46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (<i>DHH</i>) Identified by Exome Sequencing

Werner, Ralf; Merz, Hartmut; Birnbaum, Wiebke; Marshall, Louise; Schröder, Tatjana; Reiz, Benedikt; Kavran, Jennifer M.; Bäumer, Tobias; Capetian, Philipp; Hiort, Olaf

doi:10.1210/jc.2015-1314

Cited by 64 publications

(56 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To date, seven DHH mutations have been reported 14, 15, 16. Three of the seven mutations, including the mutation found in the study, cause 46XY GD with neuropathy, whereas some mutations did not cause neuropathy.…”

Section: Discussionmentioning

confidence: 53%

Partial duplication of DHH causes minifascicular neuropathy

Sato

Maekawa

Ishiura

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Minifascicular neuropathy (MN) is an extremely rare developmental malformation in which peripheral nerves are composed of many small fascicles. Only one patient with MN with 46XY gonadal dysgenesis (GD) was found to carry a mutation affecting the start codon in desert hedgehog (DHH). We identified an identical novel rearrangement mutation of DHH in two consanguineous families with MN, confirming mutations in DHH cause MN with 46XY GD. The patients with the 46XY karyotype developed GD, whereas a patient with the 46XX karyotype did not. These findings further support that DHH has important roles in perineural formation and male gonadal differentiation.

show abstract

Section: Discussionmentioning

confidence: 53%

Partial duplication of DHH causes minifascicular neuropathy

Sato

Maekawa

Ishiura

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Few reports described a unique clinical picture characterized by 46,XY GD and a specific peripheral neuropathy with minifascicular formation and decreased density of myelinated fibers [11–13]. In these patients, homozygous mutations in the DHH gene have been demonstrated (Table 2) [12-15].…”

Section: Discussionmentioning

confidence: 99%

“…Similar findings are reported in the other women with DHH variants and minifascicular neuropathy (Table 2). Thus, early derangement of the gonadal determination process is caused by homozygous DHH mutations in embryos with the 46,XY karyotype likely due to impairment of Sertoli cell-Leydig cell cross-talk during gonadal development [13], leading to a remarkable reduction of both the fetal and adult Leydig cell population [27]. The present report and the previous 46,XX woman reported by Sato et al [15] indicate that DHH mutation does not affect ovarian differentiation in a fetus with the 46,XX karyotype as well as ovarian function from puberty onward.…”

Section: Discussionmentioning

confidence: 99%

“…The first described adult 46,XY woman presented with partial gonadal dysgenesis (GD) and a homozygous DHH missense mutation; she also presented a specific minifascicular polyneuropathy [11, 12], suggesting a double effect of the genetic variant on the prenatal process of human male sex development and peripheral nervous system in adulthood. Recently, additional patients with DHH mutation, partial or complete GD, and peripheral neuropathy have been reported [13-15]. Some additional 46,XY women with homozygous DHH mutations and GD have been described, but they did not show minifascicular neuropathy [14, 16, 17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Baldinotti¹,

Cavallaro²,

Dati³

et al. 2018

Horm Res Paediatr

View full text Add to dashboard Cite

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

show abstract

“…Exome sequencing is expanding the phenotypic spectrum associated with mutations in genes known to be associated with DSD. This has included mutations in the FGFR1, LHCGR, DHH, ARX genes (59)(60)(61)(62). NGS is becoming a diagnostic tool in DSD.…”

Section: New Approaches To Understand the Genetics Of Human Sdmentioning

confidence: 99%

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

et al. 2017

View full text Add to dashboard Cite

Human sex determination (SD) involves complex mutually antagonistic genetic interactions of testis‐ and ovary‐determining pathways. For many years, both male and female SD were considered to be regulated by a linear cascade of pro‐male and pro‐female genes, respectively; however, it has become clear that male and female development is achieved through the repression of the alternative state. A gene determining the formation of a testis may function by repressing the female state and vice versa. Uniquely in development, SD is achieved by suppression of the alternate fate and maintained in adulthood by a mutually antagonistic double‐repressive pathway. Here, we review genetic data generated through large‐scale sequencing approaches that are changing our view of how this system works, including the recently described recurrent NR5A1 p.R92W mutation associated with testis development in 46,XX children. We also review some of the unique challenges in the field to establish that mutations, such as this are pathogenic. The impending surge of new genetic data on human SD from sequencing projects will create opportunities for the development of mechanistic models that will clarify how the system operates and importantly provide data to understand how selection and developmental processes interact to direct the evolution of SD across species.

show abstract

46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing

Abstract: Background: 46,XY disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions. Mutations in a variety of genes can affect gonadal development or androgen biosynthesis/action and thereby influence the development of the internal and external genital organs.

Cited by 64 publications

References 37 publications

Partial duplication of DHH causes minifascicular neuropathy

Partial duplication of DHH causes minifascicular neuropathy

Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Anomalies in human sex determination provide unique insights into the complex genetic interactions of early gonad development

Contact Info

Product

Resources

About