Fibrosis, Neurodegeneration, And Cerebral Angiomatosis

A number sign (#) is used with this entry because of evidence that fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is caused by compound heterozygous mutation in the NHLRC2 gene (618277) on chromosome 10q25.

Description

Fibrosis, neurodegeneration, and cerebral angiomatosis is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (Uusimaa et al., 2018).

Clinical Features

Uusimaa et al. (2018) studied 2 Finnish brothers and an unrelated Finnish boy with a multiorgan syndrome that the authors designated 'FINCA' for the features of fibrosis, neurodegeneration, and cerebral angiomatosis. All 3 children appeared healthy at birth, but presented at age 2 months with irritability, hypotonia, feeding difficulties, diarrhea, and growth failure. During the following months, they exhibited delayed development, reduced vision, recurrent infections, transient hepatic dysfunction, and chronic hemolytic anemia. The 2 brothers developed dystonic tetraplegia, and the other boy was dystonic as well. One patient exhibited cardiomegaly. All had progressive respiratory difficulties that culminated in death from respiratory failure in the second year of life. At autopsy, all 3 brains were atrophic and showed increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, as well as white matter degeneration and variable neuronal degeneration. Lung biopsies showed severe interstitial fibrosis, with no normal lung tissue in 2 of the patients. In addition, unusual granuloma-like lesions were observed, which were enriched with myofibroblasts. All 3 patients had hepatomegaly; transmission electron microscopy of a biopsy from 1 of the patients showed steatosis and accumulation of collagen bundles.

Molecular Genetics

In 3 Finnish male infants from 2 unrelated families with fibrosis, neurodegeneration, and cerebral angiomatosis, Uusimaa et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for a missense mutation (D148Y; 618277.0001) and a 2-bp deletion (618277.0002) in the NHLRC2 gene. Genealogy traced back 7 to 9 generations, to the 1750s, did not show common ancestors for the 2 families, and consanguinity within the families could not be confirmed because their ancestors were born in northern Finland at least 150 miles apart.