Juvenile Hemochromatosis in a Spanish Family Submitted 03/19/02; revised 04/08/02 (Communicated by E. Beutler, M.D., 04/09/02) Marco Montes-Cano, 1 Marı ´a-Francisca Gonza ´lez-Escribano, 1 Jose ´ Aguilar, 2 and Antonio Nu ´n ˜ez-Rolda ´n 1 ABSTRACT: Juvenile hemochromatosis (JH) is a characteristic form of genetic hemochromatosis with an early onset and severe clinical course leading to death if iron depletion treatment is not timely applied. Clinical complications include liver cirrhosis, heart failure, hypogonadotropic hypogonadism, and diabetes. In the present study we report the first case of JH described in Spain. Biochemical and genetic characteristics of the patient and relatives (parents and siblings) were investigated. No individual presented either the mutation at position 845 of the HFE gene or at position 750 of the TFR2 gene, associated with other types of hemochromatosis. Nevertheless, some individuals were homozygous for the mutation at position 187 of HFE. The hypothetic region of association with JH, located at chromosome 1q, was also investigated and results show that the patient presented a unique genotypic combination in 1q. The only brother with heavy iron deposits in hepatocytes was found to be heterozygous for the JH-associated region and homozygous for the HFE187 gene, suggesting a synergistic effect between both hemochromatosis-associated genes. © 2002 Elsevier Science (USA) INTRODUCTION Juvenile hemochromatosis (JH), is a rare re- cessive genetic disorder leading to progressive and severe iron overload, which is characterized by early onset with clinical manifestation before 30 years of age (1). Moreover, in contrast with other types of hemochromatosis this pathology affects both sexes equally (1, 2). The clinical features of JH patients are diabetes, liver cirrho- sis, joint disease, and skin hyperpigmentation, the most frequent complications being endocrine fail- ure (hypogonadotropic hypogonadism) and di- lated cardiomyopathy. Patients die early because of cardiac dysfunction if an aggressive and timely treatment by phlebotomy is not applied. Classic hemochromatosis is linked to HFE gene (3) and, recently, mutations in other genes related to iron metabolism, such as TFR2, ferroportin, etc. have been found to cause other types of hemochroma- tosis (4, 5). These genes have been excluded as responsible in JH (2, 6, 7). Recently, Roetto et al. have defined by linkage studies a candidate region on chromosome 1 within D1S2344 and D1S1156 marker microsatellites (2, 7). SUBJECTS AND METHODS A 29-year-old Spanish male with non-consan- guineous parents and a clinical history of hypogo- nadotropic hypogonadism in treatment with tes- tosterone since the childhood, consulted because of weakness, epigasthralgia and breathlessness. In the physical examination, dilated cardiomyopa- thy, low cardiac ejection fraction, arrhythmias, hepatomegaly (3– 4 cm), and skin hyperpigmen- tation were found. By ecco-Doppler image, pleu- ral effusions, ascites and fatty liver were demon- strated. In blood tests, normochromic normocytic ane- mia was found: Hb: 121 g/L, RBC: 3.9  10 12 /L, MCV: 97.3 fl, MCH: 31.5 pg. Liver function tests were within normal values. Analytical iron pa- rameters were consistent with hemochromatosis Correspondence and reprint requests to: Antonio Nu ´n ˜ez-Rolda ´n, Servicio de Inmunologı ´a, Hospital Universitario Virgen del Rocı ´o, Avenida Manuel Siurot s/n. 41013, Sevilla, Spain. Fax: +34 95 501 3221. E-mail: anroldan@hvr.sas.junta-andalucia.es. 1 Servicio de Inmunologı ´a, Hospital Universitario Virgen del Rocı ´o, Servicio Andaluz de Salud, Sevilla, Spain. 2 Servicio de Digestivo, Hospital Universitario Virgen del Rocı ´o, Servicio Andaluz de Salud, Sevilla, Spain. Montes-Cano et al. Blood Cells, Molecules, and Diseases (2002) 28(2) Mar/Apr: 297–300 doi:10.1006/bcmd.2002.0518, available online at http://www.idealibrary.com on 1079-9796/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved. 297