Further evidence that chondrocalcinosis 1 (CCAL1) is a confirmed mendelian phenotype with a known molecular basis

Abstract

Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop-loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in TNFRSB11B on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic TNFRSF11B loss-of-function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5-associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop-lost variant, likely a gain-of-function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.