Isolated follicle-stimulating hormone (FSH) deficiency in a young man with normal virilization who did not have mutations in the FSHbeta gene.

OBJECTIVE: To determine the cause of isolated FSH deficiency in a young infertile man. DESIGN: Case report. SETTING: Clinical and genetic studies in an academic research environment. PATIENT(S): A 19-year-old man with normal virilization, azoospermia, and isolated FSH deficiency. INTERVENTION(S): Pituitary and gonadal functions were evaluated at baseline and after repeated GnRH stimulation. FSH was tested with both immunological and biological methods. The FSHbeta gene was sequenced in the patient and in a series of 50 controls. MAIN OUTCOME MEASURE(S): Clinical, endocrine, and genetic characterization of an infertile patient with isolated FSH deficiency. RESULT(S): LH and T secretions were normal. No interference in FSH measurement was detected, and serum FSH concentrations were very low and completely unresponsive to repeated GnRH stimulation. No circulating FSH-like bioactivity was detected by means of rat Sertoli cell bioassay. Other pituitary functions were unaffected, and no lesions were seen at pituitary nuclear magnetic resonance (NMR). Inhibin B and activin levels were normal, but a progressive decrease of activin concentrations was seen during GnRH stimulation. The coding sequence of the FSHbeta gene was normal, but the patient was homozygous for a novel G/T substitution in the promoter region within a P response element. This substitution was present in heterozygosity in eight out of 50 controls and in homozygosity in one man with normal FSH levels. CONCLUSION(S): We report an infertile male with isolated FSH deficiency but no evidence of mutations in the FSHbeta gene. The G/T substitution in the FSHbeta promoter represents a novel silent polymorphism, indicating that other defects in factors involved in FSH-specific expression should be taken into account.

Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism.

Germline loss-of-function mutations of TSH receptor (TSHR) gene have been described in families with partial or complete TSH resistance. Large TSH elevations were generally found in the patients with homozygous or compound heterozygous mutations. In this study, we sequenced the entire TSHR gene in a series of 10 unrelated patients with slight (6.6-14.9 mU/liter) to moderate (24-46 mU/liter) elevations of serum TSH, associated with definitely normal free thyroid hormone concentrations. Thyroid volume was normal in all patients, except two with a modest hypoplasia. Autoimmune thyroid disease was excluded in all patients on the basis of clinical and biochemical parameters. Eight patients had at least one first-degree relative bearing the same biochemical picture. TSHR mutations were detected in 4 of 10 cases by analyzing DNA from peripheral leukocytes. A compound heterozygosity (P162A on maternal allele, and the novel mutation C600R on the paternal one) was found in the patient with the highest TSH levels. Only one TSHR allele was mutated in the remaining three cases, and no alterations in TSHR gene promoter were detected in all of these probands. A novel mutation (L467P) was detected on the maternal allele in one patient and in her monozygotic twin. Previously described inactive mutants, T655Delta and C41S, were detected in the other two cases. When tested on several occasions, circulating TSH values fluctuating above the upper limit of the normal range could be shown in heterozygous subjects of these families. A dominant mode of inheritance of the biochemical alterations was detected in these cases. Mutant TSHRs were studied during transient expression in COS7 and HEK293T cells. Their TSH-independent cAMP accumulation activities were very low or similar to mock-transfected cells, and no increases were seen after maximal hormone stimulation. Flow cytometry experiments showed a poor level of expression of all mutant TSHRs at the cell membrane. In conclusion, we found several loss-of-function mutations of TSHR, including two novel ones, in a series of unrelated patients with slightly elevated TSH levels. Therefore, partial resistance to TSH action is a frequent finding among patients with slight hyperthyrotropinemia of nonautoimmune origin. Germline mutations of TSHR may be associated with serum TSH values fluctuating above the upper limit of the normal range, also in the heterozygous state.

Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita.

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse.