Once-Daily Low-Dose Cyclosporine A Treatment with Angiotensin Blockade for Long-Term Remission of Nephropathy in Frasier Syndrome.

Cyclosporine A is known to be effective in some genetic podocyte injury. However, the efficacy of cyclosporine A depends on the degree of histopathological findings, and the relationship between long-term use and renal prognosis remains unknown. Frasier syndrome is a rare genetic disorder caused by intronic mutations in WT1, and is characterized by progressive glomerulopathy, a 46,XY disorder of sex development, and an increased risk of gonadoblastoma. We report here a 16-year-old phenotypically female patient with Frasier syndrome. A renal biopsy at the age of seven years showed segmentally effaced podocyte foot processes with no evidence of glomerulosclerosis. Steroid-resistant proteinuria progressed to the nephrotic range at the age of 10 years, which responded to once-daily administration of cyclosporine A with low two-hour post-dose cyclosporine A (C2) levels; she then achieved stable partial remission in combination with renin-angiotensin system (RAS) blockade. At the age of 12 years, examinations for delayed puberty confirmed the diagnosis of Frasier syndrome. The second renal biopsy showed widespread foot process effacement and a minor lesion of segmental glomerulosclerosis without findings suggestive of cyclosporine A nephropathy. She maintained partial remission and normal renal function with the continuation of once-daily low-dose cyclosporine A. The C2 levels required for the remission were between 212 and 520 ng/ml. Cyclosporine A dosages sufficient for maintaining the C2 levels were 1.1-1.2 mg/kg per day. In conclusion, the long-lasting treatment of once-daily low-dose cyclosporine A with RAS inhibition was effective for induction and maintenance of partial remission in Frasier syndrome.

Pituitary origin of persistently elevated human chorionic gonadotropin in a patient with gonadal failure.

OBJECTIVE: To report a case of persistently elevated low levels of hCG to increase awareness of pituitary origin of persistently elevated hCG in patients with gonadal failure. DESIGN: Case report and literature review. SETTING: Large university-affiliated infertility practice. PATIENT(S): A 16-year-old patient with primary amenorrhea, normal secondary sex characteristics, ovarian failure, and a 46,XY karyotype. Her past medical history was significant for focal segmental glomerulosclerosis, leading to a diagnosis of Frasier syndrome. INTERVENTION(S): At age 31 years, she desired pregnancy by oocyte donation and was found to have persistently elevated low levels of hCG (>35 mIU/mL). MAIN OUTCOME MEASURE(S): Pituitary hCG. RESULT(S): Both serum free ß-hCG and hyperglycosylated hCG were undetectable. Total serum hCG diluted appropriately was not blocked by blocking agent and was detected in the urine. Subsequent treatment with exogenous E(2), in preparation of a donor oocyte cycle, suppressed her hCG levels (down to 8 mIU/mL). These results indicated a pituitary source of the serum hCG. CONCLUSION(S): This report reinforces the need to consider pituitary hCG as the origin of persistently elevated hCG levels in patients with gonadal failure. Although levels of hCG <14 mIU/mL have been considered normal in postmenopausal women, our case suggests that patients with gonadal failure at younger ages might have a higher pituitary output of hCG.

Lack of puberty despite elevated estradiol in a 46,XY phenotypic female with Frasier syndrome.

Frasier syndrome is characterized by slowly progressive nephropathy, male pseudohermaphroditism, streak gonad, and high risk of gonadoblastoma development. Here we report a case of a 46,XY phenotypic female with Frasier syndrome, who was under hemodialysis. While her serum estradiol level was gradually increasing annually, gonadotropin level was constantly extremely high, and her appearance was still prepubertal. She was heterozygous for a novel guanine>adenine point mutation at position +1 of the splice donor site within intron 9 (IVS 9 + 1G>A) of the Wilms' tumor 1 gene. The possibility of this disease should be taken into consideration whenever we encounter a patient with steroid-resistant nephrotic syndrome and delayed puberty.