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Oophorectomy in McCune-Albright syndrome: a case of mistaken identity
Journal of Pediatric Surgery (2007) 42, 1578–1583
www.elsevier.com/locate/jpedsurg
Oophorectomy in McCune-Albright syndrome: a case of mistaken identity Zeina M. Nabhan a,* , Karen W. West b , Erica A. Eugster a a
Section of Pediatric Endocrinology/Diabetology, Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA b Department of Pediatric Surgery, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Index words: McCune-Albright syndrome; Oophorectomy; Ovarian tumors
Abstract Objective: The objective of the study was to determine the incidence of oophorectomy in girls presenting with precocious puberty and vaginal bleeding who are subsequently diagnosed with McCune-Albright syndrome (MAS). Study Design: Medical records of girls diagnosed with MAS between 1988 and 2005 were reviewed. Variables analyzed included presenting features, presence of café au lait macules, presence of fibrous dysplasia, radiographic studies, estradiol levels, tumor markers, surgery, and pathology reports. Results: Nine girls with MAS were identified. Average age at initial presentation was 3.2 ± 2.1 years (range, 0.6-7 years). All patients presented with sudden onset of vaginal bleeding. Eight (88%) also had breast development and 2 (22%) had associated pubic hair. Four (44%) girls underwent salpingooophorectomy before the diagnosis of MAS was made. Of these, 3 had café au lait macules on initial presentation, and 3 were later diagnosed with fibrous dysplasia. Surgical pathology revealed benign ovarian cysts in all 4 patients. Conclusion: Unnecessary oophorectomy is common in girls with MAS who are taken to the operating room for a presumed ovarian tumor. This highlights the need for increased awareness of MAS among pediatricians, pediatric surgeons, and emergency room physicians. Distinguishing features, which can be helpful in differentiating these 2 conditions, are often present. © 2007 Elsevier Inc. All rights reserved.
McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the classic triad of precocious puberty (PP), café au lait skin pigmentation, and polyostotic fibrous dysplasia of bone [1,2]. It is caused by activating mutations of GNAS1, the gene encoding for the alpha subunit of the stimulatory G-protein involved in intracellular signaling in endocrine cells and other tissues [3]. This mutation results in loss of intrinsic GTPase activity leading to abnormal * Corresponding author. Tel.: +1 317 274 3889; fax: +1 317 274 3882. E-mail address: [email protected] (Z.M. Nabhan). 0022-3468/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2007.04.021
accumulation of intracellular cyclic adenosine monophosphate and unregulated cell proliferation with overproduction of cellular product [3]. The GNAS1 activating mutation occurs sporadically in a postzygotic cell line; thus, the subsequent mosaic distribution of affected cells can be widespread or limited, depending on the timing of the mutational event [4,5]. McCune-Albright syndrome is a heterogeneous disease with variable clinical manifestations [2,6,7]. However, girls usually present between the ages of 1 and 5 years with PP and sudden onset of vaginal bleeding because of the
Oophorectomy in McCune-Albright syndrome
1579
development and subsequent resolution of unilateral autonomous estrogen-producing ovarian cysts [8]. If other classic features of the disorder are unrecognized or not present, these findings may be confused with an ovarian tumor such as a juvenile granulosa cell tumor (JGCT), resulting in unnecessary surgery. Here we report an index case of oophorectomy in a girl later diagnosed with MAS and review our experience with similar cases seen at our medical center during the last 15 years. We also compare the clinical and biochemical features seen in MAS with those typically present in girls with JGCT.
1. Patients and methods 1.1. Index case A previously healthy African American girl aged 3 years 6 months presented to the emergency room with sudden onset of heavy and painless vaginal bleeding. On physical examination, she was noted to have Tanner I breasts and Tanner I pubic hair. Initial evaluation included measurements of serum α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-HCG), both of which were normal. Estradiol level was elevated at 450 pg/mL (normal, b20 pg/mL). Pelvic computed tomography revealed a left ovarian unilocular cystic mass 6 cm in diameter in association with uterine enlargement (Fig. 1). A pediatric surgery consult was obtained, and the decision was made to take the child to the operating room, where a left salpingo-oophorectomy was performed. An intraoperative image is provided in Fig. 2. Pathology revealed a functional ovarian cyst with a granulosa cell lining. The vaginal bleeding stopped 4 days postsurgery, and the estradiol levels normalized within 2 months.
Fig. 1 Computed tomographic scan of the abdomen and pelvis in the index case. Note the unilateral left ovarian cystic mass.
Fig. 2 Intraoperative image of the left ovary (index case) after oophorectomy.
The patient continued to do well until 5 years of age, when she presented again with painless vaginal bleeding. Pelvic ultrasound revealed a right ovarian cyst 3.8 × 2.4 × 1.8 cm
Fig. 3 Bone scan with increased uptake in the left ulna and left tibia suggestive of fibrous dysplasia.
1580
Table 1
Summary of patient characteristics at initial presentation
Patient
1
2
3
4
5
6
7
8
9
Age (y) Vaginal bleeding Tanner staging Café au lait Fibrous dysplasia Abdominal pain Tumor markers
3.5 +a
5.6 +a
4 +
2 +
2.2 +a
3 +
0.6 +
0.8 +
7 +
T I breast
T II breast; T II PH
T III breast; T III PH
T II breast
T II breast
T II breast
− +
+ +
+ −
+ +
− +
− +
T II breast + −
T II breast + +
T III breast − +
−
−
+
−
−
−
−
−
−
AFP, NL
ND
AFP, NL
AFP, NL; β-HCG, NL
ND
ND
β-HCG, NL
ND
450
132.8
40
49
AFP, NL; βHCG, NL; CEA, NL 381
40
29
NA
20
Advanced (2.5 y)
Advanced (2 y)
NL
NL
NL
NL
ND
NA
R ovarian unilocular cystic mass (2.5 × x6 × 1.8); enlarged uterus L salpingooophorectomy Functional cyst with granulosa cell lining
R adnexal mass with cystic component (7 × 6.3 × 5); enlarged uterus R salpingo-oophorectomy
R cyst 4.4 × 1.6 × 2.2; L cystic mass (2.5 × 1.6 × 1.9); enlarged uterus L salpingooophorectomy Luteal cyst with multiple follicles
L cystic mass (3.5); enlarged uterus L salpingooophorectomy Luteal cyst
R cystic mass R ovarian cyst ND (3.2 × 3.3 × 3.9); (4.4 × 2.9 × 3.1); enlarged uterus enlarged uterus
NA
Advanced (3.5 y) ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Estradiol b (pg/mL) BA Pelvic US (cm)
Surgery Pathology
Benign cysts with granulosa cell lining
Z.M. Nabhan et al.
PH indicates pubic hair; NL, normal; ND, not done; CEA, cancer embryonic antigen; NA, not available; BA, bone age x-ray; US, ultrasound; R, right; L, left. a Represents patients with 2 or more episodes of vaginal bleeding. b NL b20 pg/mL.
Oophorectomy in McCune-Albright syndrome in diameter, with uterine enlargement. Estradiol level was 53 pg/mL. Plans for a partial right oophorectomy were underway when a pediatric endocrinology consult was requested by the parents. On examination in the endocrine clinic, she was found to have Tanner II breasts, Tanner I pubic hair, and no evidence of café au lait macules. Gonadotropin levels, estradiol levels, and thyroid function test results were normal. Bone age x-ray was 2.5 years (N2 SD) advanced. A bone scan was obtained, and it revealed fibrous dysplasia of the left tibia and left ulna (Fig. 3), confirming the diagnosis of MAS.
1.2. Retrospective review After institutional review board approval, medical records of girls diagnosed with MAS and followed in the pediatric endocrine clinic at Riley Hospital for Children, Indianapolis, IN, between 1988 and 2005 were reviewed. Variables extracted from the medical records included age at diagnosis, presenting features (vaginal bleeding, abdominal pain, and signs of PP), presence of café au lait spots, presence of fibrous dysplasia, pelvic ultrasound and bone age results, estradiol levels, tumor markers, surgery, and surgical pathology reports. 1.2.1. Statistical analysis Statistics were performed using Microsoft Excel 2003 (Microsoft Corp, Redmond, Wash) for descriptive statistics. Data are expressed as means ± SDs.
2. Results Nine girls with MAS were identified. Average age at presentation was 3.2 ± 2.1 years (range, 0.6-7 years). All presented with sudden onset of vaginal bleeding, which was painless except in 1 patient who had associated abdominal pain. Eight girls had Tanner II or III breast development, and 2 had Tanner II or III pubic hair. All had estrogenized vaginal mucosa. Serum estradiol level was measured in 8 patients and was elevated in 7, with a mean of 142.7 pg/mL (range, 20450 pg/mL). Tumor markers were obtained in 5 patients and were normal in all (100%). Pelvic ultrasound was performed in 6 girls and revealed an enlarged uterus and unilateral ovarian cystic mass in all. Computed tomographic scan was obtained in 2 cases and revealed a left ovarian unilocular cystic mass in the index case (patient no. 1) and a right adnexal cyst (4.5 × 3.0 cm) in patient no. 3.
2.1. Patients with oophorectomy On the basis of these findings, 4 (44%) girls were taken to the operating room and underwent salpingo-oophorectomy. Pathology revealed a benign ovarian cyst in all cases. The 4 patients who underwent oophorectomy were all subse-
1581 Table 2
Clinical and laboratory features of MAS vs JGCT
Features
MAS
JGCT
PP (%) Onset of PP Vaginal bleeding Presenting symptoms
N90 Sudden Single to recurrent episodes Occasional abdominal pain
Up to 70 Gradual Single episode
Café au lait spots (%) Fibrous dysplasia (%) Estradiol levels Tumor markers Bone age Pelvic US
50-93
Abdominal pain, mass, or distension (most common features) 0
40-50
0
Normal to elevated
Normal to elevated
Normal
Normal or elevated
Normal or advanced Unilateral cyst or cystic mass; size N2 cm
Normal or advanced Solid, or cystic mass 10%-15% bilateral; size usually N5 cm
quently diagnosed with MAS. Patient no. 1 is the index case. Patient no. 2 developed another episode of vaginal bleeding as well as progression of puberty 2 months after surgery and was then referred to our pediatric endocrine clinic, where the diagnosis was made. Before she underwent surgery, patient no. 3 was already scheduled to see a pediatric endocrinologist, who confirmed the diagnosis. Patient no. 4 did not develop any additional episodes of vaginal bleeding but was referred 6 years later for subclinical hyperthyroidism and was diagnosed with MAS at that time. Of the 9 girls, 5 had café au lait macules, including 3 of 4 girls who had undergone surgery. Seven were found to have fibrous dysplasia of bone, which was asymptomatic and diagnosed on bone scan in all cases. Thus, 3 girls had the classic triad of MAS, and 6 had 2 of 3 of the typical manifestations. Clinical characteristics of the 9 girls with MAS are summarized in Table 1.
3. Discussion The natural history of PP in MAS consists of intermittent episodes of autonomously functioning unilateral ovarian cysts at unpredictable intervals [9,10]. Regression of the cysts results in estrogen withdrawal and sudden onset of vaginal bleeding [8]. Medical therapy in girls with frequent episodes usually consists of tamoxifen or a third-generation aromatase inhibitor, both of which have been reported to have good safety and efficacy [11,12]. In the largest trial of tamoxifen treatment in girls with MAS, significant
1582 reductions in the number of vaginal bleeding episodes, growth velocity, and rates of skeletal maturation were observed [11]. No side effects during tamoxifen treatment were reported except for an increase in average uterine volumes, the significance of which remains to be determined. The third-generation aromatase inhibitors letrozole and anastrozole have also been found anecdotally to have minimal side effects, such as transient hand and foot discomfort [13]. Once central puberty in MAS begins, the hypothalamicpituitary-gonadal axis overrides the autonomous ovarian activation, and normal ovulatory cycles ensue. Reproductive function and fertility in girls with MAS are normal [14]. Thus, oophorectomy is contraindicated in this disorder. In our series, 4 of 9 girls were taken to the operating room for a presumed ovarian tumor before we made the diagnosis of MAS. Germ cell tumors (dysgerminoma, teratoma, and embryonal carcinoma) are the most common ovarian tumors in children and are rarely associated with PP [15]. In contrast, sex cord–stromal cell tumors such as JGCT cause peripheral PP in up to 70% of affected patients [16]. Up to 10% of all JGCTs occurs in prepubertal girls, and approximately 10% are bilateral [17]. Overlap between MAS and JGCT may exist in the form of an elevated estradiol level, presence of PP, and radiographic evidence of an apparent cystic ovarian mass on pelvic ultrasound or computed tomographic scan. However, girls with JGCT typically present with abdominal pain, mass, or distension [18], whereas girls with MAS usually present with painless vaginal bleeding. In our case series, only 1 of 9 girls had abdominal pain, and none presented with an abdominal mass or distension. In addition, girls with MAS have negative tumor markers, whereas tumor markers such as AFP, cancer embryonic antigen, and β-HCG are typically elevated in patients with pathologic ovarian tumors, including JGCT [19,20]. The presence of café au lait spots and/or fibrous dysplasia in association with PP is diagnostic of MAS. In our series, 3 of the 4 girls who had oophorectomy had obvious café au lait macules at initial presentation, although the significance of this finding went unrecognized. Thus, failure to include MAS in the differential diagnosis resulted in irreversible and unnecessary loss of an intrinsically normal ovary in these patients. The use of pelvic ultrasound in differentiating between malignant and benign ovarian lesions is controversial. In a recent study, ultrasonography was found to be very useful in localizing ovarian lesions but not helpful in determining their pathologic nature [21]. Although ovarian lesions N10 cm in diameter are more likely to be neoplastic [21], the size of the lesion cannot be used to differentiate between JGCT and autonomous ovarian cysts [22]. In addition, the nature of the lesion (solid vs cystic or mixed) is not very helpful. Although JGCTs are usually solid, cystic forms have also been reported [15], making it very difficult to distinguish these lesions from benign ovarian cysts. Table 2 compares and contrasts the clinical features of MAS and JGCT in girls presenting with an apparent ovarian tumor.
Z.M. Nabhan et al. This report delineates the inherent clinical challenge of differentiating between 2 extremely rare conditions that have a dramatically different prognosis and therapeutic approach. Although speculative, we believe our experience is similar to other tertiary care centers in which both highly trained pediatric surgeons and pediatric endocrinologists are readily available. Given the potential overlap in the clinical features of these disorders, we would recommend obtaining a pediatric endocrine consult for any girl presenting with vaginal bleeding and an ovarian mass, especially when tumor markers are negative. Even when other obvious manifestations of MAS such as café au lait macules are absent, obtaining a bone scan can be extremely helpful in confirming the diagnosis if increased uptake consistent with fibrous dysplasia is found. Alternatively, a short period of watchful waiting before going to the operating room would be reasonable because ultrasonographic monitoring will reveal spontaneous resolution of the cystic lesion in girls with MAS [23]. Increased awareness of this complex disease among all pediatric practitioners is needed to prevent inadvertent oophorectomy in prepubertal girls with MAS.
References [1] Albright F, Butler AM, Hampton AO, et al. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. Report of five cases. N Engl J Med 1937;216:727-46. [2] Feuillan PP. McCune-Albright syndrome. Curr Ther Endocrinol Metab 1994;5:205-9. [3] Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;325:1688-95. [4] Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet 1986;29:321-4. [5] Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 1987;16:899-906. [6] Collins MT, Shenker A. McCune-Albright syndrome: new insights. Curr Opin Endocrinol Diabetes 1999;6:119-25. [7] de Sanctis C, Lala R, Matarazzo P, et al. McCune-Albright syndrome: a longitudinal clinical study of 32 patients. J Pediatr Endocrinol Metab 1999;12:817-26. [8] Foster CM, Feuillan P, Padmanabhan V, et al. Ovarian function in girls with McCune-Albright syndrome. Pediatr Res 1986;20:859-63. [9] de Sanctis C, Lala R, Matarazzo P, et al. Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism. J Pediatr Endocrinol Metab 2003;16(Suppl 2):293-6. [10] Feuillan PP, Jones J, Cutler Jr GB. Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 1993;77:647-51. [11] Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003;143:60-6. [12] Eugster EA. Aromatase inhibitors in precocious puberty: rationale and experience to date. Treat Endocrinol 2004;3:141-51. [13] Feuillan P, Karim C, Suvimol H. Letrozole treatment of precocious puberty in girls with McCune-Albright syndrome. Proceedings of the
Oophorectomy in McCune-Albright syndrome
[14]
[15] [16] [17] [18]
Pediatric Academic Societies Annual Meetings, SeattlePediatr Res 2003;53(Suppl 4):136 [Abstract 778]. Laven JSE, Lumbroso S, Sultan C, et al. Dynamics of ovarian function in an adult woman with McCune-Albright syndrome. J Clin Endocrinol Metab 2001;86:2625-30. Pepus M, Hutcheson JB, Ruffolo EH, et al. Ovarian neoplasia and sexual precocity. Obstet Gynecol 1967;29:828-33. Breen JL, Maxson WS. Ovarian tumors in children and adolescents. Clin Obstet Gynecol 1977;20:607-23. Schneider A. Granulosa cell tumour in a child. Prog Pediatr Surg 1983;16:127-32. Zaloudek C, Norris HJ. Granulosa tumors of the ovary in children: a clinical and pathologic study of 32 cases. Am J Surg Pathol 1982;6:503-12.
1583 [19] Schultz KP, Sencer SF, Messinger Y, et al. Pediatric ovarian tumors: a review of 67 cases. Pediatr Blood Cancer 2005;44:167-73. [20] Chan LF, Storr HL, Scheimberg I, et al. Pseudo-precocious puberty caused by a juvenile granulosa cell tumour secreting androstenedione, inhibin and insulin-like growth factor-I. J Pediatr Endocrinol 2004;17:679-84. [21] de Silva KS, Kanumakala S, Grover SR, et al. Ovarian lesions in children and adolescents: an 11 year review. J Pediatr Endocrinol Metab 2004;17:951-7. [22] Adelman S, Benson CD, Hertzler JH. Surgical lesions of the ovary in infancy and childhood. Surg Gynecol Obstet 1975;141:219-26. [23] Warner BW, Kuhn JC, Barr LL. Conservative management of large ovarian cysts in children: the value of serial pelvic ultrasonography. Surgery 1992;112:749-55.
www.elsevier.com/locate/jpedsurg
Oophorectomy in McCune-Albright syndrome: a case of mistaken identity Zeina M. Nabhan a,* , Karen W. West b , Erica A. Eugster a a
Section of Pediatric Endocrinology/Diabetology, Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA b Department of Pediatric Surgery, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Index words: McCune-Albright syndrome; Oophorectomy; Ovarian tumors
Abstract Objective: The objective of the study was to determine the incidence of oophorectomy in girls presenting with precocious puberty and vaginal bleeding who are subsequently diagnosed with McCune-Albright syndrome (MAS). Study Design: Medical records of girls diagnosed with MAS between 1988 and 2005 were reviewed. Variables analyzed included presenting features, presence of café au lait macules, presence of fibrous dysplasia, radiographic studies, estradiol levels, tumor markers, surgery, and pathology reports. Results: Nine girls with MAS were identified. Average age at initial presentation was 3.2 ± 2.1 years (range, 0.6-7 years). All patients presented with sudden onset of vaginal bleeding. Eight (88%) also had breast development and 2 (22%) had associated pubic hair. Four (44%) girls underwent salpingooophorectomy before the diagnosis of MAS was made. Of these, 3 had café au lait macules on initial presentation, and 3 were later diagnosed with fibrous dysplasia. Surgical pathology revealed benign ovarian cysts in all 4 patients. Conclusion: Unnecessary oophorectomy is common in girls with MAS who are taken to the operating room for a presumed ovarian tumor. This highlights the need for increased awareness of MAS among pediatricians, pediatric surgeons, and emergency room physicians. Distinguishing features, which can be helpful in differentiating these 2 conditions, are often present. © 2007 Elsevier Inc. All rights reserved.
McCune-Albright syndrome (MAS) is a sporadic disorder characterized by the classic triad of precocious puberty (PP), café au lait skin pigmentation, and polyostotic fibrous dysplasia of bone [1,2]. It is caused by activating mutations of GNAS1, the gene encoding for the alpha subunit of the stimulatory G-protein involved in intracellular signaling in endocrine cells and other tissues [3]. This mutation results in loss of intrinsic GTPase activity leading to abnormal * Corresponding author. Tel.: +1 317 274 3889; fax: +1 317 274 3882. E-mail address: [email protected] (Z.M. Nabhan). 0022-3468/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2007.04.021
accumulation of intracellular cyclic adenosine monophosphate and unregulated cell proliferation with overproduction of cellular product [3]. The GNAS1 activating mutation occurs sporadically in a postzygotic cell line; thus, the subsequent mosaic distribution of affected cells can be widespread or limited, depending on the timing of the mutational event [4,5]. McCune-Albright syndrome is a heterogeneous disease with variable clinical manifestations [2,6,7]. However, girls usually present between the ages of 1 and 5 years with PP and sudden onset of vaginal bleeding because of the
Oophorectomy in McCune-Albright syndrome
1579
development and subsequent resolution of unilateral autonomous estrogen-producing ovarian cysts [8]. If other classic features of the disorder are unrecognized or not present, these findings may be confused with an ovarian tumor such as a juvenile granulosa cell tumor (JGCT), resulting in unnecessary surgery. Here we report an index case of oophorectomy in a girl later diagnosed with MAS and review our experience with similar cases seen at our medical center during the last 15 years. We also compare the clinical and biochemical features seen in MAS with those typically present in girls with JGCT.
1. Patients and methods 1.1. Index case A previously healthy African American girl aged 3 years 6 months presented to the emergency room with sudden onset of heavy and painless vaginal bleeding. On physical examination, she was noted to have Tanner I breasts and Tanner I pubic hair. Initial evaluation included measurements of serum α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-HCG), both of which were normal. Estradiol level was elevated at 450 pg/mL (normal, b20 pg/mL). Pelvic computed tomography revealed a left ovarian unilocular cystic mass 6 cm in diameter in association with uterine enlargement (Fig. 1). A pediatric surgery consult was obtained, and the decision was made to take the child to the operating room, where a left salpingo-oophorectomy was performed. An intraoperative image is provided in Fig. 2. Pathology revealed a functional ovarian cyst with a granulosa cell lining. The vaginal bleeding stopped 4 days postsurgery, and the estradiol levels normalized within 2 months.
Fig. 1 Computed tomographic scan of the abdomen and pelvis in the index case. Note the unilateral left ovarian cystic mass.
Fig. 2 Intraoperative image of the left ovary (index case) after oophorectomy.
The patient continued to do well until 5 years of age, when she presented again with painless vaginal bleeding. Pelvic ultrasound revealed a right ovarian cyst 3.8 × 2.4 × 1.8 cm
Fig. 3 Bone scan with increased uptake in the left ulna and left tibia suggestive of fibrous dysplasia.
1580
Table 1
Summary of patient characteristics at initial presentation
Patient
1
2
3
4
5
6
7
8
9
Age (y) Vaginal bleeding Tanner staging Café au lait Fibrous dysplasia Abdominal pain Tumor markers
3.5 +a
5.6 +a
4 +
2 +
2.2 +a
3 +
0.6 +
0.8 +
7 +
T I breast
T II breast; T II PH
T III breast; T III PH
T II breast
T II breast
T II breast
− +
+ +
+ −
+ +
− +
− +
T II breast + −
T II breast + +
T III breast − +
−
−
+
−
−
−
−
−
−
AFP, NL
ND
AFP, NL
AFP, NL; β-HCG, NL
ND
ND
β-HCG, NL
ND
450
132.8
40
49
AFP, NL; βHCG, NL; CEA, NL 381
40
29
NA
20
Advanced (2.5 y)
Advanced (2 y)
NL
NL
NL
NL
ND
NA
R ovarian unilocular cystic mass (2.5 × x6 × 1.8); enlarged uterus L salpingooophorectomy Functional cyst with granulosa cell lining
R adnexal mass with cystic component (7 × 6.3 × 5); enlarged uterus R salpingo-oophorectomy
R cyst 4.4 × 1.6 × 2.2; L cystic mass (2.5 × 1.6 × 1.9); enlarged uterus L salpingooophorectomy Luteal cyst with multiple follicles
L cystic mass (3.5); enlarged uterus L salpingooophorectomy Luteal cyst
R cystic mass R ovarian cyst ND (3.2 × 3.3 × 3.9); (4.4 × 2.9 × 3.1); enlarged uterus enlarged uterus
NA
Advanced (3.5 y) ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
Estradiol b (pg/mL) BA Pelvic US (cm)
Surgery Pathology
Benign cysts with granulosa cell lining
Z.M. Nabhan et al.
PH indicates pubic hair; NL, normal; ND, not done; CEA, cancer embryonic antigen; NA, not available; BA, bone age x-ray; US, ultrasound; R, right; L, left. a Represents patients with 2 or more episodes of vaginal bleeding. b NL b20 pg/mL.
Oophorectomy in McCune-Albright syndrome in diameter, with uterine enlargement. Estradiol level was 53 pg/mL. Plans for a partial right oophorectomy were underway when a pediatric endocrinology consult was requested by the parents. On examination in the endocrine clinic, she was found to have Tanner II breasts, Tanner I pubic hair, and no evidence of café au lait macules. Gonadotropin levels, estradiol levels, and thyroid function test results were normal. Bone age x-ray was 2.5 years (N2 SD) advanced. A bone scan was obtained, and it revealed fibrous dysplasia of the left tibia and left ulna (Fig. 3), confirming the diagnosis of MAS.
1.2. Retrospective review After institutional review board approval, medical records of girls diagnosed with MAS and followed in the pediatric endocrine clinic at Riley Hospital for Children, Indianapolis, IN, between 1988 and 2005 were reviewed. Variables extracted from the medical records included age at diagnosis, presenting features (vaginal bleeding, abdominal pain, and signs of PP), presence of café au lait spots, presence of fibrous dysplasia, pelvic ultrasound and bone age results, estradiol levels, tumor markers, surgery, and surgical pathology reports. 1.2.1. Statistical analysis Statistics were performed using Microsoft Excel 2003 (Microsoft Corp, Redmond, Wash) for descriptive statistics. Data are expressed as means ± SDs.
2. Results Nine girls with MAS were identified. Average age at presentation was 3.2 ± 2.1 years (range, 0.6-7 years). All presented with sudden onset of vaginal bleeding, which was painless except in 1 patient who had associated abdominal pain. Eight girls had Tanner II or III breast development, and 2 had Tanner II or III pubic hair. All had estrogenized vaginal mucosa. Serum estradiol level was measured in 8 patients and was elevated in 7, with a mean of 142.7 pg/mL (range, 20450 pg/mL). Tumor markers were obtained in 5 patients and were normal in all (100%). Pelvic ultrasound was performed in 6 girls and revealed an enlarged uterus and unilateral ovarian cystic mass in all. Computed tomographic scan was obtained in 2 cases and revealed a left ovarian unilocular cystic mass in the index case (patient no. 1) and a right adnexal cyst (4.5 × 3.0 cm) in patient no. 3.
2.1. Patients with oophorectomy On the basis of these findings, 4 (44%) girls were taken to the operating room and underwent salpingo-oophorectomy. Pathology revealed a benign ovarian cyst in all cases. The 4 patients who underwent oophorectomy were all subse-
1581 Table 2
Clinical and laboratory features of MAS vs JGCT
Features
MAS
JGCT
PP (%) Onset of PP Vaginal bleeding Presenting symptoms
N90 Sudden Single to recurrent episodes Occasional abdominal pain
Up to 70 Gradual Single episode
Café au lait spots (%) Fibrous dysplasia (%) Estradiol levels Tumor markers Bone age Pelvic US
50-93
Abdominal pain, mass, or distension (most common features) 0
40-50
0
Normal to elevated
Normal to elevated
Normal
Normal or elevated
Normal or advanced Unilateral cyst or cystic mass; size N2 cm
Normal or advanced Solid, or cystic mass 10%-15% bilateral; size usually N5 cm
quently diagnosed with MAS. Patient no. 1 is the index case. Patient no. 2 developed another episode of vaginal bleeding as well as progression of puberty 2 months after surgery and was then referred to our pediatric endocrine clinic, where the diagnosis was made. Before she underwent surgery, patient no. 3 was already scheduled to see a pediatric endocrinologist, who confirmed the diagnosis. Patient no. 4 did not develop any additional episodes of vaginal bleeding but was referred 6 years later for subclinical hyperthyroidism and was diagnosed with MAS at that time. Of the 9 girls, 5 had café au lait macules, including 3 of 4 girls who had undergone surgery. Seven were found to have fibrous dysplasia of bone, which was asymptomatic and diagnosed on bone scan in all cases. Thus, 3 girls had the classic triad of MAS, and 6 had 2 of 3 of the typical manifestations. Clinical characteristics of the 9 girls with MAS are summarized in Table 1.
3. Discussion The natural history of PP in MAS consists of intermittent episodes of autonomously functioning unilateral ovarian cysts at unpredictable intervals [9,10]. Regression of the cysts results in estrogen withdrawal and sudden onset of vaginal bleeding [8]. Medical therapy in girls with frequent episodes usually consists of tamoxifen or a third-generation aromatase inhibitor, both of which have been reported to have good safety and efficacy [11,12]. In the largest trial of tamoxifen treatment in girls with MAS, significant
1582 reductions in the number of vaginal bleeding episodes, growth velocity, and rates of skeletal maturation were observed [11]. No side effects during tamoxifen treatment were reported except for an increase in average uterine volumes, the significance of which remains to be determined. The third-generation aromatase inhibitors letrozole and anastrozole have also been found anecdotally to have minimal side effects, such as transient hand and foot discomfort [13]. Once central puberty in MAS begins, the hypothalamicpituitary-gonadal axis overrides the autonomous ovarian activation, and normal ovulatory cycles ensue. Reproductive function and fertility in girls with MAS are normal [14]. Thus, oophorectomy is contraindicated in this disorder. In our series, 4 of 9 girls were taken to the operating room for a presumed ovarian tumor before we made the diagnosis of MAS. Germ cell tumors (dysgerminoma, teratoma, and embryonal carcinoma) are the most common ovarian tumors in children and are rarely associated with PP [15]. In contrast, sex cord–stromal cell tumors such as JGCT cause peripheral PP in up to 70% of affected patients [16]. Up to 10% of all JGCTs occurs in prepubertal girls, and approximately 10% are bilateral [17]. Overlap between MAS and JGCT may exist in the form of an elevated estradiol level, presence of PP, and radiographic evidence of an apparent cystic ovarian mass on pelvic ultrasound or computed tomographic scan. However, girls with JGCT typically present with abdominal pain, mass, or distension [18], whereas girls with MAS usually present with painless vaginal bleeding. In our case series, only 1 of 9 girls had abdominal pain, and none presented with an abdominal mass or distension. In addition, girls with MAS have negative tumor markers, whereas tumor markers such as AFP, cancer embryonic antigen, and β-HCG are typically elevated in patients with pathologic ovarian tumors, including JGCT [19,20]. The presence of café au lait spots and/or fibrous dysplasia in association with PP is diagnostic of MAS. In our series, 3 of the 4 girls who had oophorectomy had obvious café au lait macules at initial presentation, although the significance of this finding went unrecognized. Thus, failure to include MAS in the differential diagnosis resulted in irreversible and unnecessary loss of an intrinsically normal ovary in these patients. The use of pelvic ultrasound in differentiating between malignant and benign ovarian lesions is controversial. In a recent study, ultrasonography was found to be very useful in localizing ovarian lesions but not helpful in determining their pathologic nature [21]. Although ovarian lesions N10 cm in diameter are more likely to be neoplastic [21], the size of the lesion cannot be used to differentiate between JGCT and autonomous ovarian cysts [22]. In addition, the nature of the lesion (solid vs cystic or mixed) is not very helpful. Although JGCTs are usually solid, cystic forms have also been reported [15], making it very difficult to distinguish these lesions from benign ovarian cysts. Table 2 compares and contrasts the clinical features of MAS and JGCT in girls presenting with an apparent ovarian tumor.
Z.M. Nabhan et al. This report delineates the inherent clinical challenge of differentiating between 2 extremely rare conditions that have a dramatically different prognosis and therapeutic approach. Although speculative, we believe our experience is similar to other tertiary care centers in which both highly trained pediatric surgeons and pediatric endocrinologists are readily available. Given the potential overlap in the clinical features of these disorders, we would recommend obtaining a pediatric endocrine consult for any girl presenting with vaginal bleeding and an ovarian mass, especially when tumor markers are negative. Even when other obvious manifestations of MAS such as café au lait macules are absent, obtaining a bone scan can be extremely helpful in confirming the diagnosis if increased uptake consistent with fibrous dysplasia is found. Alternatively, a short period of watchful waiting before going to the operating room would be reasonable because ultrasonographic monitoring will reveal spontaneous resolution of the cystic lesion in girls with MAS [23]. Increased awareness of this complex disease among all pediatric practitioners is needed to prevent inadvertent oophorectomy in prepubertal girls with MAS.
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