Failure of Sexual Maturation in Mulibrey Nanism
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《新英格兰医药杂志》
To the Editor: We report an association between a rare genetic disease and both premature ovarian failure and fibrothecomas (ovarian stromal tumors). Mulibrey nanism, an autosomal recessive disorder in which growth restriction begins in utero,1 is caused by mutations in the TRIM37 gene for a peroxisomal protein of unknown function.2,3 Worldwide, approximately 110 patients with this disorder are known, of whom 85 are Finnish. We reviewed the hospital and autopsy reports of the 22 Finnish female postpubertal patients with mulibrey nanism; 15 had a follow-up that included a gynecologic examination, pelvic ultrasonography, and a biochemical assessment of ovarian function. Five of these patients had died and two had undergone hystero-salpingo-oophorectomy; these seven patients were studied only retrospectively.
All patients had spontaneous pubarche with menarche at a median age of 14.7 years. Breast development was poor. The first signs of ovarian failure appeared at approximately 1.8 years after menarche. Five years after menarche, only three patients (14 percent) menstruated regularly; the others reported menstrual irregularity ranging from oligomenorrhea to long periods of amenorrhea with episodes of menometrorrhagia. None had been pregnant.
Only 1 of the 15 patients who underwent pelvic ultrasonography had ovaries with normal morphologic features; the others had small ovaries with only a few or no antral follicles. The uteri were small. Of the 15 clinically examined patients, 10 had high serum concentrations of follicle-stimulating hormone (>10 IU per liter; range, 11.6 to 127.0), indicating ovarian failure. The concentrations of estradiol were low normal. Six patients had undergone surgery for an ovarian fibrothecoma. During this study, we found six additional tumors, for a risk of fibrothecoma of 55 percent. The median age at the diagnosis of tumor was 29 years. All but one patient presented with oligomenorrhea or amenorrhea before the diagnosis (Figure 1). Recurrences necessitating reoperation occurred in three patients.
Figure 1. Menstrual History and Age at the Diagnosis of Fibrothecoma in 12 Patients with Mulibrey Nanism.
In the figure, the open circles denote menarche, solid lines normal menstrual periods, thick dashed lines oligomenorrhea, thin dashed lines amenorrhea, downward-pointing arrows tumors, and asterisks deaths.
Our study indicates that hypergonadotropic premature ovarian failure with spontaneous puberty, incomplete breast development, and early irregularity of menstrual periods with subsequent ovarian failure and infertility ultimately develop in female patients with mulibrey nanism. Furthermore, such patients are at a very high risk for ovarian fibrothecoma. We conclude that TRIM37 is a novel gene associated with premature ovarian failure and a putative tumor-suppressor gene for ovarian stromal cells. A limited number of gene mutations are known to cause premature ovarian failure in humans.4 Moreover, little is known about genes that control the function and growth of thecal cells.5 More precise knowledge of the function of the TRIM37 protein is likely to increase our understanding of the early stages of gonadogenesis and of the pathogenesis of premature ovarian failure and ovarian stromal tumors.
Susann Karlberg, M.D.
Hospital for Children and Adolescents
FIN-00029 HUS Helsinki, Finland
Aila Tiitinen, M.D., Ph.D.
Hospital for Women
FIN-00029 HUS Helsinki, Finland
Marita Lipsanen-Nyman, M.D., Ph.D.
Hospital for Children and Adolescents
FIN-00029 HUS Helsinki, Finland
marita.lipsanen@hus.fi
References
Karlberg N, Jalanko H, Perheentupa J, Lipsanen-Nyman M. Mulibrey nanism: clinical features and diagnostic criteria. J Med Genet 2004;41:92-98.
Avela K, Lipsanen-Nyman M, Id?nheimo N, et al. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Nat Genet 2000;25:298-301.
Kallij?rvi J, Avela K, Lipsanen-Nyman M, Ulmanen I, Lehesjoki A-E. The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. Am J Hum Genet 2002;70:1215-1228.
Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal H. Genetic disorders in premature ovarian failure. Hum Reprod Update 2002;8:483-491.
Richards JS. The ovarian follicle -- a perspective in 2001. Endocrinology 2001;142:2184-2193.
All patients had spontaneous pubarche with menarche at a median age of 14.7 years. Breast development was poor. The first signs of ovarian failure appeared at approximately 1.8 years after menarche. Five years after menarche, only three patients (14 percent) menstruated regularly; the others reported menstrual irregularity ranging from oligomenorrhea to long periods of amenorrhea with episodes of menometrorrhagia. None had been pregnant.
Only 1 of the 15 patients who underwent pelvic ultrasonography had ovaries with normal morphologic features; the others had small ovaries with only a few or no antral follicles. The uteri were small. Of the 15 clinically examined patients, 10 had high serum concentrations of follicle-stimulating hormone (>10 IU per liter; range, 11.6 to 127.0), indicating ovarian failure. The concentrations of estradiol were low normal. Six patients had undergone surgery for an ovarian fibrothecoma. During this study, we found six additional tumors, for a risk of fibrothecoma of 55 percent. The median age at the diagnosis of tumor was 29 years. All but one patient presented with oligomenorrhea or amenorrhea before the diagnosis (Figure 1). Recurrences necessitating reoperation occurred in three patients.
Figure 1. Menstrual History and Age at the Diagnosis of Fibrothecoma in 12 Patients with Mulibrey Nanism.
In the figure, the open circles denote menarche, solid lines normal menstrual periods, thick dashed lines oligomenorrhea, thin dashed lines amenorrhea, downward-pointing arrows tumors, and asterisks deaths.
Our study indicates that hypergonadotropic premature ovarian failure with spontaneous puberty, incomplete breast development, and early irregularity of menstrual periods with subsequent ovarian failure and infertility ultimately develop in female patients with mulibrey nanism. Furthermore, such patients are at a very high risk for ovarian fibrothecoma. We conclude that TRIM37 is a novel gene associated with premature ovarian failure and a putative tumor-suppressor gene for ovarian stromal cells. A limited number of gene mutations are known to cause premature ovarian failure in humans.4 Moreover, little is known about genes that control the function and growth of thecal cells.5 More precise knowledge of the function of the TRIM37 protein is likely to increase our understanding of the early stages of gonadogenesis and of the pathogenesis of premature ovarian failure and ovarian stromal tumors.
Susann Karlberg, M.D.
Hospital for Children and Adolescents
FIN-00029 HUS Helsinki, Finland
Aila Tiitinen, M.D., Ph.D.
Hospital for Women
FIN-00029 HUS Helsinki, Finland
Marita Lipsanen-Nyman, M.D., Ph.D.
Hospital for Children and Adolescents
FIN-00029 HUS Helsinki, Finland
marita.lipsanen@hus.fi
References
Karlberg N, Jalanko H, Perheentupa J, Lipsanen-Nyman M. Mulibrey nanism: clinical features and diagnostic criteria. J Med Genet 2004;41:92-98.
Avela K, Lipsanen-Nyman M, Id?nheimo N, et al. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Nat Genet 2000;25:298-301.
Kallij?rvi J, Avela K, Lipsanen-Nyman M, Ulmanen I, Lehesjoki A-E. The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. Am J Hum Genet 2002;70:1215-1228.
Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal H. Genetic disorders in premature ovarian failure. Hum Reprod Update 2002;8:483-491.
Richards JS. The ovarian follicle -- a perspective in 2001. Endocrinology 2001;142:2184-2193.