessels in all
dactyly of both hands and feet and short stature. His organs investigated. The histopathological findings on
short stature was proportionate and a skeletal survey the temporal artery biopsied was characteristic of the
showed brachydactyly of the hands and feet with intimal fibroplastic type of fibromuscular dysplasia,
brachymetacarpalia and brachyphalangy, brachymeta- and, angiographically, the distribution of arterial ste-
tarsalia, and cone-shaped epiphyses. Renal function noses in major systemic arteries, together with a single
was normal and his ophthalmological findings were aneurysm in a subclavian artery, resembles the pat-
normal. tern described in previously reported cases with this
The other affected members of this family had hy- disorder [Fleisher et al., 1978; Siegal and Dunton,
pertension, detected in childhood and diagnosed as es- 1991]. Arteritides such as Takayasu disease, temporal
sential hypertension, after a thorough investigation (giant-cell) arteritis, and polyarteritis nodosa were
failed to delineate the etiology. Unlike the family re- clearly absent and the artery showed no scarring that
ported by Bilginturan et al. [1973] none of the affected may have represented healed inflammation. Since only
members of this family had strokes (apart from the the propositus in family A had arteriography (which
propositus whose hypertension was detected only after was normal), the vascular changes in this patient were
he developed seizures which may have been the sequeli most probably the cause and not the result of the un-
of vascular occlusion). Moreover, some unaffected rela- treated hypertension. However, the lack of compliance
tives were short (patient II-5 and II-2) and none of the with treatment with antihypertensive medication may
Brachydactyly-Hypertension 285

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