title: Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma.
abstract: Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Blackburn
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Hickey
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Nace
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nasra H
authors.initials: NH
authors.lastname: Giama
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kraft
authors.affiliation: Palo Alto Medical Foundation, Mountain View, California.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bordner
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.|Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Pathumwan.
authors.forename: Roongruedee
authors.initials: R
authors.lastname: Chaiteerakij
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: McCormick
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Maja
authors.initials: M
authors.lastname: Radulovic
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rondell P
authors.initials: RP
authors.lastname: Graham
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Torbenson
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tortorelli
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Scott
authors.affiliation: Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Milliner
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Devin
authors.initials: D
authors.lastname: Oglesbee
authors.affiliation: Deptartment of Pediatrics, Faculty of Medicine, University of Kuwait, 24923 Safat, Kuwait City, Kuwait.
authors.forename: Wafa'a
authors.initials: W
authors.lastname: Al-Qabandi
authors.affiliation: Department of Pediatrics, Papé Family Pediatric Research Institute, Oregon Science & Health University, Portland, Oregon.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dimitar K
authors.initials: DK
authors.lastname: Gavrilov
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mounif
authors.initials: M
authors.lastname: El-Youssef
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Clark
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Jacksonville, Florida.
authors.forename: Paldeep S
authors.initials: PS
authors.lastname: Atwal
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota. klee.eric@mayo.edu.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota. ekker.stephen@mayo.edu.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
mesh_terms: D000293:Adolescent; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006537:Heptanoates / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000235:genetics*; D007223:Infant; D008103:Liver Cirrhosis / Q000150:complications / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014443:Tyrosine / Q000378:metabolism; D020176:Tyrosinemias / Q000150:complications / Q000175:diagnosis* / Q000235:genetics
chemical_list: D006537:Heptanoates; D014443:Tyrosine; C020804:succinylacetone; D006867:Hydrolases; C020156:fumarylacetoacetase
keywords: FAH; TYR I; TYRSN1; fumarylacetoacetate hydrolase; newborn screening; pediatric liver cancer; tyrosinemia type I; whole exome sequencing