Response to Letter to the Editor From Janot et al: “Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia”

We thank Janot et al (1) for their interest in our article and for sharing clinical information of an additional female patient with a ZNRF3 exon 2 deletion.

The authors report a 33-year-old female patient who had neonatal-onset adrenal insufficiency with mineralocorticoid deficiency (1). She showed normal pubertal development and experienced 2 successful spontaneous pregnancies, indicating normal ovarian function. Our 10-year-old female patient also showed breast development (2); however, the long-term prognosis of ovarian function has not been elucidated. Janot et al (1) provided a novel and valuable insight into gonadal function in patients with exon 2 deletions of ZNRF3. On the other hand, our male patient also showed pubertal development; however, spermatogenesis was not evaluated. We speculated that constitutive activation of ZNRF3 due to exon 2 deletions of the ZNRF3 gene might not necessarily cause testicular failure as opposed to the absence of ZNRF3 resulting in defects in testis determination (3). As for extra-adrenal manifestation, our 2 cases with relatively large deletions (73.5 kb and 59.1 kb) had congenital heart disease (CHD). We are interested in the size and region of the identified exon 2 deletion in the case reported by Janot et al (1). Future studies with more cases and accurate delineation of the deleted regions are needed to elucidate the association between ZNRF3 exon 2 deletions and CHD.

We agree that Wnt/β-catenin signaling plays an essential role in adrenal development in humans, and we expect that other genetic defects affecting Wnt/β-catenin signaling would be identified in congenital adrenal hypoplasia.

Disclosures

The authors have nothing to disclose.

References

Abbreviation

 
• CHD

  congenital heart disease