Chronic renal failure and XY gonadal dysgenesis: “Frasier” syndrome—a commentary on reported cases

American Journal of Medical Genetics Supplement 3:297-302 (1987)

Chronic Renal Failure and XY Gonadal Dysgenesis: ‘ ‘Frasier” Syndrome-A Commentary on Reported Cases A. Vishnu Moorthy, Russell W. Chesney, and Mark Lubinsky Departments of Medicine and Pathology, University of Wisconsin and Veterans Administration Hospital, Madison, Wisconsin (A. V.M.); Department of Pediatrics, University of California Davis Medical Center, Sacramento, California (R. W.C.); University of Nebraska Medical Center, Omaha, Nebraska (M.L.) The development of chronic renal failure because of parenchymatous renal disease in patients in 46,XY gonadal dysgenesis was noted initially by Drash et al [J Pediatr 76:585-593, 19701. However, we think that some of the cases reported as examples of the Drash syndrome are a different disorder. In this paper, we review six previously reported patients with streak gonads, pseudohermaphroditism, and renal failure. In several of these patients the diagnosis was established only after a successful kidney transplantation during evaluation for primary amenorrhea. Gonadoblastoma arising from the streak gonad was noted in five of the six patients. “Frasier” syndrome would be a suitable term to denote this association after Frasier et al, who described two patients in 1964. We recommend evaluation of the gonads in prepubertal girls with end-stage renal disease at risk for this syndrome. Key words: 46,XY gonadal dysgenesis, gonadoblastoma

INTRODUCTION Structural anomalies of the urinary system are commonly seen in patients with abnormalities in genital differentiation [Curry et al, 19841. Much less commonly appreciated is the development of chronic renal failure because of glomerular disease in patients with XY gonadal dysgenesis [Drash et al. 1970; Habib et al, 1985; Eddy and Mauer. 1985; Blanchet et al, 1977; Frasier et al, 1964: Harkins et al, 1980, Haning et al, 19851. Drash syndrome has been defined a s male pseudohermaphroditism, progressive Received for publication November 17, 1986; revision received February 2, 1987. Dedicated to Dr. Enid F. Gilbert for her friendship and inspiring work over 30 years in fetal genetic pathology and in experimental teratology. Addresp reprint requests to Dr. A.V. Moorthy, Renal Section, V.A. Hospital, 2500 Overlook Terrace, Madison, WI 53705. 0 1987 Alan R. Liss, Inc.

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renal failure because of parenchymatous renal disease occurring early in life, and high risk for Wilms tumor [Eddy and Mauer, 19851. However, we think that some cases with this diagnosis represent a separate disorder. In this paper, we delineate this other condition and reevaluate the spectrum of findings in Drash syndrome. Eddy and Mauer [1985] and Habib et al [ I9851 have divided Drash syndrome into groups based on the presence or absence of Wilms tumor. This is somewhat arbitrary in that the tumor may appear as late as the sixth year of life, and many affected children die before this time. Therefore, some of cases without Wilms tumor may represent children who did not live long enough to develop the tumor. If children with early death are withdrawn from the class of cases without Wilms tumor, group B of Eddy and Mauer [1985] is left with four cases, all with normal female external genitalia. It has been suggested [Haning et al, 19851 that this finding denotes a separate group. In this report, we review six cases of male pseudohermaphroditism with streak gonads, none of whom having developed Wilms tumor and all having had relatively late onset of renal failure (Table I). In 1964, Frasier et al described a pair of presumed monozygotic twins concordant for 46,XY gonadal dysgenesis; one of them presented with an abdominal mass at 6 years. At laparotomy, she was found to have a teratoma arising from one streak gonad. Histologically small nodules of gonadoblastoma were also noted in the tumor mass. At that time, urinalysis also showed proteinuria. Renal function deteriorated gradually, and she died 18 months later of renal failure. Evaluation of the asymptomatic twin sister also showed proteinuria. She was reported to have had progressive kidney failure necessitating transplantation with one of her father’s kidneys [Drash et al, 19701. CLINICAL REPORTS

Two patients with this syndrome have been reported from Madison, Wisconsin. The first patient was a black woman evaluated at age 23 years for chronic renal failure [Harkins et al, 19801. She was first noted to have microscopic hematuria at age 14 years, but the results of renal evaluation at that time were lost and were no longer available. Renal ultrasonography showed small contracted kidneys consistent with chronic renal parenchymatous disease, and maintenance hemodialysis was begun. Because of primary amenorrhea, further investigations were performed and she was diagnosed to have 46,XY gonadal dysgenesis. At laparotomy she had bilateral streak gonads with gonadoblastoma on one side. The second patient was a girl noted to have proteinuria and microscopic hematuria at age 4 years [ Haning et al, 19851. A kidney biopsy documented focal glomerulosclerosis. Renal function deteriorated gradually, and she received a kidney from her brother at age 16 for end-stage renal disease. Two years after transplantation, she was evaluated for primary amenorrhea and determined to have 46,XY gonadal dysgenesis. At laparotomy fallopian tubes, small uterus, and streak gonads were noted. A tumor in the right streak gonad was found to be a combined dysgerminoma and gonadoblastoma. REVIEW

Blanchet et al [1977] and Simpson et al [1982] each reported one patient with chronic renal failure and 46,XY gonadal dysgenesis. Both had received a kidney transplant for end-stage renal disease and were investigated for primary amenorrhea and both were noted to have a gonadoblastorna in their streak gonads.

6

5

4

3

2

Frasier et al,

I

1985

Haning el al,

1982

S i m p n e t al.

I980

Blanche1et al. I977 Harkinset al.

I964

Frasier et al.

I964

Reference

No.

Case

Primary amenorrhea

Primary amenorrhea

I7

20

23

Primary amenorrhea Primary amenorhea

Asymptomatic (twin of pt. I)

6

I6

Lower abdominal mass with pain

Clinical presentation

6

Age at diagnosis of gonadal dysgenesis (years)

Female

Female

Female

Female

Female

Female

External genitalia

Female, streak gonad: dysgerminomaf gonadoblastomaon the right

Female, left streak gonad and right go. nadoblastoma

Female, streak gonads, gonadoblasloma on the right side Female. streak gonads

Female. streak gonads, gonadoblastoma

Female. streak gonad with large gonadoblastoma

Internal genitalia

TABLE 1. An Outline of Patients Previouslv Reported in the Literature

46,XY

Proteinuria on routine urinalySUI at age 17 Hematuria and proteinuria at age 4

14

Microscopic hernaturia at age

46,XY

46.XY

Unknown

6

Proteinuria and hematuria at age 6 Proteinuria at age

46.XY

46,XY

46,XY

Karye type

Age at onset of renal diseaseand symptom (yean)

Bilateral nephrectomy at the timeof renal transplantation. glomerulcsclerosis Focal glomerulcsclerosis on two renal biopsies

Small kidneys on ultrasonogrdphy

Membranous and focal proliferative glomerulonephritis with interstitial foam cells “lnterstital nephritis”

Chronic and subacute gtomerulonephritis

Natue of renal disease

Rogrssive renal failure, renal transplantalion at age 21, also had m p tonic dystrophy Prqressive renal failure, unresponsive to prednime. renal transplant at age 16

End-stage renal failure, renal transplantation at age 14 End-stage renal failure by age 23, maintenance h e d i a l y s i s

Progressive renal failure, renal transplantation

Died of chmnic renal failure at age 7

Clinical m u m

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The recognition of the syndrome of 46,XY gonadal dysgenesis and chronic renal failure calls for a high index of suspicion on the part of the clinician. Chronic renal failure developing during adolescence often is associated with sexual infantilism and primary amenorrhea [Oertel et al, 19831. After a successful kidney transplant, patients usually undergo puberty [ Broyer et al, 19811. In several previously reported patients, the diagnosis of 46,XY gonadal dysgenesis was made only after several years of renal transplantation when menstruation did not commence despite successful renal allograft function. These patients would have died if renal dialysis or transplantation had not been available, so it is possible that other individuals with this syndrome died from end-stage renal failure before the diagnosis of XY gonadal dysgenesis. Thus gonadal dysgenesis may be manifested only by the failure of spontaneous puberty in a patient with successful renal transplantation. A delay in the diagnosis of XY gonadal dysgenesis in women with chronic renal failure could potentially lead to serious complications with the development of gonadoblastoma. Five of the six patients with this syndrome who lived beyond infancy developed tumors in the streak gonads. In three patients, prior renal transplantation had been performed and they were receiving immunosuppressive treatment. However, the development of malignancy in the streak gonads in the patients with this syndrome cannot be attributed solely to the immunosuppressive therapy. The incidence of gonadoblastoma is known to be increased in patients with XY gonadal dysgenesis without renal failure [Fine et al, 1962; Manuel et al, 1976; Bolande, 19761. An increased incidence of gonadal malignancy has also been described in patients with the syndrome of congenital androgen insensitivity [Bolande, 19761. Although the incidence of malignancy is increased in patients receiving immunosuppressive treatment after renal transplantation, most of the tumors arise in the reticuloendothelial system or the skin [Penn, 19781. Only 8%)of these tumors are gynecologic in origin, and most of those reported tend to be squamous cell carcinoma of the cervix, gonadoblastoma being uncommon [Porreco et al, 19751. DISCUSSION

The cases reviewed in this report differ in several aspects from the patients described as having Drash syndrome (Table 11). Patients with streak gonads and renal disease tend to be older, do not develop Wilms tumor, and have an increased likelihood of developing gonadal tumors. The age of onset of the renal disorder is difficult to assess. The cases of Habib et al [ 19851 indicate an onset as early as the first year of life in the Drash syndrome. Progression is typically rapid, with renal failure often within 1 year, the decade-long course of their case 8 being exceptional. In contrast, the patients with streak gonads seem to have onset of renal disease at age 4 years or later and a course of at least 2 years. Eddy and Mauer [ 19851 found a 55% incidence of Wilms tumor in their review of Drash syndrome. Our analysis removes several cases without tumor. Therefore, the expected incidence of Wilms in “true” Drash syndrome is considerably higher. If an affected child survives with kidneys in place, it is exceptional not to have evidence of the cancer by the sixth year of life. There seems to have been only one exception to this, case 8 of Habib et a1 [ 19851, who interestingly also had a later onset of renal failure than is usual in Drash syndrome. In contrast, the girls with streak gonads have a lower risk for Wilms tumor, or none at all since there are no documented cases; however the total number reported is small. In contrast, the risk for gonadal tumors with streak gonads is very high, manifesting in five of the six cases. Most of the patients with Drash syndrome have presented earlier with renal disease and have also had their gonads removed early. Their risk for gonadal tumors is

Renal Failure and XY Gonadal Dysgenesis

301

TABLE 11. Two SyndromesWith Gonadal Dvsgenesis and Renal Disease Drash syndrome Gonadal dysgenesis

Wilms tumor Gonadal tumor Renal disease Onset Course

Frasier syndrome

Varying degrees, possibly from minimal or none through streaks with few normal elements Almost always if patient lives to 6 years Uncertain, presumed significant risk

Streak gonads

Early childhood, often infancy Rapid, often less than 1 year

Age 4 and up Slowly progressive, at least 2 years

Not seen to date Five of six cases

therefore difficult to assess. Although it may be lower than with streak gonads, it is presumed that, as with other cases of gonadal dysgenesis, the risk is significant and justifies prophylactic removal. Our patients all had normal female external genitalia. The same findings can be seen in an extreme form of the Drash syndrome. The case of Gertner et al [1980], previously suggested as separate from Drash syndrome [Haning et al, 19851, had such testicular gonadal elements. Case 3 of Habib et al [1985] also had female external genitalia but ovotestes. Both of these had other characteristics, such as early renal failure, to indicate that they belong in the “classic” Drash syndrome group. The patients with both conditions have all been genetic males. Habib et al [ 19851 suggested the possibility of female involvement, but gonadal findings in the proposed cases were not reported. There is no reason to exclude chromosomal females from inclusion in either of the syndromes discussed. However, the effects of the interaction between the presumed cause (perhaps a tissue abnormality) and XX chromosomes on the gonads is uncertain. If normal ovaries were present, some cases would not be recognized as anything other than idiopathic renal failure. Also, there may be normal external genitalia in Drash syndrome. Some male cases mentioned in passing in Wolff et a1 [1978] suggest that this is indeed the case. The patient studied by us had two renal biopsies during the course of her renal disease at 6 and 16 years [Haning et al, 19851. The changes could be described as focal global glomerulosclerosis with variable mesangial matrix expansion and segmental hyaline sclerosis in other glomeruli. Detailed accounts of renal histopathology are not available in the other reported cases, and it is difficult to determine if these changes are indeed different from those described by Habib et al [ 19851 in patients with Drash syndrome. We conclude that these characteristics define a disorder different from Drash syndrome (Table 11). “Frasier” syndrome would be an appropriate term to define this disorder after Frasier et al, who reported the first two patients in 1964. Some overlap between the two exists, but the differences are sufficient to support two presumably causally different conditions. If these are merely two ends of a spectrum, it is hard to understand greater severity of one component (streak gonads instead of ovotestes) with less severity in another (absent Wilms tumor). Cases of both conditions are common and distinct enough to leave little doubt that they represent specific disorders rather than simple coincidence. Although their causes are unknown, clinical similarities suggest a similar pathogenesis, perhaps related to differentiation of similar embryologic tissues. The recognition of a syndromal association between XY gonadal dysgenesis and renal disease is important. Gonadoblastoma could be a potentially fatal complication in patients with chronic renal failure and undiagnosed XY gonadal dysgenesis. Harkins et a1 [ 19801 have noted previously that in groups at risk follicle-stimulating hormone (FSH)

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studies are appropriate. Significant elevation in serum FSH levels would support the diagnosis of gonadal dysgenesis. However, chromosome studies need to be performed to confirm the diagnosis. Chromosome studies need especially to be performed in children between 5 and 1 1 years of age; serum FSH levels may be similar to those of normal children of the same age, making FSH determinations less reliable for detecting the agonadal condition [Conte et al, 19801. ACKNOWLEDGMENT

Typing assistance was from the Secretarial Center. REFERENCES Blanchet P. Daloze P, Lesage R, Papas S, Compenhout JV (1977): XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantation. Am J Obstet Gynecol 129:221-222. Bolande RP (1976): Neoplasia of early life and its relationship to teratogenesis. Perspect Pediatr Pathol 3:145-183. Broyer RM, Scharer K, Castanier M (1981): Gonadotropines et androgenes plasmatiques chei les garcons traites pour insufficance renale chronique. Pathol Biol29:378-379. Conte FA, Grumbach MM, Kaplan S L (1 980): Correlation of luteinizing hormone-releasing factor-inducing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: Relation to the restraint of puberty. J Clin Endocrinol Metab 50:163-168. Curry CJR, Jensen K, Holland J, Miller L, Hall BD (1984): The Potter sequence: A clinical analysis of 80 cases. Am J Med Genet 19:679-702. Drash A, Sherman F, Hartmann WH, Blizzard RM (1970): A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension and degenerative renal disease. J Pediatr 76585-593. Eddy AA, Mauer S M (1 985): Pseudohermaphrcditism, glomerulopathy and Wilms’ tumor (Drash syndrome): Frequency in end stage renal failure. J Pediatr 106:584-587. Fine G, Mellinger R, Canton J (1962): Gonadoblastoma occurring in a patient with familial gonadal dysgenesis. Am J Clin Pathol 38:615419. Frasier SD, Bashore RA, Mosier HD (1964): Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J Pediatr 64:740-745. Gertner JM, Kauschansky A, Giesker DW, Siege1 NJ, Brac WR, Gene1 M (1980): XY gonadal dysgenesis associated with congenital nephrotic syndrome. Obstet Gynecol 55:655495. Habib R, Loirat C, Gubler MC, Niaudet P, Bensman A, Levy M, Broyer M (1985): The nephropathy associated with male pseudohermaphroditism and Wilms’ tumor (Drash syndrome): A distinctive glomerular lesion-Report of 10 cases. CIin Nephrol 24:269-278. Haning RV Jr, Chesney RW, Moorthy AV, Gilbert EF (1985): A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without gonadal ambiguity. Am J Kidney Dis 6:40-48. Harkins PG. Haning RV Jr, Shapiro SS (1980): Renal failure with XY gonadal dysgenesis: Report of the second case. Obstet Gynecol 56:75 1-752. Manuel M, Katayama K, Jones H (1976): The age of Occurrence of gonadal tumors in intersex patients with Y chromosome. Am J Obstet Gynecol I24:293-296. Oertel PJ, Lichtwald K, Hafner S, Rauh W, Schonberg D, Scharer K (1983): Hypothalamepituitary-gonadal axis in children with chronic renal failure. Kidney Int 24:S3-39. Penn I ( 1978): Malignancies associated with immunosuppressive or cytotoxic therapy. Surgery 83:492-502. Porreco R, Penn I, Droegemueller W, Greer B, Makowski E (1975): Gynecologic malignancies in immunosuppressed organ homograft recipients. Obstet Gynecol 45:359-366. Simpson JL, Chaganti RSK, Mourandian J, German J (1982): Chronic renal disease, myotonic dystrophy and gonadoblastoma in XY gonadal dysgenesis. J Med Genet 79:73-76. Wolf OH, Barratt JM, Pincott J, Cameron JS, Black D, Milne MD, MacRae JHH, Dillon MHJ, Brown MJ, Nepson EM (1978): Two children with kidney disease. Br Med J 22367-869.

Edited by John M. Opitz and Jay Bernstein