Eur J Pediatr (2011) 170:103–106 DOI 10.1007/s00431-010-1280-x ORIGINAL PAPER Diagnosis of alpha-1-antitrypsin deficiency in bleeding disorder-related neonatal death Gursah Kats-Ugurlu & Marije Hogeveen & Ann Driessen & Ans M. W. van den Ouweland & Christina Hulsbergen-van de Kaa Received: 27 May 2010 / Accepted: 12 August 2010 / Published online: 2 September 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disorder characterized by hepatitis in neonates, childhood and adulthood (protease inhibitor (PI)*ZZ) and emphysema with or without hepatitis (PI*ZZ)/(PI*SS,SZ or null) in adulthood. We report the case of a female neonate born at 40 weeks of gestation who presented with vitamin K deficiency-related intracranial bleeding and cholestasis of which she died at 28 days of age. At autopsy, the infant was found to have intracranial bleeding, hepatomegaly, and cholestasis with paucity of bile ducts in the liver. Small periodic acid-Schiff diastase positive intrahepatic granules and positive staining with antibodies against AAT protein suggested an AAT deficiency. AAT is a glycoprotein that has a protease inhibitor function. Its deficiency can be the result of various point mutations in Serpin 1 located on chromosome 14. The diagnosis AAT deficiency was confirmed by mutation analysis showing the PI*ZZ genotype in the neonate. In conclusion, AAT deficiency is a rare genetic disorder that can lead to a serious G. Kats-Ugurlu : C. H.-v. de Kaa (*) Department of Pathology, Radboud University Nijmegen Medical Centre, 824, PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: C.Hulsbergen@pathol.umcn.nl M. Hogeveen Department of Paediatrics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands A. Driessen Department of Pathology, University Hospital of Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands A. M. W. van den Ouweland Department of Clinical Genetics, Erasmus Medical Centre, PO Box 2040, 3000 CA Rotterdam, The Netherlands bleeding disorder in the neonatal period if not recognised on time. Pathological diagnosis together with verifying molec- ular analysis can be used to identify index patients. Keywords Alpha-1-antitrypsin . Death . Deficiency . Neonatal Introduction Alpha-1-antitrypsin (AAT) deficiency, an autosomal recessive disorder, is caused by inheritance of two severe deficient alleles of Serpin 1 (located on chromosome 14q31-32) encoding AAT [2]. AAT is a protease inhibitor with three β-sheets and eight α-helices. The reactive loop site in the β-sheet contains the neutrophil elastase binding site with a methionine residue [3]. The protease inhibitor (PI)*MM wild-type allele is the most prevalent normal allele and has many variants [2]. The most important pathogenic PI*S and PI*Z variants show mutations Glu264Val and Glu342Lys, respectively, whereas PI*null variant has no protein production. The patient can be homozygous or compound heterozygous for pathogenic variants. The protein product contains variable amounts of abnormal polymers of AAT molecules which retain in the endoplasmic reticulum (ER) in the liver. These retained abnormal polymers can lead to hepatic cell injury and result in haemorrhagic disease and or cholestasis in infancy and chronic liver disease in childhood or adulthood. In addition, the uninhibited action of the neutrophil elastase in the lungs can cause alveolar damage resulting in emphysema in adulthood [3]. The highest PI*Z variant prevalence was recorded in northern and western Europe (mean gene frequency, 0.0140) [9]. Persons with the PI*ZZ phenotype have 10–15% of normal AAT plasma levels. About 12% of ZZ infants