Five Cases with MAFB Variants

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Introduction: The pathogenic variants in MAFB gene cause multicentric carpal tarsal osteolysis syndrome (MCTO) (OMIM: # 166300), an N-terminal variant characterized by progressive destruction of the bones, and Duane retraction syndrome (DRS) (OMIM: # 617041), a C-terminal variant characterized by congenital eye movement abnormalities, whose inheritance pattern is autosomal dominant. Nephropathy have been reported in about half of the patients with MCTO and in five patients in three families with DRS. Only one case with DRS family history of nephropathy without extrarenal manifestations (isolated-FSGS) has been reported in the past. Case Description: Five cases with pathogenic variants in MAFB were diagnosed in our department, four with MCTO and one with isolated-FSGS. Among four cases with MCTO, case1 showed congenital nephrotic syndrome (CNS), case 2 nephrotic syndrome, case 3 persistent proteinuria, and case 4 bone lesions, respectively. Genetic analysis revealed heterozygous missense variants in all four cases with MCTO (case 1 and 2: c. 212 C > T, p. (Pro 71 Leu), case 3: c. 188 C > A, p. (Pro 63 Gln), and case 4: c. 188 C > G, p. (Pro 63 Arg)), all of which were de novo variants and N-terminal side. Case 1, case 2, and case 3 developed nephropathy at the ages of 0 months, 1 year 11 months, and 3 years, and led to end-stage kidney disease (ESKD) at the ages of 6 months, 3 years and 20 years, respectively. On the other hand, the isolated-FSGS patient has developed persistent proteinuria since12 years old, but his renal function was still normal at the age of 19. Genetic analysis revealed a novel heterozygous missense variant at c. 755 C > G, p. (Ala 252 Gly) which was a de novo variant and C-terminal side. Discussion: Case 1 was the youngest case of developing ESKD and the first case manifesting CNS. In case 5, who was the isolated-FSGS case, a variant near the DRS hotspot was identified, but no eye movement abnormalities were observed. This case is the second case showing isolated nephropathy among cases with MAFB variants. MCTO should be included in the differential diagnosis as a cause of CNS disease. Isolated-FSGS may be a new phenotype of MAFB abnormalities different from MCTO and DRS.

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