American Journal of Medical Genetics 121A:156 –158 (2003) Clinical Report Cardiovascular Abnormalities Associated With the Stuve–Wiedemann Syndrome Annick Raas-Rothschild,1* Zivanit Ergaz-Schaltiel,2 Jakob Bar-Ziv,3 and Azaria J.J.T. Rein4 1 Department of Department of 3 Department of 4 Department of 2 Human Genetics, Hadassah University Hospital, Jerusalem, Israel Neonatology, Hadassah University Hospital, Jerusalem, Israel Radiology, Hadassah University Hospital, Jerusalem, Israel Pediatric Cardiology, Hadassah University Hospital, Jerusalem, Israel The Stuve–Wiedemann syndrome (SWS) is a congenital bone dysplasia characterized by camptodactyly with ulnar deviation and congenital bowing of the long bones. Affected patients present with respiratory difficulties in the neonatal period or later and recurrent episodes of hyperthermia. The typical radiological findings are bowing of the long bones of the lower limbs, wide metaphyses with decreased density, and abnormal trabecular pattern. Generally, respiratory insufficiency and hyperthermia are reported to be the cause of death. We report on two sibs with SWS, who died from severe pulmonary hypertension with pulmonary artery wall abnormality. We suggest a common pathophysiological process, which could explain the cardiovascular findings that we observed immediately after birth in the two affected sibs. We hypothesize that the severe pulmonary hypertension due to the arterial wall abnormality could explain the neonatal death of these two children. ß 2003 Wiley-Liss, Inc. KEY WORDS: Stuve–Wiedemann syndrome; pulmonary hypertension; pulmonary vascular disease INTRODUCTION The Stuve–Wiedemann syndrome (SWS) is an autosomal recessive congenital bone dysplasia, which was *Correspondence to: Dr. Annick Raas-Rothschild, MD, Department of Human Genetics, Hadassah University Hospital, Jerusalem, 91120, Israel. E-mail: annick@Hadassah.org.il Received 1 February 2002; Accepted 12 August 2002 DOI 10.1002/ajmg.a.20066 ß 2003 Wiley-Liss, Inc. first described in 1971 [Stuve and Wiedemann, 1971]. It is characterized by camptodactyly with ulnar deviation, and congenital bowing of long bones. Affected patients often present with respiratory difficulties in the neonatal period and recurrent episodes of hyperthermia. The typical radiological findings are bowing of the long bones of the lower limbs and wide metaphyses with decreased density and abnormal trabecular pattern. Some patients die from the respiratory insufficiency and hyperthermia. Recently, we had the opportunity to diagnose a newborn with SWS that died from severe pulmonary hypertension. Echocardiographic examination showed a severe pulmonary artery abnormality. CLINICAL REPORT The proband was the 9th child of healthy first cousins Muslim Arab. This family originated from the Jerusalem area. He had five healthy sibs while three other sibs, two boys and one girl died in the neonatal period from respiratory failure and hyperthermia. The first affected child was a boy who died soon after birth from respiratory failure. According to the father’s description he presented with contractures of the hands and overriding toes. The second affected child was a full term baby girl born with limited extension of the elbows and hip. Bilateral single transverse creases were noticed on the report. She was transferred to the intensive care unit soon after birth because of respiratory failure and hypotension. The report specified that she died from recurrent pneumothorax at the age of 7 days. The third affected child was a full term baby boy who developed respiratory failure due to pulmonary hypertension. He was born after an uneventful pregnancy by normal delivery. He had hypotonia, limited extension of the elbows, camptodactyly, and bilateral single palmar creases. He had a hypoplastic right kidney and a hydronephrotic left kidney. Chromosomes, acetoacetate and ammonia in blood, amino and organic acids in urine were normal. Echocardiographic examination revealed Cardiovascular Abnormalities in SWS pulmonary hypertension with a closed ductus arteriosus. During the course of his hospitalization he had spiking high temperature although all investigation showed no evidence of sepsis. He died from suspected sepsis following necrotizing enterocolitis. The proband was the 4th affected child. He was a full term boy born at term, after an uneventful pregnancy; Apgar score was 9 at 1 and 5 min. Birth weight was 4.080 g (>90th centile), and head circumference 36.2 cm (90th centile). Respiratory support was needed immediately after birth. On physical examination he had a short neck, an hypoplastic mandible, bilateral camptodactyly of the 3rd, 4th and 5th fingers, bilateral single transverse palmar creases, proximal shortening of the upper and lower limbs, and bowing of legs with overriding toes bilaterally (Fig. 1). Roentgen examination showed large irregular metaphyses with abnormal trabecular pattern and cortical thickening (Fig. 2). Echocardiography revealed severe pulmonary hypertension with right to left shunting through the patent foramen ovale. The ductus arteriosus was not seen. The pulmonary artery was dilated with a 13-mm width (normal 8–9 mm) and stiff thickened walls of 2-mm thickness (Fig. 3). He suffered from general seizures; head ultrasound was normal. He died from pulmonary hypertension refractory to ventilatory treatment at the age of 40 hr. The clinical and the radiographic findings of this child were compatible with the diagnosis of SWS. The findings in the 4th baby led us to reevaluate the radiographics of the 3rd affected child retrospectively. These showed bowing of the lower limb bones with cortical thickness and abnormal metaphyses of humerus compatible with the diagnosis of SWS (Fig. 4). Review of the third child’s echocardiography revealed the following findings: a closed ductus arteriosus at birth, an extreme pulmonary and right ventricular (hypersystemic) hypertension, dilated pulmonary arteries with extremely hypertrophied wall, and right to left shunting through a patent foramen ovale. These findings and the family history suggested that the 3rd child was affected with the SWS as well. Fig. 1. Left foot of the 4th proband with overriding of the 2nd toe. 157 Fig. 2. X-rays of the 4th affected child showing the large irregular metaphyses with abnormal trabecular pattern and cortical thickening of the femur. DISCUSSION The Stuve–Wiedemann syndrome (SWS) is a congenital bone dysplasia characterized by bowing of the long bones, respiratory insufficiency, hyperthermic episodes, and death in the first year of life [Wiedemann and Stuve, 1996]. The differential diagnosis includes the campomelic and kyphomelic dysplasias, which also present with bowing of the lower limbs but differ in their clinical and radiographic features [Kozlowski and Tenconi, 1996]. Respiratory complications and unexplained hyperthermia were reported to be the cause of Fig. 3. Postnatal subxyphoid short axis echocardiographic view of the 4th sib. The right ventricle (RV) pressure is nearly or slightly hypersystemic as reflected by the interventricular septum (IVS) which flattens or slightly bows toward the left ventricle (LV) at end systole. Note the dilated main pulmonary artery (PA) taking off the RV with thickened and hyperechogenic wall (arrows). 158 Raas-Rothschild et al. Fig. 4. Chest X-rays of the 3rd affected child. Note the cortical thickening and the abnormal trabecular pattern of the large irregular humeral metaphyses. death in some infants affected with SWS. Although originally described as an early lethal condition, it is clear by now that survival is possible. Al-Gazali et al. [1996] reported 11 patients from five families who were diagnosed as affected with the ‘‘neonatal’’ variant of Schwartz–Jampel (SJS) syndrome. Nine out of these 11 children died from respiratory complications, five of them in the neonatal period while the etiology of the respiratory insufficiency was not clear. Three patients had an echocardiographic examination, which was normal in two cases and revealed a small ventricular septal defect in one child. Superti-Furga et al. [1998] later showed that this neonatal variant of SJS was genetically distinct from classical SJS and suggested that the condition may be identical (not similar) to the SWS. A specific pattern of radiographic changes was observed in several long-term survivors, confirming the independence of SWS (or formerly the ‘‘neonatal’’ SJS) from the classical SJS [Cormier-Daire et al., 1998; Chen et al., 2001]. Cormier-Daire et al. [1998] reported on eight patients with SWS. Six of them died following recurrent episodes of unexplained fever. Four of the eight reported cases had pulmonary hypoplasia. In two of the four affected sibs affected with SWS in this family, we found similar cardiovascular anomalies: lack of ductus arteriosus patency at birth, extreme pulmonary and right ventricular (hypersystemic) hypertension, dilated pulmonary arteries with extremely hypertrophied wall, and right to left shunting through a patent foramen ovale. We suggest a common pathophysiological process, which could explain all these cardiovascular findings that were observed immediately after birth in two of these four affected infants in which echocardiography was performed: the mechanism could be the antenatal premature closure or even constriction of the ductus arteriosus, which increases the right ventricular afterload in the fetus with very high pulmonary artery pressure and resistance. We hypothesize that if this antenatal pathophysiological process is long enough, it might have stimulated pulmonary arterial wall hypertrophy with further elevation of pulmonary artery resistance. At birth, the clinical condition of the baby resembles the primary pulmonary hypertension of the newborn although with the major difference being the already-obliterated ductus arteriosus. Filling pressure of this failing right ventricle is extremely elevated which in turn explains the obligatory right to left shunt through the foramen ovale. This is an ominous condition in which the returning systemic venous blood cannot be oxygenated with pulmonary hypertension causing the death of the newborn. We suggest that in some patients with Stuve–Wiedemann and early neonatal death, the respiratory insufficiency might be due to severe pulmonary hypertension due to pulmonary arterial wall medial hypertrophy. This vascular pathology could be related to the premature obliteration of the ductus arteriosus. Systematic echocardiography of newborns affected with SWS might provide more insights on the cardiovascular pathology associated with SWS. REFERENCES Al-Gazali LI, Varghese M, Varady E, Al Talabani J, Scorer J, Bakalinova D. 1996. Neonatal Schwartz–Jampel syndrome: A common autosomal recessive syndrome in the United Arab Emirates. J Med Genet 33:203– 211. Chen E, Cotter PD, Cohen RA, Lachman RS. 2001. Characterization of a long-term survivor with Stuve–Wiedemann syndrome and mosaicism of a supernumerary marker chromosome. 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