Young Woman Affected by a Rare Form of Familial ......A Rare Form of Connective Tissue Disorder 165...
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Circulation Journal Vol.72, January 2008 tenosis of the pulmonary artery (PA) may occur as single or numerous lesions located anywhere from the main pulmonary trunk to the smaller peripheral arterial branches. Associated defects are observed in most patients and include pulmonic valvular stenosis, ventricular septal defect, tetralogy of Fallot, and supravalvular stenosis. Several other congenital diseases have been also associated with pulmonary stenosis (eg, rubella and Noonan, William’s, Argille’s and Apert’s syndromes). 1–3 Among the several connective tissue disorders, recently a new clinical and molecular entity was recognized as associ- ated with tortuosity and elongation of the major arteries, and often associated with pulmonary stenosis, pulmonary hyper- tension, and aneurysms. Arterial tortuosity syndrome (ATS) is a rare hereditary disorder characterized by the same clini- cal skin – joint – vasculature signs of Ehlers-Danlos syn- drome (ie, skin and joint laxity, contractures and dislocation, arachnodactyly, inguinal hernias and facial features, recur- rent fever, bronchitis and pneumonia). 4,5 This connective disorder frequently involves the arterial (systemic and pul- monary) circulation; aneurysms, and less frequently vascular stenoses, are the clinical manifestation of a structural ab- normality of the arterial wall. 6 Unfortunately, these patients may have major vascular and pulmonary complications, such as rupture of arteries and recurrent bronchitis and pneu- monitis. 7,8 ATS is typically transmitted in an autosomal recessive mode and the causal gene is still unknown, 9,10 although Coucke et al recently mapped a gene for this syndrome to chromosome 20q13. 11 Case Report We report a rare case of a 20-year-old woman affected by ATS with the same clinical skin signs of Ehlers-Danlos syndrome, admitted to our Cardiology Unit suffering from right chest pain, fever (38°C) and dyspnoea, with signs of right congestive heart failure (ascites and pedal oedema). In the family history her 21-year-old sister had already been found to have the same skin and vascular findings (Ehlers- Danlos signs with severe multiple peripheral arterial pulmo- nary stenosis). 3 The electrocardiogram showed sinus rhythm of 100 beats/min, right axis deviation, increased P wave amplitude, incomplete right bundle branch block and signs of right ventricular hypertrophy and overload (Fig 1). The echocardiogram color Doppler showed severe PA hypertension (110 mmHg). The right ventricle and atrium were both dilated, with moderate – severe tricuspid regurgi- tation. The inferior caval vein was enlarged, with mild respiratory excursion. The left ventricular diameter was reduced (Fig 2). She had been evaluated using right cardiac catheterisa- tion and pulmonary arteriography (Table 1) at 2 years of age and then again at 16 years, with the diagnosis of stenosis/ hypoplasia of the major right end left PA and severe steno- sis at the origin of the lobar PA segments. Right ventricular angiocardiogram showed bilateral artery pulmonary obstruc- tion with numerous sites of stenosis and post-stenotic dilata- tion of the peripheral pulmonary arterial tree (Figs 3,4). The patient and her sister both had an arterial anomaly, with elongation of the aortic arch and kinking and coiling of Circ J 2008; 72: 164 – 167 (Received February 27, 2007; revised manuscript received August 13, 2007; accepted September 5, 2007) Cattedra di Cardiologia, Università di Brescia, Brescia, Italy Mailing address: Gregoriana Zanini, MD, Via Redipuglia 11; 25050 Passirano (BS), Italy. E-mail: [email protected] All rights are reserved to the Japanese Circulation Society. For per- missions, please e-mail: [email protected] Young Woman Affected by a Rare Form of Familial Connective Tissue Disorder Associated With Multiple Arterial Pulmonary Stenosis and Severe Pulmonary Hypertension Antonio D’Aloia, MD; Enrico Vizzardi, MD; Gregoriana Zanini, MD; Elena Antonioli, MD; Pompilio Faggiano, MD; Livio Dei Cas, MD A woman with skin findings of a connective tissue disorder, typical of Ehlers-Danlos syndrome, was admitted to the Cardiology Division because of signs of congestive heart failure. Electrocardiogram showed sinus tachycar- dia, signs of right ventricular enlargement and hypertrophy. Echocardiogram showed right ventricular dilatation, and severe tricuspid regurgitation with indirect signs of severe pulmonary systolic hypertension. Chest computed tomography revealed bilateral and diffuse involvement of the peripheral pulmonary arteries, with kinking and elongation of the pulmonary vessels associated with multiple stenoses and post-stenotic dilatation. On artery angiography an elongation of the aortic root with kinking and coiling of the carotid and vertebral vessels was also detected. This young patient exhibited features of arterial tortuosity syndrome, an uncommon connective tissue disorder, with peculiar dysmorphism and clinical signs overlapping Ehlers-Danlos syndrome. (Circ J 2008; 72: 164 – 167) Key Words: Arterial tortuosity syndrome; Congestive heart failure; Ehlers-Danlos syndrome S
Transcript of Young Woman Affected by a Rare Form of Familial ......A Rare Form of Connective Tissue Disorder 165...
Circulation Journal Vol.72, January 2008
tenosis of the pulmonary artery (PA) may occur assingle or numerous lesions located anywhere fromthe main pulmonary trunk to the smaller peripheral
arterial branches. Associated defects are observed in mostpatients and include pulmonic valvular stenosis, ventricularseptal defect, tetralogy of Fallot, and supravalvular stenosis.Several other congenital diseases have been also associatedwith pulmonary stenosis (eg, rubella and Noonan, William’s,Argille’s and Apert’s syndromes).1–3
Among the several connective tissue disorders, recently anew clinical and molecular entity was recognized as associ-ated with tortuosity and elongation of the major arteries, andoften associated with pulmonary stenosis, pulmonary hyper-tension, and aneurysms. Arterial tortuosity syndrome (ATS)is a rare hereditary disorder characterized by the same clini-cal skin – joint – vasculature signs of Ehlers-Danlos syn-drome (ie, skin and joint laxity, contractures and dislocation,arachnodactyly, inguinal hernias and facial features, recur-rent fever, bronchitis and pneumonia).4,5 This connectivedisorder frequently involves the arterial (systemic and pul-monary) circulation; aneurysms, and less frequently vascularstenoses, are the clinical manifestation of a structural ab-normality of the arterial wall.6 Unfortunately, these patientsmay have major vascular and pulmonary complications,such as rupture of arteries and recurrent bronchitis and pneu-monitis.7,8 ATS is typically transmitted in an autosomalrecessive mode and the causal gene is still unknown,9,10
although Coucke et al recently mapped a gene for thissyndrome to chromosome 20q13.11
Case ReportWe report a rare case of a 20-year-old woman affected
by ATS with the same clinical skin signs of Ehlers-Danlossyndrome, admitted to our Cardiology Unit suffering fromright chest pain, fever (38°C) and dyspnoea, with signs ofright congestive heart failure (ascites and pedal oedema). Inthe family history her 21-year-old sister had already beenfound to have the same skin and vascular findings (Ehlers-Danlos signs with severe multiple peripheral arterial pulmo-nary stenosis).3
The electrocardiogram showed sinus rhythm of100 beats/min, right axis deviation, increased P waveamplitude, incomplete right bundle branch block and signsof right ventricular hypertrophy and overload (Fig1).
The echocardiogram color Doppler showed severe PAhypertension (110mmHg). The right ventricle and atriumwere both dilated, with moderate–severe tricuspid regurgi-tation. The inferior caval vein was enlarged, with mildrespiratory excursion. The left ventricular diameter wasreduced (Fig2).
She had been evaluated using right cardiac catheterisa-tion and pulmonary arteriography (Table1) at 2 years of ageand then again at 16 years, with the diagnosis of stenosis/hypoplasia of the major right end left PA and severe steno-sis at the origin of the lobar PA segments. Right ventricularangiocardiogram showed bilateral artery pulmonary obstruc-tion with numerous sites of stenosis and post-stenotic dilata-tion of the peripheral pulmonary arterial tree (Figs3,4). Thepatient and her sister both had an arterial anomaly, withelongation of the aortic arch and kinking and coiling of
Circ J 2008; 72: 164–167
(Received February 27, 2007; revised manuscript received August13, 2007; accepted September 5, 2007)Cattedra di Cardiologia, Università di Brescia, Brescia, ItalyMailing address: Gregoriana Zanini, MD, Via Redipuglia 11; 25050Passirano (BS), Italy. E-mail: [email protected] rights are reserved to the Japanese Circulation Society. For per-missions, please e-mail: [email protected]
Young Woman Affected by a Rare Form of Familial Connective Tissue Disorder Associated
With Multiple Arterial Pulmonary Stenosis and Severe Pulmonary Hypertension
Antonio D’Aloia, MD; Enrico Vizzardi, MD; Gregoriana Zanini, MD; Elena Antonioli, MD; Pompilio Faggiano, MD; Livio Dei Cas, MD
A woman with skin findings of a connective tissue disorder, typical of Ehlers-Danlos syndrome, was admitted tothe Cardiology Division because of signs of congestive heart failure. Electrocardiogram showed sinus tachycar-dia, signs of right ventricular enlargement and hypertrophy. Echocardiogram showed right ventricular dilatation,and severe tricuspid regurgitation with indirect signs of severe pulmonary systolic hypertension. Chest computedtomography revealed bilateral and diffuse involvement of the peripheral pulmonary arteries, with kinking andelongation of the pulmonary vessels associated with multiple stenoses and post-stenotic dilatation. On arteryangiography an elongation of the aortic root with kinking and coiling of the carotid and vertebral vessels wasalso detected. This young patient exhibited features of arterial tortuosity syndrome, an uncommon connectivetissue disorder, with peculiar dysmorphism and clinical signs overlapping Ehlers-Danlos syndrome. (Circ J2008; 72: 164–167)
Key Words: Arterial tortuosity syndrome; Congestive heart failure; Ehlers-Danlos syndrome
S
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carotid and vertebral vessels detected by aortic and carotidartery angiography (Figs5,6). To confirm the examinationan ultrafast chest computed tomography scan was per-formed, which demonstrated the pulmonary stenosis andaneurysms and/or kinking of major arterial vessels, withnarrowing at the bifurcation of the PA, extending into boththe right and left branches with a combination of main andperipheral stenosis at numerous sites (Figs7,8); pulmonary
Fig1. ECG on admission.
Fig2. Echocardiogram on admission.
Pulmonary systolic pressure 110 mmHgPulmonary diastolic pressure 36 mmHgPulmunary capillary wedge pressure 10 mmHgCardiac output 5.5 L/min
Table 1 Hemodynamic Data
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perfusion scintigraphy was normal.The patient had undergone a genetic study at another in-
stitution and it was positive for a mutation in GLUT10; inthe present study genomic DNA was extracted from periph-eral blood leukocytes by a standard technique. A set of 400highly polymorphic microsatellite markers (ABI PRISM
Linkage Mapping Set Version 2; Applied Biosysytems,Foster City, CA, USA) with an average spacing of 10 centi-morgans was analyzed on a capillary sequencer (ABI3100;Applied Biosystems) and then the DNA sample was ana-lyzed. The data were processed using Genescan andGenemapper software (Applied Biosystem). Patient DNA
Fig3. Catheterization and angiography of the patient. Fig4. Catheterization and angiography of the patient’s sister.
Fig5. Carotid and vertebral angiography of the patient. Fig6. Carotid and vertebral angiography of the patient’s sister.
Fig7. Thoracic computed tomography scan of the patient.
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was analysed with microsatellite markers from theGenethon genetic map. Markers were investigated on anABI3100 capillary sequencer, and alleles were numberedaccording to length, with the shortest allele being assignednumber. MLINK was used to calculate 2-point lod scoresbetween the ATS locus and the markers.
DiscussionATS is a rare autosomal recessive disorder characterized
by tortuosity, elongation, stenosis and aneurysm formationin the major arteries, because of disruption of the elasticfibers in the medial layer of the arterial wall. It is caused bymutations in SLC2A10, which encodes the facilitativeglucose transporter GLUT10; GLUT10 deficiency is associ-ated with upregulation of the TGFβpathway in the arterialwall, a finding also observed in another syndrome, Loeys-Dietz syndrome in which aortic aneurysms are associatedwith arterial tortuosity. A correct diagnosis gives informa-tion useful in preventing rapid progression of the disease,for example, because of pregnancy in affected females, andenables stratification of patients for the risks of aneurysmalrupture. Furthermore, a correct diagnosis is important forfamilial screening. In the family tree of the present case, a21-year-old sister had the same skin and vascular findings(the same Ehler-Danlos type skin features), with severemultiple peripheral arterial pulmonary stenosis and elonga-tion of the aortic root, carotid and vertebral vessels; so 2siblings have clinical manifestations of the syndrome.
Mild to moderate unilateral or bilateral stenoses do notrequire surgical relief, and numerous stenotic areas areunsuitable for correction, even with intra-operative balloonangioplasty. Well-localized obstruction of a severe degreein the main PA or its major branches may be alleviated bypercutaneous transcatheter balloon angioplasty, often ac-companied by endovascular stent implantation or bypassedwith a tubular conduit. Recently, the effectiveness of angio-plasty, with stent implantation or cutting balloon therapy,was evaluated for peripheral pulmonary stenoses, but de-spite successful dilatation, only modest improvement of theclinical status after the procedure was reported.12,13
The natural history of peripheral pulmonary stenoses,and of arterial abnormalities as in the present case, are well
known, but the consequence could be relevant, consideringthe severity of the pulmonary arterial stenoses and of pul-monary hypertension and the risk of arterial rupture. In fact,it is difficult to speculate about the prognosis and therapyof these patients because there are no data about the courseof this rare disease. Therefore, this case interestingly under-lines that the clinical features of 2 different uncommon syn-dromes can coexist and overlap in the same patient.
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Fig8. Thoracic computed tomography scan of the patient.
