DHH – Disorder of Sexual Differentiation

Desert hedgehog (DHH) is a Hedgehog family ligand critical for Sertoli–Leydig cell interaction during gonadal development. Bi-allelic DHH variants underlie autosomal recessive 46,XY disorders of sexual differentiation, often presenting with partial or complete gonadal dysgenesis and peripheral neuropathy. Genetic and functional studies confirm that loss of DHH signaling disrupts testicular differentiation and Schwann cell function, leading to gonadal dysgenesis, seminoma risk, and minifascicular neuropathy.

Genetic evidence includes at least 12 probands from six unrelated families with homozygous or compound heterozygous DHH mutations segregating with disease ([PMID:25927242], [PMID:28708305], [PMID:35971145]). Consanguineous sib pairs carrying c.371G>A (p.Arg124Gln) and c.519G>T (p.Trp173Cys) homozygous variants exhibit 46,XY gonadal dysgenesis, Leydig cell loss, seminoma in situ, and polyneuropathy. Additional compound heterozygous frameshift and missense alleles (e.g., c.602delC (p.Pro201ArgfsTer?); c.937G>T (p.Val313Leu)) have been reported in siblings with variable external genitalia anomalies.

The variant spectrum is dominated by missense substitutions in conserved residues (Arg124Gln, Trp173Cys) and truncating alleles (c.602delC (p.Pro201ArgfsTer?)), all fitting an autosomal recessive inheritance pattern. Recurrent homozygous alleles arise in consanguineous populations, but no founder effect has been conclusively established.

Segregation analysis reveals multiple affected sib pairs with concordant bi-allelic DHH genotypes; in three families each, one additional affected relative segregated the familial variant. Functional assays of DHH mutants demonstrate impaired precursor autocleavage and reduced activation of Hedgehog signaling in co-culture Leydig cell systems, correlating with human phenotypes ([PMID:23786321], [PMID:30298535], [PMID:32504121]).

In vitro molecular dynamics and structural modeling predict that pathogenic missense variants increase conformational flexibility, disrupt DHH–BOC interactions, and abrogate N-terminal fragment release. Loss of DHH signaling impairs both gonadal and Schwann cell development, explaining the combined gonadal dysgenesis and polyneuropathy phenotype.

No strong evidence supports pathogenicity of heterozygous DHH variants in isolation; heterozygotes display intact signaling when co-expressed with wild-type DHH in functional assays, reaffirming autosomal recessive inheritance.

Overall, the association between DHH and disorder of sexual differentiation meets ClinGen Strong criteria based on multiple familial segregation events and robust experimental concordance. Key take-home: Bi-allelic DHH mutations cause autosomal recessive 46,XY disorders of sexual differentiation with seminoma susceptibility and neuropathy, supporting targeted genetic testing in DSD work-up for accurate diagnosis and management.

References

• The Journal of Clinical Endocrinology and Metabolism • 2015 • 46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog Identified by Exome Sequencing. PMID:25927242
• Clinical Endocrinology • 2017 • A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations. PMID:28708305
• BMC Medical Genomics • 2022 • Novel compound heterozygous mutations in the desert hedgehog (DHH) gene in cases of siblings with 46,XY disorders of sexual development. PMID:35971145
• DNA and Cell Biology • 2013 • In vitro and molecular modeling analysis of two mutant desert hedgehog proteins associated with 46,XY gonadal dysgenesis. PMID:23786321
• Human Mutation • 2018 • In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis. PMID:30298535
• Human Genetics • 2020 • DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation. PMID:32504121

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