Phenotypic and Genotypic Features of the FAN1 Mutation-Related Disease in a Large Hungarian Family

Abstract

Pathogenic variants in the FAN1 gene lead to a systemic disease with karyomegalic interstitial nephritis (KIN) at the forefront clinically. The phenotypic-genotypic features of a FAN1 mutation-related disease involving five members of a Hungarian Caucasian family are presented. Each had adult-onset chronic kidney disease of unknown cause treated with renal replacement therapy and elevated liver enzymes. Short stature, emaciation, latte-colored skin, freckles, and a hawk-like nose in four patients, a limited intellect in two patients, and chronic restrictive lung disease in one patient completed the phenotype. Severe infections occurred in four patients. All five patients had ceased. Four patients underwent autopsy. KIN and extrarenal karyomegaly were observed histologically; the livers showed no specific abnormality. The genotyping using formalin-fixed tissue samples detected a hitherto undescribed homozygous FAN1 mutation (c.1673_1674insT/p.Met558lfs*4; exon 5) in three of these patients and a heterozygous FAN1 mutation in one patient. The reason for the heterozygosity is discussed. In addition, 56 family members consented to the screening for FAN1 mutation from which 17 individuals proved to be heterozygous carriers; a blood chemistry evaluation of their kidney and liver function did not find any abnormality. The clinical presentation of FAN1-related disease was multifaceted, and not yet described manifestations were observed besides kidney and liver disease. Mutation in this gene should be suspected in adults with small kidneys of unknown cause, elevated liver enzymes, and recurrent infections, even without a family history.

Keywords: DNA damage; FAN1 mutation; chronic kidney disease; hepatopathy; karyomegalic interstitial nephritis; proteinuria; systemic karyomegaly.

Figure 1

Morphologic findings in the FAN1-mutation related disease. (A) Patient C, liver biopsy. Focal, non-specific degeneration of hepatocytes in the intermediary zone of liver acinus. CV—central vein. Hematoxylin and eosin (HE), 20×. (B) The Prussian blue staining demonstrated hemosiderin (blue) located exclusively in Kupffer cells, 40×. (C) Patient A, end-stage kidney. Karyomegaly of tubular epithelial cells (arrows), tubular atrophy, and interstitial fibrosis with focal and mild lymphocytic infiltrates can be seen. G—patent glomerulus. HE, 20×. (D) Patient A, lung. Karyomegaly in a non-specified cell of alveolar septum (arrow). HE, 20×. (E) Patient B, end-stage kidney. The widespread loss of tubules and cystic dilation of atubular glomeruli (asterisks) can be seen. Periodic acid–Schiff, 10×. (F) Patient B, end-stage kidney. Bizarre karyomegaly in a tubular epithelial cell (arrow) is present. G—patent glomerulus. HE, 40×. (G) Patient E, end-stage kidney. Karyomegaly of tubular epithelial cell (arrow). G—patent glomerulus, SG—sclerosed glomerulus. HE, 20×. (H) Patient E, subepicardial tissue. Bizarre karyomegaly in the Schwann cell (arrow) of a small peripheral nerve. HE, 40×. (I) Patient E, liver. The hepatocytes and sinusoids do not show specific abnormality. The portal tract (PT) shows mild infiltration mainly by lymphocytes. “Onion-skin fibrosis” of the bile duct is not present. HE, 10×. The bar represents 100 μm.

Figure 2

Results of the genetic analysis of the FAN1 gene. Part of exon 5 is shown. A single nucleotide (T) insertion was detected in the blood DNA sample of symptomatic Patient III/B, and its presence was also confirmed in her DNA purified from paraffin-embedded pancreas and kidney tissue samples. Her symptomatic brother (III/A) also carried the same FAN1 mutation in the homozygous state. Their asymptomatic uncle (II/57) and his wife (II/43) proved to be heterozygous carriers. Three of their sons (C, D, and E) were symptomatic. III/C was proven to be a heterozygous carrier, while his brother III/E carried the FAN1 mutation in a homozygous state. III/D had no available biological sample to analyze.

Figure 3

The genealogical chart of the five-generation Hungarian family under investigation. (A) All 60 lettered or numbered individuals underwent genetic testing except III/D for whom no biological sample was available. (B) The segment of the family tree highlighted includes all family members who exhibited clinical symptoms of karyomegalic interstitial nephritis. Circles denote females, while boxes represent males. Individuals without a letter or a number did not agree to genetic testing. A dot in a circle or box indicates heterozygous carriers of the FAN1 mutation, while a black circle or box represents those individuals in the homozygous state of the FAN1 mutation.