Desert hedgehog (DHH) is a secreted signaling protein that functions as a morphogen in development and tissue homeostasis. DHH signals through the patched (PTCH1) and smoothened (SMO) receptor complex to activate transcription of target genes. The protein undergoes dually lipidation and autoprocessing to generate its active N-terminal form, which binds PTCH1 to initiate hedgehog pathway signaling. DHH plays critical roles in male sexual development and peripheral nerve formation. It is essential for normal testis development and spermatogenesis, including formation of adult-type Leydig cells and proper development of peritubular cells and seminiferous tubules. Beyond gonadal function, DHH activates signaling in neighboring cells through paracrine mechanisms—for example, it activates primary cilia signaling on valve interstitial cells. Recent evidence suggests DHH secreted from epithelial neuroendocrine cells orchestrates tissue regeneration and protection; in airway and pancreatic tissue, DHH from neuroendocrine cells amplifies a regenerative response in mesenchymal cells following injury, with Hedgehog pathway agonists showing protective potential against airway or pancreatic damage 1. Mutations in DHH cause 46,XY gonadal dysgenesis often accompanied by minifascicular peripheral neuropathy 23. A homozygous mutation at the translation initiation codon results in complete loss of protein function and gonadal dysgenesis with polyneuropathy. Mutations ranging from mild synonymous variants to frameshift insertions have been associated with male infertility, undescended testis, and gonadal dysgenesis 4, demonstrating that DHH mutations impact reproduction across a severity spectrum.