Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes.
OBJECTIVE
Juvenile hemochromatosis is a severe form of hereditary iron overload that has thus far been linked to pathogenic mutations of the gene coding for hemojuvelin (HJV), on chromosome 1, or, more rarely, that coding for hepcidin ( HAMP ), on chromosome 19. A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2.


METHODS
We studied a pedigree with siblings affected by both juvenile and adult-onset hereditary hemochromatosis. Affected subjects underwent full clinical evaluation, as well as microsatellite and gene sequencing analysis.


RESULTS
Two siblings (male and female, aged 24 and 25 years, respectively) were hospitalized for severe endocrinopathy and cardiomyopathy. At age 18 and 17 years, they had presented with impotence and amenorrhea, respectively, and increased serum iron levels. Hypogonadotropic hypogonadism was confirmed in both, and liver biopsy showed marked hepatic iron accumulation and micronodular cirrhosis. Iron levels were normalized after 24 months (female) and 36 months (male) of weekly phlebotomies. Microsatellite analysis showed no linkage with chromosome 1 and 19, and gene sequencing showed no hemojuvelin or hepcidin gene mutations. Instead, combined mutations of HFE (C282Y/H63D compound heterozygosity) and serum transferrin receptor 2 (Q317X homozygosity) were found. A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation.


CONCLUSIONS
Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis.
Pietrangelo
Antonello
A
Department of Internal Medicine, University of Modena and Regio Emilia, Policlinico, Modena, Italy. pietrangelo.antonello@unimore.it
Caleffi
Angela
A
Henrion
Jean
J
Ferrara
Francesca
F
Corradini
Elena
E
Kulaksiz
Hasan
H
Stremmel
Wolfgang
W
Andreone
Pietro
P
Garuti
Cinzia
C
D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D002648:Child; D005260:Female; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
D023181:Antimicrobial Cationic Peptides; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins