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Birth after TESE-ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation.

Frapsauce C, Ravel C, Legendre M, Sibony M, Mandelbaum J, Donadille B, Achermann JC, Siffroi JP, Christin-Maitre S - Hum. Reprod. (2011)

Bottom Line: Histology revealed severe hypospermatogenesis.Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed.Four embryos were obtained and, after a frozen-thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy.

View Article: PubMed Central - PubMed

Affiliation: UPMC, AP-HP, Hôpital Tenon, Service de Biologie de la Reproduction, 75020 Paris, France.

ABSTRACT
DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12-40) with low FSH and LH levels at 2.1 IU/l (N: 1-5 IU/l) and 0.1 IU/l (N: 1-4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur(®):150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen-thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE-ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH.

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(A) Nonsense p.Q404X (Gln404Stop) mutation in DAX1. (B) Control sequence (arrow: nucleotide exchange). (C) The mutation, as shown by a red star, is located in the ligand-like binding domain leading to a premature stop codon and predicted non-functional protein.
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DEQ372F1: (A) Nonsense p.Q404X (Gln404Stop) mutation in DAX1. (B) Control sequence (arrow: nucleotide exchange). (C) The mutation, as shown by a red star, is located in the ligand-like binding domain leading to a premature stop codon and predicted non-functional protein.

Mentions: Considering the association of adrenal insufficiency and HH, genetic testing of the NR0B1/DAX1 gene was conducted, after obtaining informed consent according to the French ethics law. As shown in Fig. 1, a change in nucleotide sequence (c.1210C>T) was identified, leading to a stop codon in position 404 (p.Gln404X). This mutation in our patient is found in a large cohort of ACH patients (Lin et al., 2006).Figure 1


Birth after TESE-ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation.

Frapsauce C, Ravel C, Legendre M, Sibony M, Mandelbaum J, Donadille B, Achermann JC, Siffroi JP, Christin-Maitre S - Hum. Reprod. (2011)

(A) Nonsense p.Q404X (Gln404Stop) mutation in DAX1. (B) Control sequence (arrow: nucleotide exchange). (C) The mutation, as shown by a red star, is located in the ligand-like binding domain leading to a premature stop codon and predicted non-functional protein.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3037794&req=5

DEQ372F1: (A) Nonsense p.Q404X (Gln404Stop) mutation in DAX1. (B) Control sequence (arrow: nucleotide exchange). (C) The mutation, as shown by a red star, is located in the ligand-like binding domain leading to a premature stop codon and predicted non-functional protein.
Mentions: Considering the association of adrenal insufficiency and HH, genetic testing of the NR0B1/DAX1 gene was conducted, after obtaining informed consent according to the French ethics law. As shown in Fig. 1, a change in nucleotide sequence (c.1210C>T) was identified, leading to a stop codon in position 404 (p.Gln404X). This mutation in our patient is found in a large cohort of ACH patients (Lin et al., 2006).Figure 1

Bottom Line: Histology revealed severe hypospermatogenesis.Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed.Four embryos were obtained and, after a frozen-thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy.

View Article: PubMed Central - PubMed

Affiliation: UPMC, AP-HP, Hôpital Tenon, Service de Biologie de la Reproduction, 75020 Paris, France.

ABSTRACT
DAX1/NR0B1 mutations are responsible for X-linked congenital adrenal hypoplasia (AHC) associated with hypogonadotropic hypogonadism (HH). Few data are available concerning testicular function and fertility in men with DAX1 mutations. Azoospermia as well as failure of gonadotrophin treatment have been reported. We induced spermatogenesis in a patient who has a DAX1 mutation (c.1210C>T), leading to a stop codon in position 404 (p.Gln404X). His endocrine testing revealed a low testosterone level at 1.2 nmol/l (N: 12-40) with low FSH and LH levels at 2.1 IU/l (N: 1-5 IU/l) and 0.1 IU/l (N: 1-4 IU/l), respectively. Baseline semen analysis revealed azoospermia. Menotropin (Menopur(®):150 IU, three times weekly) and human chorionic gonadotrophin (1500 IU, twice weekly) were used. After 20 months of treatment, as azoospermia persisted, bilateral multiple site testicular biopsies were performed. Histology revealed severe hypospermatogenesis. Rare spermatozoa were extracted from the right posterior fragment and ICSI was performed. Four embryos were obtained and, after a frozen-thawed single-embryo transfer, the patient's wife became pregnant and gave birth to a healthy boy. We report the first case of paternity after TESE-ICSI in a patient with DAX1 mutation, giving potential hope to these patients to father non-affected children. Furthermore, this case illustrates the fact that patients with X-linked AHC have a primary testicular defect in addition to HH.

Show MeSH
Related in: MedlinePlus