Mutations of SRY are the cause of complete pure gonadal dysgenesis (PGD) in 10-15% of patients. In the remaining individuals, it has been suggested that mutations in other genes involved in the testis-determining pathway could be causative. We describe the first report in which three cases of 46,XY complete PGD are attributed to mutations of the Desert hedgehog (DHH) gene. DHH was sequenced using genomic DNA from paraffin-embedded gonadal tissue from six patients with complete 46,XY PGD. Mutations were found in three patients: a homozygous mutation in exon 2, responsible for a L162P, and a homozygous 1086delG in exon 3. Mutated individuals displayed 46,XY complete PGD, differentiating from the only previously described patient with a homozygous DHH mutation, who exhibited a partial form of PGD with polyneuropathy, suggesting that localization of mutations influence phenotypic expression. This constitutes the first report where mutations of DHH are associated with the presence of 46,XY complete PGD, demonstrating that the genetic origin of this entity is heterogeneous and that disorders in other genes, different from SRY, involved in the testis-determining pathway are implicated in abnormal testicular differentiation in humans. These data extend previous reports demonstrating DHH is a key gene in gonadal differentiation.

No abstract

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. To date, 4 different genes have been identified as responsible for the presence of KS; however, in many cases no mutations have been found in any of these genes. Herein, we report the molecular findings regarding the analysis of fibroblast growth factor receptor 1 (FGFR1), prokineticin receptor 2 (PROKR2), and prokineticin (PROK2) in patients with KS. Twenty-four patients with KS were studied in whom mutations in KAL1 had been investigated previously. Polymerase chain reaction products from FGFR1, PROKR2, and PROK2 were sequenced and mutations were sought in the open reading frame of the 3 genes. Two patients presented a heterozygous T-to-G transversion in exon 2 (c.518T.G) of the PROKR2, which results in a leucine-to-arginine substitution at codon 173. Our results strengthen the hypothesis of possible digenic inheritance in some patients with KS. Likewise, our data extend previous reports demonstrating that PROKR2 plays a role in the etiology of this syndrome.

Aetiology of mixed gonadal dysgenesis (MGD) has not been completely elucidated. Molecular analyses have failed to demonstrate the presence of mutations in sex-determining region on Y chromosome (SRY); it has been suggested that these individuals may bear mutations in other genes involved in the testis-determining pathway. Desert hedgehog's (DHH) importance regarding male sex differentiation has been demonstrated in various studies we describe here, for the first time, two cases of MGD in which a monoallelic single base deletion in DHH is associated with the disorder. Genomic DNA was isolated from paraffin-embedded gonad tissue from 10 unrelated patients with MGD and three controls; in addition to, DNA from peripheral blood leukocytes in 100 controls. Coding sequence abnormalities in DHH were assessed by exon-specific PCR, single-stranded conformation polymorphism (SSCP) and direct sequencing. In two patients, a heterozygous 1086delG in exon 3 was found. Comparing previously described mutations in DHH to the one observed in this study, we can affirm that the phenotypic spectrum of patients with gonadal dysgenesis due to mutations in DHH is variable. This study continues to demonstrate the importance that DHH has in mammalian male sexual differentiation, providing extended evidence that DHH constitutes a key gene in gonadal differentiation.

No abstract

, Genny FERNÁNDEZ 6) , and Ramón CORAL-VÁZQUEZ

The presence of the same mutation in 4 patients from 3 families indicates the increased prevalence of this mutation in a particular ethnic group, suggesting a common ancestry for the gene defect in these patients. The existence of hot spots is supported by the mutations in codons 34 and 207 which have also been found in other ethnic groups. Interestingly, the patient who presented 2 different mutations, one of them previously undescribed, was reared as a male and exhibited a more masculine phenotype. Further studies in patients with this and other mutations will be needed to verify genotype-phenotype correlation.

Cytogenetic studies have shown that 40-60% of patients with Ullrich-Turner syndrome (UTS) are 45,X, whereas the rest have structural aberrations of the X chromosome or mosaicism with a second cell line containing a structurally normal or abnormal X or Y chromosome. However, molecular analysis has demonstrated a higher proportion of mosaicism, and studies in different populations have shown an extremely variable frequency of Y mosaicism of 0-61%. We used Southern blot analysis and polymerase chain reaction (PCR) to detect the presence of Ycen, ZFY, SRY, and Yqh in 50 Mexican patients with UTS and different karyotypes to determine the origin of marker chromosomes and the presence of Y sequences. Our results indicated the origin of the marker chromosome in 1 patient and detected the presence of Y sequences in 4 45,X patients. Taken together, we found a 12% incidence of Y sequences in individuals with UTS. The amount of Y-derived material was variable, making the correlation between phenotype and molecular data difficult. Only 1 patient had a gonadoblastoma. We discuss the presence of Y chromosomes or Y sequences in patients with UTS and compare our frequency with that previously reported.