Klinefelter'S Syndrome-Associated Alpha-1 Antitrypsin Cholestatic Phenotype: A Genetic Linkage Between Two Congenital Diseases

Klinefelter's Syndrome (KS) is a sex chromosome disorder causing primary hypogonadism. It is frequently associated with diseases of the lung, liver, kidneys, and skin. Alpha-1 antitrypsin (AAT) is a serine protease inhibitor with an important role in normal mitosis and meiosis. Previous studies have shown an increased frequency of AAT heterozygosity in patients with sex chromosome mosaicism such as KS. However, the genotype and phenotype linkages between these diseases are unclear. To date, there have been only 3 reports on the association of KS with AAT deficiency. Here we report a rare case of KS associated with AAT cholestatic phenotype. A 46 year old male presented with an incidentally found elevated liver enzymes. He has known history of KS, insulin-dependent diabetes mellitus, and diabetic gastroparesis. His physical examination showed no chronic liver disease stigmata. His labs were remarkable for alanine aminotransferase of 182 IU/L, aspartate aminotransferase of 131 IU/L, alkaline phosphatase (ALP) of 1,446 IU/L, gamma glutamyl transpeptidase of 666 IU/L, and low serum AAT level of 116 mg/dL. A total bilirubin was normal at 0.8 mg/dL. His ferritin was elevated at 1102 ng/mL but transferrin saturation was 15%. Subsequent testing confirmed AAT deficiency (MZ phenotype). Abdominal MRI revealed normal liver size and enhancement but with mild biliary ductal dilatation (Figure 1). Liver biopsy demonstrated PAS positive globules in the periportal hepatocytes, diagnostic of AAT deficiency (Figure 2). Over the course of 4-month follow up, his transaminases fluctuated and normalized, while his ALP remained elevated at 1391 IU/L with no symptoms. Our case underscores the potential genetic association between AAT deficiency and KS. This is the fourth reported case of AAT deficiency with liver disease in KS patients. Our finding is in accordance with early studies reporting the possibility of a genetic linkage between KS and AAT deficiency. In patients with KS and unexplained elevated liver enzymes, AAT deficiency should be ruled out, even in the absence of pulmonary disease.Figure 1Figure 2Table 1: Pertinent Laboratory Findings