1 Department of Nephrology and 2 Department of Human Genetics, University Hospital Gasthuisberg, Leuven B-3000, Belgium Email: bart.maes{at}uz.kuleuven.ac.be
Case
A 40-year-old woman was referred to our out-patient clinic with moderate renal failure (serum creatinine, 2.35 mg/dl; urea, 76 mg/dl) and slight proteinuria (0.2 g/24 h). Urine microscopy was normal. She had no specific complaints and she did not take any medication. She had a history of a surgically corrected congenital stenosis of the pylorus and was known with multiple vascular abnormalities, attributed to a congenital rubella syndrome. The vascular abnormalities included peripheral pulmonary stenosis, total occlusion of the superior mesenteric artery with hypertrophy of the inferior mesenteric artery, severe stenosis of the right renal artery and a hypoplastic left renal artery. The family history was blank, except for one uncle who had been operated for coarctation aortae.
The patient weighed 60 kg and was 1.71 m tall. She was slim and had a rather triangular face (Figure 1). Systolic hypertension of 190 mmHg was repeatedly noted, with a persistent low diastolic pressure of 60 mmHg. Thoracic and abdominal auscultation revealed loud systolic murmurs, the precise vascular origin of which could not be defined clinically. Peripheral pulses were normal and the blood pressure index (anklearm) was 1.0 (normal). No other abnormal findings were retained on clinical examination.
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Chest roentgenogram was normal; an abdominal X-ray showed only an occult spina bifida S1. ECG and cardiac ultrasound were normal, but a rather small aorta was noted with indirect signs of stenosis of the ostial subclavian artery (turbulent flow). Lung function tests were normal. An ultrasound of the abdomen showed two kidneys with a diminished bipolar diameter (left, 60 mm; right, 70 mm) with diminished cortical reflectivity. Angiography (Figures 2 and 3) confirmed the peripheral pulmonary stenoses, stenosis of the left subclavian artery, as well as stenosis of the right renal artery, a narrow left renal artery and total occlusion of the superior mesenteric artery. Fundoscopic examination of the eyes revealed a bilateral posterior embryotoxon, normal ocular pressure and an excavated papilla.
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Question
What is your diagnosis?
Answer to the quiz on the preceding page
The diagnosis is Alagille syndrome [13], an autosomal dominant disorder, characterized by typical changes in liver, eyes, skeleton and the cardiovascular system. Paucity of intrahepatic bile ducts (91%), posterior embryotoxon (88%), peripheral pulmonary stenosis (often accompanied by other cardiac malformations) (85%), butterfly vertebrae (87%) and a typical triangular face (95%) give us the typical picture of a complete Alagille syndrome [4,5]. In patients with a partial form of Alagille syndrome (as presented in this case) we expect at least three of these major criteria, of which bile duct paucity or pulmonary stenosis have to be present [2,3]. Variable other abnormalities often accompany those criteria: a variety of renal pathology, mental and/or growth retardation, delayed puberty, high-pitched voice and vascular malformations [2].
Alagille syndrome is caused by mutations in the Jagged1 (JAG1) gene, a ligand for the Notch transmembrane receptor. JAG1 and the Notch receptor are parts of the Notch signalling pathway, which plays a critical role in cell differentiation. JAG1 is located on the short arm of chromosome 20 (20p12). Over 100 different JAG1 mutations have been identified in patients with this syndrome, but no clear relationship has been found between the genotype and clinical phenotype. In our patient, DNA was analysed for the specific mutations of the JAG1 gene on chromosome 20. Sequence analysis showed a deletion of 2 bp (2357 del TG), confirming our clinical diagnosis. This frame-shift mutation causes a prematurely truncated protein at amino acid 633. Although Alagille syndrome is inherited in an autosomal dominant way, the syndrome is often not recognized unless one patient develops severe medical problems in the setting of a typical family history because of its variable expression and independent inheritance of the major characteristics and the occurrence of skipped generations [2,6].
Hepatic involvement is one of the most important characteristics of Alagille syndrome. Generally, Alagille syndrome is diagnosed after a prolonged period of neonatal jaundice and severe cholestasis during childhood. Clinical hepatic problems are not necessarily required though. In this case, no clinical evidence was found of liver disease, until an MRI cholangiography showed (asymptomatic) vanishing bile ducts. Vascular abnormalities are the second major feature of Alagille syndrome [2,3]. Most common is the peripheral pulmonary stenosis, but other cardiac or vascular malformations are often observed (tetralogy of Fallot, ventricular septal defects, atrial septal defects, aortic stenosis and coarctation of the aorta). The more severe cardiac anomalies are one of the major causes of early mortality in Alagille syndrome.
A broad spectrum of ocular anomalies can be found, involving the cornea, iris, retina and optic discs [2,7]. The most common feature is the posterior embryotoxon, a prominent Schwalbe's line, and is found in 88% of patients with Alagille syndrome. Other ocular features include a striking mosaic iris pattern, retinal depigmentation and optic disc anomalies with pseudo papilledema and optic nerve atrophy. The triangular face consists of a prominent forehead, deep eyes and a protruding chin. This feature is typically present, but its recognition is a subjective finding of the investigator. Butterfly vertebrae are the typical presentation of skeleton abnormalities, although spina bifida (as in this case) is often seen too. The butterfly form is seen on radiography due to an incomplete formation of the anterior arcs of the vertebrae. It is of no pathological meaning and is only found by accident or when specifically looked for.
A wide variety of renal disorders can be seen: agenesis of a kidney, cystic disease, mesangiolipidosis of the kidney, vascular problems (renal artery stenosis as in the case presented), reflux disease, tubulointerstitial nephritis [8]. Mesangiolipidosis is common and is most probably related to the hypercholesterolaemia that is associated with chronic cholestasis [9]. The other kidney abnormalities seem to appear independently of one of the major characteristics of Alagille syndrome. All kidney disorders can lead to renal failure with the need for renal replacement therapy. Case reports of renal transplantation are described in adults as well as in children. With a good pre-operative vascular screening, transplantation seems to be a good option in selected patients. Hepatic problems due to the possibly hepatotoxic medication given after transplantation did not cause problems in reported cases [10].
Acknowledgments
The authors thank Dr Giannakudis, Halle, Germany for the skilful execution of the mutation analysis.
References