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,3Chin-To Fong,3 Meredith M. Silver,1 Devereux N. Saller Jr.,3 George H. Bresnick,3 Andres Giedion,4Ralph S. Lachman,5 and David L. Rimoin5

1Hospital for Sick Children, Toronto, Ontario, Canada2The Permanente Medical Group, Sacramento, California3Strong Memorial Hospital, Rochester, New York4Kinderspital Zurich, Zurich, Switzerland5Cedars-Sinai Medical Center, Los Angeles, California

We report on two families with autosomaldominant brachydactyly of hands and feetand hypertension. All affected members ofthe first family had proportionate shortstature. However, the propositus and the af-fected relatives in the second family wereonly short compared to unaffected relatives.The hypertension was medically responsivein all cases. The propositus in the secondfamily had poor compliance and a strikinggeneralized vasculopathy. All patients wereof normal intelligence and had a normal fa-cial appearance. The brachydactyly-shortstature-hypertension syndrome was first re-ported by Bilginturan et al. [1973] in a Turk-ish family and the families reported by usare Caucasian and Hispanic. The gene caus-ing this condition in the original Turkishfamily was recently mapped to 12p. Our re-port expands our existing knowledge andthe 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

INTRODUCTION

Hypertension is a heterogeneous condition affectingabout 20% of the world population [Lifton, 1996]. Inspite 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 hypertensionhas 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 bloodpressure in the affected persons by age 50 years.

We report on two families with autosomal dominantbrachydactyly-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 thesecond family was investigated for hypertension andchest 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 withbrachydactyly for hypertension. Treatment with anti-hypertensive medications resulted in a good prognosisand the prevention of complications in the affectedmembers of the English family. The propositus in fam-ily B had severe stenosing vasculopathy, which mostprobably caused his high blood pressure, although hispoor compliance may have increased the severity ofthis condition. Further reports are needed to find if thevasculopathy is part of the genetic condition in thisfamily.

CLINICAL REPORTSFamily A (Fig. 1)

The propositus (III-2) (Fig. 2) presented at age 7years age with headaches and 3 days later developed

Contract grant sponsor: NIH Program Project Grant; Contractgrant number: HD 22657; Contract grant sponsor: The Interna-tional Skeletal Dysplasia Registry; Contract grant sponsor:Steven Spielberg Pediatric Research Center at Cedars-SinaiMedical Center.

*Correspondence to: Dr. D. Chitayat, The Hospital for SickChildren, 555 University Avenue, Toronto, Ontario, Canada,M5G 1X8.

Received 2 April 1997; Accepted 12 April 1997

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

© 1997 Wiley-Liss, Inc.

seizures. On examination, he was short [111 cm (−3.5SD)], his OFC was 51 cm (−1 SD), and weight was 20.2kg (5th centile). His armspan minus height and U/Lsegment ratio were normal. He had brachydactyly ofhands (Fig. 3) and feet (Fig. 4) (total hands, palms, and3rd fingers measured <3rd centile). His blood pressurewas 175/135 mm Hg and ophthalmologic findings werenormal. An echocardiogram showed thickening of the

interventricular septum. Results of coagulation stud-ies, plasma electrolytes, creatinine, and urinalysiswere normal. Captopril DTPA scan, 24 hour urine forVMA, and cathecholamines were normal. An abdomi-nal CT scan demonstrated normal kidneys and adre-nals. Renal and adrenal arteriography findings werenormal 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 alsonormal. A complete skeletal survey showed generalizedbrachymetacarpalia but more marked shortness of the4th and 5th metacarpals, brachyphalangy, and un-usual cone-shaped epiphyses of the phalanges (Fig. 5).The feet showed generalized brachymetatarsalia and

Fig. 2. The propositus. Note normal facial appearance.

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. 1. Family A: pedigree.

Fig. 3. The propositus’s hands showing brachydactyly.

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brachyphalangy, mainly of the basal phalanges withpremature closure or absence of the epiphyses (Fig. 6).There was also mild scoliosis of the thoracic spine withflattening of the posterior parts of the vertebral bodiesT10-12.

Detailed family history (Fig. 1) showed that the pro-positus’ brother, his father (II-1), a paternal uncle andhis son, and the paternal grandmother all had shortstature, brachydactyly (Fig. 7) and high blood pressure,well controlled with medication. Their skeletal changeswere confined to hands and feet. The grandmother (I-2)showed more pronounced brachymetacarpalia com-pared to the propositus but her brachymetatarsaliaand brachyphalangy were similar to that of the pro-

positus, except for more cone epiphyses residua in theproximal phalanges (Fig. 8). Her lumbar spine showedventral osteophytes on the vertebral bodies mostmarked between L4/L5 with narrowing of the disc. Thepelvic bones and acetabula were normal. Ophthalmo-logic findings including ERG’s on the propositus’sbrother, 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 forchronic severe hypertension. He was initially found tobe 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), weighed55.2 kg (5th centile), and his blood pressure was 250/170 mm Hg before treatment and 174/110 mm Hg aftertherapy. He had brachydactyly of hands and feet, hispalm length was 9.3 cm, and the 3rd finger length was6.3 cm, both below the 3rd centile. Ophthalmologic ex-amination showed retinal hard exudates. Radiographsshowed shortness of the metacarpals (Fig. 9), metatar-sals, and phalanges, and scalloping of the vertebralbodies. Echocardiography showed severe concentric leftventricular hypertrophy with global hypokinesia andthickened aortic valve annulus and leaflets. Cardiaccatheterization 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.

Fig. 5. Radiograms of the propositus’ feet showing generalizedbrachymetatarsalia and brachyphalangy with cone shaped epiphyses andpremature closure of the epiphyses.

Fig. 7. Radiograms of the propositus’ paternal grandmother showingsimilar brachymetacarpalia and brachyphalangy.

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amination showed normal renal size [right 9.5 and left10 cm (normal 4 10–12 cm)]. There was an area ofparenchymal loss in the lower pole of the right kidneyin 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 [normal4 0.6–1.2]. His plasma electrolyte levels were normaland 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 functionswere normal as were urinary VMA and metanephrineand salt-loaded aldosterone levels in supine and stand-ing position.

The propositus’ blood pressure was stabilized and hewas discharged on antihypertensive medication. Hewas re-admitted 10 months later for evaluation of chestpain and shortness of breath. His blood pressure onadmission 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 leftsubclavian artery distal to the left vertebral artery, 20–30% stenosis of the distal left common carotid artery, along segment of less than 50% stenosis of the proximal

left internal carotid artery, and complete occlusion ofthe left middle cerebral artery with a well developedcollateral from the anterior cerebral artery and exter-nal carotid artery. The right internal carotid arterywas 90% stenotic at its origin and the left vertebralartery 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 mediawith local loss and/or reduplication of the internal elas-tic lamina. Occasional foci of dystrophic calcificationwere present in the outer zone of the intima. The mediaand adventitia showed no inflammation, either chronicor granulomatous, nor scarring that could have markedhealed inflammation. The changes were consistentwith the intimal fibroplastic subtype of fibromusculardysplasia.

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 or40’s of a stroke. His father, as well as one of his pater-nal half sisters, also had brachydactyly of the handsand feet as well as short stature but their blood pres-sure was not known. All unaffected members of hisfamily were 180 cm tall and our patient was also ex-

Fig. 9. X-rays films of the propositus’ (family B) hands showing brachymetacarpalia and brachyphalangy.

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ceptionally short. The patient was treated with antihy-pertensive medication and was subsequently lost to fol-low-up.

DISCUSSION

Hypertension is a heterogeneous condition affectingabout 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 isthe subject of ongoing debate. The Pickering school[Pickering, 1978] advocates that blood pressure has acontinuous distribution and high blood pressure is theupper end of the distribution. Thus, essential hyper-tension is a multifactorial trait with multiple genes aswell 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 arenot necessarily contradictory in that many genes areinvolved in controlling blood pressure and mutations incertain 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 ofhypertension has concentrated on single gene disordersassociated with high blood pressure [Lifton, 1996].These conditions may simplify the genetic analysis,

mapping, and eventually the detection of the genes in-volved in regulating blood pressure.

Two autosomal dominant conditions associated withhypertension have been delineated. Glucocorticoid-remediable aldosteronism is caused by a chimeric genearising from unequal crossing-over between the aldo-sterone synthase and 11b-hydroxylase genes. Thisfuses the 58 regulatory sequences from the latter ontothe coding sequences of the former. As a result, theexpression of the aldosterone synthase gene is broughtunder the control of ACTH [Ulick et al., 1990].

Another autosomal dominant condition associatedwith high blood pressure is Liddle’s syndrome or pseu-dohypoaldosteronism. This syndrome is the result of amutation in genes encoding either the b or g subunitsof the amiloride-sensitive distal renal epithelial sodiumchannel [Shimkets et al., 1994]. Neither of these twosyndromes 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 etal., 1984]. However, unlike the two families discussedin 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-generationTurkish family from the eastern Black Sea coast, with

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

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autosomal dominant brachydactyly, short stature, andhypertension. The hypertension increased in severitywith age and many of the affected relatives died at arelatively young age of stroke. Intensive investigationsfailed to delineate the etiology of this condition. Recentlinkage 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 byus have many similarities to the family reported byBilginturan et al. [1973] and later by Schuster et al.[1996]. In our family A, the propositus presented withhigh blood pressure and seizures. He also had brachy-dactyly of both hands and feet and short stature. Hisshort stature was proportionate and a skeletal surveyshowed brachydactyly of the hands and feet withbrachymetacarpalia and brachyphalangy, brachymeta-tarsalia, and cone-shaped epiphyses. Renal functionwas normal and his ophthalmological findings werenormal.

The other affected members of this family had hy-pertension, detected in childhood and diagnosed as es-sential hypertension, after a thorough investigationfailed to delineate the etiology. Unlike the family re-ported by Bilginturan et al. [1973] none of the affectedmembers of this family had strokes (apart from thepropositus whose hypertension was detected only afterhe developed seizures which may have been the sequeliof 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 hypertensiveretinopathy. Most of the dissimilarities and the mildermanifestations in family A might be attributed to themonitoring and early treatment with antihypertensivemedications.

The propositus in family B (the only member of thisfamily examined by us) had severe hypertension de-tected at the age of 26. He was not treated for the next12 years until he was seen by us and had poor compli-ance thereafter. Unlike family A in our report, he hadextensive vasculopathy affecting the large vessels in allorgans investigated. The histopathological findings onthe temporal artery biopsied was characteristic of theintimal fibroplastic type of fibromuscular dysplasia,and, angiographically, the distribution of arterial ste-noses in major systemic arteries, together with a singleaneurysm in a subclavian artery, resembles the pat-tern described in previously reported cases with thisdisorder [Fleisher et al., 1978; Siegal and Dunton,1991]. Arteritides such as Takayasu disease, temporal(giant-cell) arteritis, and polyarteritis nodosa wereclearly absent and the artery showed no scarring thatmay have represented healed inflammation. Since onlythe propositus in family A had arteriography (whichwas normal), the vascular changes in this patient weremost probably the cause and not the result of the un-treated hypertension. However, the lack of compliancewith treatment with antihypertensive medication may

Fig. 11. The temporal artery biopsy (propositus, family B) showing a marked intimal fibrous thickening and lumenal lies at the bar of the ‘‘H’’ causedby 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 adjacentto 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. (Hematoxylinand eosin ×10 [original magnification]).

284 Chitayat et al.

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 fromthe family reported by Bilginturan et al. [1973]. Simi-lar increased growth of fibroblast and smooth musclecells was reported in spontaneously hypertensive rats[Haller et al., 1995]. These observations might providea clue to the cause of the vasculopathy detected in thepropositus in family B.

Short stature was present in the family of Bilgin-turan et al. [1973] and both families reported herein. Inour family A, all affected members were below −2 SD inheight and in our family B the propositus, and theother affected members of his family were muchshorter than the unaffected sibs. However, Bilginturanet al. [1973] did not mention the normal height of un-affected patients in the Turkish family. Since shortpeople, 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 thisfinding may not serve as a characteristic finding of thissyndrome. The families reported by us were of Englishand Hispanic descent, which extends the ethnic diver-sity of this condition. The propositus in family B waslost to follow-up and cannot be investigated further.However, attempts are ongoing to demonstrate linkageof the condition in family A to markers at 12p11.2-12.1[Schuster et al., 1996a,b].

Recent research has demonstrated that cases withessential hypertension have an increased incidence ofneurovascular compression at the ventrolateral me-dulla [Naraghi et al., 1994] and similar findings[Naraghi et al., in press] were detected in members ofthe Turkish family reported by Bilginturan et al.[1973]. Further studies are ongoing to determine if theaffected members in our family A have similar neuro-vascular compression.

Although most cases with essential hypertensionhave a multifactorial condition, it is by studying therare single gene disorders, associated with hyperten-sion, that the major genes involved in the pathogenesisof this common condition will be identified and theirrole delineated.

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