British journal of haematology
September 17, 2026 · via Europe PMC
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).
Ravindranath Y, Craig DB, Parajuli P, +8 more, Bieker JJ.
AI summary — for doctors, generated from the abstract only
This study proposes a novel mechanism linking a rare anemia-causing gene mutation to disorders of sex development via disrupted growth factor signaling, based on findings in an extremely rare patient population.
What was studied
A mechanistic study investigating why some children with the rare KLF1 E325K mutation, which causes a severe form of congenital dyserythropoietic anemia (CDA-IV, with only 15 cases known worldwide), also develop 46,XY disorders of sex development, examining gene expression in gonadal and blood tissue from an affected case.
Key findings
- Among 7 known 46,XY children with the KLF1 E325K mutation, 4 (57%) had abnormal external genitalia, including 2 (28.5%) with complete 46,XY sex reversal; in contrast, no genital abnormalities were reported in a boy with a different KLF1 mutation type (double heterozygous null mutations).
- Expression of fibroblast growth factor 9 (FGF9) was decreased in the gonads and peripheral blood of the studied case.
- The authors propose that combined loss of FGF9 and CD44 (a gene affected by the CDA-IV-causing KLF1 mutation) disrupts FGF9 signaling and likely contributes to the 46,XY sex reversal seen in these patients.
Clinical relevance
The findings suggest a novel genetic mechanism linking this specific red blood cell disorder mutation to disorders of sex development, which may inform genetic counseling and diagnostic evaluation for children with this rare anemia who also have atypical genitalia, and the authors suggest whole-blood gene expression testing in patient-parent trios could provide useful diagnostic clues more broadly in undiagnosed disorders of sex development.
Who should care
Limitations
This research is based on an extremely rare condition (only 15 known cases worldwide) and the proposed mechanism relies on limited gene expression data from a single case, so substantially more validation would be needed before these findings could broadly guide diagnostic or counseling practice.
This study proposes that a rare anemia-causing gene mutation can also disrupt a growth factor pathway involved in male sex development, offering a possible explanation for an unusual combination of conditions seen in a handful of known cases.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
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.
DOI
10.1111/bjh.70760
PMID
42753106
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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