Professional Documents
Culture Documents
Brachydactyly-Short Stature-Hypertension (Bilginturan) Syndrome: Report On Two Families
Brachydactyly-Short Stature-Hypertension (Bilginturan) Syndrome: Report On Two Families
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
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