Heterotaxy syndrome with severe pulmonary hypertension in an adult.

ABSTRACT: Heterotaxy syndrome is a rare clinical entity in adults, characterized by situs ambiguus, congenital heart defects, and splenic malformations. We report the case of an adult with heterotaxy syndrome (including situs ambiguus, bilateral superior vena cava, hypoplastic right-sided spleen and portosystemic shunts) presenting with dyspnea due to severe pulmonary hypertension. Vasodilatory therapy was initiated, leading to marked reduction of clinical symptoms. This case exhibits 2 particular and partially novel features: primary diagnosis of heterotaxy syndrome may be delayed until adulthood, and heterotaxy syndrome maybe associated with pulmonary hypertension, possibly on the basis of longstanding portosystemic shunts.

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PATIENTS WITH HETEROTAXY SYNDROME (polysplenia-asplenia syndrome, also formerly known as Ivemark's syndrome) present with a rare anatomic phenotype, characterized by arrangement of the internal organs along the left-right body axis in neither normal (sims solitus) nor completely reversed (situs inversus viscerum) position. Various clinical manifestations, including congenital heart defects (CHD), altered lung lobulation, splenic malformations, and situs ambiguus, are observed. (1,2) Due to complex cyanotic CHD, heterotaxy syndrome presents early in childhood in most affected individuals. We report the case of a 31-year-old patient in whom exercise-induced dyspnea due to severe primary pulmonary hypertension led to the diagnosis of heterotaxy syndrome unusually late in adulthood.

CASE REPORT

A 31-year-old previously healthy white man was admitted to the hospital with progressive, atypical chest pain and shortness of breath on exertion. Personal and family history were otherwise unremarkable. His blood pressure, temperature, and pulse rate were normal, and physical examination revealed no abnormalties. Routine laboratory values were in the normal range. The electrocardiogram (EGG) showed signs of right ventricular hypertrophy with right bundle branch block, positive Sokolow-Lyon index (2.1 mV), and [S.sub.1][Q.sub.3] pattern. Chest radiograph showed dilated central pulmonary arteries and abnormal proximal-to-distal tapering of the pulmonary arteries. Arterial blood gas analysis was normal. Lung diffusion capacity was shown to be 62.9% of normal when tested with carbon monoxide; otherwise, results of pulmonary function tests were normal. Transthoracic and transesophageal ECGs demonstrated a dilated right ventricle and atrium, right ventricular concentric hypertrophy, and a persisting left superior vena cava, which drained into the dilated coronary sinus (Fig 1). The presence of left-right cardiac shunting was excluded by injection of saline echo contrast medium. Left ventricular function and heart valves were normal. The patient had an invasive cardiac diagnostic procedure. Left-sided cardiac catheterization, including coronary angiography, was normal. Right heart catheterization proved severe pulmonary arterial hypertension, with pulmonary artery pressure of 78/30mm Hg (mean systolic pressure of 53 mm Hg), pulmonary capillary wedge pressure of 14 mm Hg, and an excessively elevated pulmonary vascular resistance (PVR) of 369 dyne.sec.[cm.sup.5]. Neither application of nasal oxygen nor treatment with intravenous nitroglycerin resulted in a significant decrease in PVR. Pulmonary magnetic resonance angiography showed prominent central pulmonary arteries with abnormal proximal-to-distal tapering of the pulmonary arteries, but no sign of acute or chronic pulmonary embolism. Lung lobulation was normal. Inte rstitial pulmonary disease was ruled out by spiral computed tomography (CT), and no evidence of secondary pulmonary hypertension was present.

Spiral CT of the abdomen showed situs ambiguus, with the liver in midline position, and a small, hypoplastic spleen (3 cm) in the right upper abdomen (Fig 2). The small intestine was located almost completely in the right abdomen. Abdominal angiography revealed complex vascular malformations, with aneurysms of the right and left renal artery, drainage of the inferior mesenteric vein into the superior mesenteric vein, and from there into the inferior vena cava. The portal vein and hepatic veins were hypoplastic. Peripheral blood smear showed numerous Howell-Jolly bodies. Blood ammonia levels were consistently elevated, up to 130 [micro]mol/L (normal 15-60 [micro]mol/L). No reason for the portal hypertension was found; a liver biopsy specimen showed normal histology. The diagnosis of heterotaxy syndrome with severe pulmonary hypertension was, therefore, established.

Symptomatic treatment with diltiazem hydrochloride led to gradual improvement of dyspnea. The patient remained clinically stable throughout a 1-year follow-up period, though pulmonary pressure and cardiac function parameters did not change significantly.

DISCUSSION

In heterotaxy syndrome, the predominant malformations occur in the cardiovascular system, the lungs (symmetric lobulation), the spleen (polysplenia, asplenia, or hypoplastic spleen), and the gastrointestinal tract (situs ambiguus, other forms of malrotations, liver and pancreatic malformation). (1-3) Moreover, the syndrome includes a wide variety of clinical manifestations, and no single anomaly is pathognomonic. Most cases are sporadic, but familial cases have been reported. The overall prognosis of children with heterotaxy syndrome is significantly reduced, due to early manifestations in childhood or infancy. Mortality and morbidity are usually related to the degree of CHD. (2) The anatomy of CHD is highly variable. Abnormal localization of the cardiac apex, a common atrioventricular canal, anomalous systemic venous return (eg, bilateral superior vena cava, interruption of the inferior vena cava with azygos continuation), atrial and ventricular malformations and septal defects, absent coronary sinus, malpo sition or transposition of the great arteries, pulmonic stenosis, pulmonary atresia, patent ductus arteriosus, and anomalous pulmonary venous connection have often been described. (1-3) The most likely reason that our patient with heterotaxy syndrome was asymptomatic and felt well until he was 30 years old was that he had no relevant structural or functional cardiac defect. Overall, the presentation of heterotaxy syndrome in adulthood as an incidental finding is rare. (4-6)

Our patient presented with symptoms of severe pulmonary hypertension. To the best of our knowledge, pulmonary hypertension has not been previously described as the prominent clinical feature of patients with heterotaxy syndrome. The development of pulmonary hypertension in heterotaxy syndrome is possible (eg, in the setting of left-right blood shunting); however, a significant cardiac shunt volume was ruled out in our patient. We suggest that the development of pulmonary hypertension in our patient may be pathophysiologically linked to heterotaxy syndrome by the presence of severe visceral malformations.

Patients with liver cirrhosis or portal hypertension are at greater risk of having pulmonary hypertension (portopulmonary hypertension) (7,8) Altered hemodynamics or incomplete metabolism of vasoactive substances in the liver are possible mechanisms for the development of pulmonary hypertension in these patients. (9) Although parenchymal liver disease was excluded by biopsy results, a portocaval shunt was present in our patient, with drainage of the mesenteric blood into the inferior vena cava. As a result, blood ammonia levels were constantly elevated.

On the other hand, an increased risk for pulmonary hypertension has also been found in patients with functional asplenia or after splenectomy. (10,11) It has been hypothesized that the lack of splenic filter function predisposes patients to increased thrombocyte aggregation, due to persistence of abnormal erythrocytes in the circulation, which leads to widespread chronic pulmonary microthromboembolisms. The abnormally high number of Howell-Jolly bodies in our patient was indicative of altered splenic function.

There are a broad variety of clinical manifestations in heterotaxy syndrome, which can present late in adulthood if substantial cardiovascular defects are absent. The number of asymptomatic patients with heterotaxy syndrome diagnosed in adulthood may rise with the increased utilization of CT and magnetic resonance imaging. Pulmonary hypertension may develop in heterotaxy syndrome as a consequence of underlying splenic, hepatic, or vascular malformations.

References

(1.) Phoon GK, Neill CA: Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 1994; 73:581-587

(2.) Peoples WM, Moller JH, Edwards JE: Polysplenia: a review of 146 cases. Pediatr Cardiol 1983; 4:129-137

(3.) Rothmaler G, Gdanietz K, Peschel HG: The Ivemark syndrome. 7 own cases and review of the literature [in German]. Arch Kinderheilkd 1968; 77:74-97

(4.) Gayer G, Apter S, Jonas T, et al: Polysplenia syndrome detected in adulthood: report of eight cases and review of the literature. Abdom imaging 1999; 24:178-184

(5.) Winer-Muram HT, Tonkin IL, Gold RE: Polysplenia syndrome in the asymptomatic adult: computed tomography evaluation. J Thorac Imaging 1991; 6:69-7.1

(6.) Winer-Muram HT: Adult presentation of heterotaxic syndromes and related complexes. J Thorac imaging 1995; 10:43-57

(7.) McDonnell PJ, Toye PA, Hutchins GM: Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437-441

(8.) Hadengue A, Benhayoun MK, Lebrec D, et al: Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991; 100:520-528

(9.) Robalino BD, Moodie DS: Association between primary pulmonary hypertension and portal hypertension: analysis of its pathophysiology and clinical, laboratory and hemodynamic manifestations. J Am Coil Cardiot 1991; 17:492-498

(10.) Aessopos A, Stamatelos G, Skoumas V, et al: Pulmonary hypertension and right heart failure in patients with betathalassemia intermedia. Chest 1995; 107:50-53

(11.) Hoeper MM, NiedermeyerJ, Hoffmeyer F, et al: Pulmonary hypertension after splenectomy? Ann Intern Med 1999; 130:506-509

RELATED ARTICLE: KEY POINTS

* Heterotaxy syndrome is characterized by situs ambiguus, congenital heart defects, and splenic malformations.

* The syndrome usually presents in childhood due to severe cardiovascular malformations. Late presentation of heterotaxy syndrome in adulthood is rare.

* Pulmonary hypertension may develop on the basis of congenital portosystemic shunts in patients with heterotaxy syndrome.

From the Departments of Nephrology, cardiology, and Diagnostic Radiology, University Hospital, Aachen, Germany.

Reprint requests to Vincent M. Brandenburg, MD, University Hospital, Department of Nephrology (Internal Medicine II), Rheinisch-Westfalische Technische Hochschule, D-52057 Aachen, Germany.