A number sign (#) is used with this entry because of evidence that Alagille syndrome-2 (ALGS2) is caused by heterozygous mutation in the NOTCH2 gene (600275) on chromosome 1p12.

For a general phenotypic description and a discussion of genetic heterogeneity of Alagille syndrome, see ALGS1 (118450).

Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. McDaniell et al. (2006) identified 2 probands with mutation in the NOTCH2 gene who, in addition to meeting the diagnostic criteria for ALGS, had severe renal disease. The first proband had cholestatic liver disease, cardiac disease (peripheral pulmonic stenosis and a small atrial septal defect), characteristic facial features, and severe infantile renal disease (small kidneys with cysts bilaterally, renal tubular acidosis, and renal insufficiency). He died of cardiopulmonary arrest at age 2 years. His mother had valvular and peripheral pulmonic stenosis, characteristic facial features, and dysplastic kidneys and proteinuria that resulted in renal failure and a kidney transplant. The second proband had cholestatic liver disease, which led to liver transplant, cardiac disease (tetralogy of Fallot), and ocular findings (posterior embryotoxon). She demonstrated renal disease (tubular acidosis and dysplastic kidneys) and at age 8 years was awaiting a renal transplant. Her mother had a history of asymptomatic hematuria and proteinuria, having come to medical attention at age 26 years with a mildly elevated urine protein level, which increased steadily over the next 10 years. Hypertension was diagnosed at the age of 36 years. Abdominal ultrasound indicated normal-sized kidneys. No cardiovascular or gastrointestinal abnormalities were present. A dysmorphologist recognized facial features characteristic of ALGS. The proband's maternal grandmother had advanced chronic renal insufficiency first noted at age 59 years. Her renal insufficiency worsened until age 65 years, when she began peritoneal dialysis. An ultrasound of the kidneys showed a right atrophic kidney, which was thought to be congenital. Cardiac evaluation was negative for a murmur, and there was no history of liver disease. Adult-onset diabetes, diagnosed just before dialysis was begun, was well controlled with diet alone. McDaniell et al. (2006) remarked that renal manifestations, noted in only 40 to 70% of patients with a clinical diagnosis of ALGS, were present in all affected individuals. There is evidence from mouse studies that functional NOTCH2 is required for normal kidney development, because mice homozygous for a hypomorphic Notch2 mutation died perinatally secondary to defects in glomerular development (McCright et al., 2001). McDaniell et al. (2006) concluded that ALGS caused by NOTCH2 mutations may have a phenotypic profile different from that of ALGS caused by JAG1 (601920) mutations.

The transmission pattern of ALGS2 in the families reported by McDaniell et al. (2006) was consistent with autosomal dominant inheritance.

About 94% of patients with ALGS had been found to have mutations in the gene encoding the Notch signaling pathway ligand JAG1. McDaniell et al. (2006) screened 11 JAG1 mutation-negative probands with ALGS for alterations in the gene encoding the NOTCH2 receptor and found mutations (600275.0001, 600275.0002) in 2 families.