A family with partially penetrant multicentric carpotarsal osteolysis due to gonadal mosaicism: First reported case

Abstract

Multicentric carpotarsal osteolysis (MCTO) is an autosomal dominant condition characterized by carpal-tarsal abnormalities; over half of affected individuals also develop renal disease. MCTO is caused by mutations of MAFB; however, there is no clear phenotype-genotype correlation. We describe the first reported family of variable MCTO phenotype due to mosaicism: the proband had classical skeletal features and renal involvement due to focal segmental glomerulosclerosis (FSGS), and the father had profound renal impairment due to FSGS, necessitating kidney transplantation.Mosaicism was first suspected in this family due to unequal allele ratios in the sequencing chromatograph of the initial blood sample of proband's father and confirmed by sequencing DNA extracted from the father's hair, collected from different bodily parts. This case highlights the need for a high index of clinical suspicion to detect low-level parental mosaicism, as well as a potential role for MAFB mutation screening in individuals with isolated FSGS.

An unusual manifestation in a pediatric patient with MAFB mutation: Sacroiliitis in multicentric carpotarsal osteolysis syndrome

“…Most of them resembled JIA; however, treatment could not prevent disease progression and bone loss. 2,[4][5][6][7][8][9][10][11][12][14][15][16][17][18] Similarly, although pain did improve with anti-tumor necrosis factor medications in our patient, osteolysis could not be avoided. The main problem in MCTO was suggested to be increased RANKL activation and excessive osteoclastic activity, but the cause of the selection of distinctive bones remains unclear.…”

Multicentric Carpotarsal Osteolysis Syndrome Associated Nephropathy: Novel Variants of MAFB Gene and Literature Review

“…A total of 18 (3 novel) disease-causing variants in MAFB gene were identified and were classified according to the American College of Medical Genetics and Genomics (ACGM) classification (see Supplementary Material Table S1 and Figure S1 ). All subjects carried missense variants in heterozygous state and all variants lie within a short region of amino-terminal transcriptional activation domain (amino acids 54–71) [ 1 ], one subject presented somatic mosaicism [ 2 ]. Genetic testing of parents was available in 22 cases: 60% (13/22) resulted sporadic cases (i.e., de novo mutations), 40% (9/22) resulted inherited mutations.…”

“…In 2012, Zankl et al [ 1 ] for the first time identified missense mutations clustering within a 51 base pair region of the single exon of MAFB in five unrelated simplex cases of MCTO. After that, 57 cases with genetic diagnosis were reported in the literature [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. All cases showed a large phenotypical heterogeneity, even among patients presenting the same variant [ 4 ].…”

“…Nephrotic-range proteinuria was never accompanied by nephrotic syndrome, neither in the nine cases of FSGS [ 2 , 9 , 12 , 14 ]. The kidney involvement in MCTO may be explained by the essential role of MAFB gene in the function and differentiation of glomerular podocytes.…”

Podocyte-specific Transcription Factors: Could MafB Become a Therapeutic Target for Kidney Disease?

“…The mechanisms responsible for osteoclast disease as a result of the MAFB mutation are unknown. MCTO cases are reportedly complicated by hereditary FSGS, which is characterized by podocyte injury (31)(32)(33). To analyze the pathogenesis of this syndrome, we used CRISPR/Cas9 genome editing to create homozygous mice harboring the MCTO mutation.…”