Interplay between fibroblast growth factor 9 (FGF9) and CD44 underlies 46,XY disorders of sex development in Kruppel‐like factor 1 (KLF‐1)‐E325K‐associated congenital dyserythropoietic anaemia (CDA‐IV)

A heterozygous Kruppel-like factor 1 (KLF1) E325K mutation causes a severe form of congenital dyserythropoietic anaemia (CDA), designated CDA-IV (Online Mendelian Inheritence in Man, OMIM 613673), a rare disease with only 15 cases known. In addition to haemolytic anaemia, manifest often at birth, four of seven (57%) of 46,XY children with KLF1 E325K mutation exhibit a range of dysmorphic external genitalia including 46,XY complete sex reversal (2/7 or 28.5%). No genital abnormalities were reported in a boy with double heterozygous KLF1 null mutations, suggesting that the KLF1 E325K variant causes, in addition to its negative impacts on erythroid differentiation, disruptions in male sex differentiation. Our studies suggest a role for a cooperative effect of concurrent 'non-pathogenic' polymorphisms in multiple genes associated with disorders of sex differentiation (DSD), notably fibroblast growth factor 9 (FGF9), whose expression was decreased in the gonads and peripheral blood in the case described here. We propose that the combined loss of FGF9 and CD44 (a target for CDA-IV KLF1) resulted FGF9 signalling loss and likely caused 46,XY sex reversal. Our studies also suggest that whole-blood gene expression studies in the proband/parent triad may provide critical clues in evaluating children with DSD, the cause of which remains undiagnosed in many cases.