Precocious pseudopuberty with testicular enlargement
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《美国医学杂志》
Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Abstract
Gonadotropins independent precocious puberty (GIPP) in male is characterized by early appearance of sexual hairs and phallic growth but without testicular enlargement. We report a case of GIPP with testicular enlargement who was diagnosed to have testotoxicosis and successfully managed with spironolactone.
Keywords: Precocious pseudopuberty; Testotoxicosis
Puberty is the process of physical maturation manifested by an increase in growth rate and appearance of secondary sexual characteristics. Puberty is said to be precocious if it occurs in boys younger than 9 years of age, while in girls, less than 7 years of age, and in African American girls younger than 6 years of age.[1] Precocious puberty can be divided into two categories. The first category is gonadotropins dependent precocious puberty (GDPP) or true precocious puberty, which involves the premature activation of hypothalamic-pituitary-gonadal axis and characterized by appearance of axillary and pubic hairs along with testicular enlargement. The second category is gonadotropins independent precocious puberty (GIPP) or precocious pseudopuberty in which the increase in sex steroids is independent of pituitary gonadotropins release, and axillary and pubic hairs appear along with phallic enlargement but without associated testicular enlargement.[1], [2]
We describe a case of a five and a half year old boy who presented with precocious pseudopuberty with testicular enlargement.
Case Report
A five and a half-year-old boy presented with progressive phallic enlargement, development of axillary and pubic hairs, aggressive behavior and rapid increase in height over the last two years. The child was born of a non-consanguineous marriage and had no family history of precocious puberty. He had no history of central nervous system infections, head injury, neoplasm or prior radiation and exposure to exogenous sex steroids. On examination, his height was 128 cm (90th percentile) and weight was 23.4 kg, with target height of 165.3cm. He had no cafι-au-lait spots and bony swellings. Systemic examination was unremarkable. Genital examination revealed a stretched penile length (SPL) of 6 cm and testicular volume of 6 ml bilaterally (Prader's orchidometer). Both testes were firm, symmetrical and non-tender Figure1. Axillary and pubic hairs were Tanner stage 2 and had no gynecomastia. Investigations revealed a bone age of 10 years. Basal serum lentiaisling hormone (LH) was <0.07 mIU/ml (prepubertal N<1.56mIU/ml); follicle stimulating hormene (FSH) was 0.45 mIU/ml (prepubertal N< 1.25mIU/ml); and serum testosterone was 64.2 ng/dl (prepubertal N 10-30 ng/dl). LH stimulation with 100mg IV bolus GnRH had a flat response. Serum 17OHP, thyroid function test, b-hCG and α-fetoprotein (AFP) were normal. Ultrasonography examination of the abdomen and testes was unremarkable. MRI of head and contrast enhanced computed tomography of the chest and abdomen did not reveal any pathology. Fine needle aspiration cytology from the testis showed matured Sertoli cells More Details and few spermatids and spermatozoa. Therefore, the diagnosis of testotoxicosis was considered and he was successfully treated with spironolactone 4mg/kg PO in two divided doses.
Discussion
Clinically, this young boy seems to have true precocious puberty in view of his testicular enlargement and early appearance of axillary and pubic hair. The various causes of GIPP with symmetrical testicular enlargement include male-limited precocious puberty or testotoxicosis, adrenal rest tumor due to untreated congenital adrenal hyperplasia, b-hCG secreting tumors and juvenile hypothyroidism.[3] Since the patient's 17-OHP levels were within normal limits and there was no evidence of adrenal tumor on CT scan of the abdomen, congenital adrenal hyperplasia (CAH) and adrenal tumors are unlikely. Also, negative imaging of the brain, chest, abdomen and testis, normal b-hCG and normal thyroid function tests exclude most of the causes of precocious pseudopuberty with testicular enlargement. Therefore, male-limited precocious puberty or testotoxicosis is the likely cause in this case.
The diagnosis of testotoxicosis is made in the presence of following clinical and laboratory characteristics including (a) sex-limited autosomal dominant inheritance, (b) early onset of sexual precocity in boys with bilateral testicular enlargement, (c) prepubertal LH response to GnRH, (d) concentration of plasma testosterone in pubertal range, (e) premature Leyding cell maturation, (f) no CNS, adrenal, or testicular abnormality demonstrable by radiologic or hormonal studies.[4] This case fulfills all criteria for making a diagnosis of testotoxicosis in this case except the absence of family history. Since the patients investigative work-up was negative for all other mentioned causes of precocious pseudopuberty, so even though we are not able to demonstrate the activating mutation of LH receptor in this case, his history, clinical and hormonal workup is consistent with diagnosis of testotoxicosis. Also, the documentation of spermatogenesis with flat gonadotropin response to GnRH further substantiates this diagnosis, as increase in intratesticular testosterone concentration induces spermatogenesis.
Testotoxicosis, also known as familial male-limited precocious puberty, is inherited as autosomal dominant trait with more than 90% penetrance. However, denovo mutations may arise; therefore it should be considered even in cases without a clear family history of precocious puberty. It is caused by the activating mutation in LH receptor gene that results in constitutive activation in the absence of either LH or hCG.[5] The LH receptor is an 80 to 90 Kd glycoprotein encoded by a gene on chromosome 2p21. The gene spans at least 70 kb and contains 11 exons separated by 10 introns. Till now, thirteen constitutively activating heterozygous missense mutations, all residing within exon 11, in over 60 patients have been reported.[5],[6] Six involves the transmembrane helix VI; two involves the flanking third cytoplasmic loop, and one each in helix V and II. Less commonly, there are mutations in the first transmembrane helix.[5], [6]
Since the underlying pathophysiology in testotoxicosis is autonomous functioning of Leyding cells, GnRH agonistic analogs are not effective in the management of such cases. The available treatment options for such instances include steroid synthesis inhibitors like ketoconazole, antiandrogens like spironolactone, and aromatous inhibitors like letrazole.[7] Ketoconazole inhibits several enzymes including 17, 20 desmolase involved in the cortisol and androgen biosynthesis. The successful use of ketoconazole is limited in patients whose bone age has reached the normal pubertal range, since the ketoconazole-induced blockade of testosterone synthesis is overridden by pubertal increase in gonadotropins secretion. Antiandrogens like spironolactone and aromatase inhibitors like letrazole, either alone or in combination, can be used in the treatment of testotoxicosis. However, the combination of both is better than either drug alone. The patient reported was treated with spironolactone, and at 6 months follow-up there was no further progression of secondary sexual characters, and his aggressive behaviour has settled down with both parents and child feeling better psychologically. If testotoxicosis is not recognized early and treatment is delayed, then secondary true precocious puberty often occurs, when bone age advances or has already reached pubertal stage (usually around 11.5 years). In such cases addition of GnRH agonistic analogs is helpful in arresting the further progression of puberty.[8] Thus, the present case highlights the importance of having high index of suspicion for testotoxicosis in male patients with gonadotropins-independent precocious puberty.
References
1. Kaplowit PB, Oberfield SE. Reexamination of age limit for defining when puberty is precocious in girls in United States: implications for evaluation and treatment. Drug and Therapeutic and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999; 104 : 936-941.
2. Marke DP, Cutler GB Jr. Evaluation and management of Precocious puberty. Arch Dis Child 1996: 296-371.
3. Low LC, Wang Q: Gonadotropin indepaendent precocious puberty. J Pediatr Endocrinol Metab 1998: 497-507.
4. Melvin M Grumbach, Dennis M Styne. Puberty: Ontogeny, meuroendocronology, physiology and disorders. In Larsen, Kronenberg, Metmed, polonsky, eds. Williams's textbook of Endocrinology. Phialdelphia; WB Saunders, 2003; 1219-1221.
5. Egli CA, Rosenthal SM, Grumbach MM et al. Pituitiary gonadotropin-independent male-limited autosomal domonant sexual precocity in nine generations: familial testotoxicosis. Arch Pathol Lab Med 1985; 109 : 990-995.
6. Shenker A, Laue L, kosugi S et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993; 365: 652-654.
7. Laue L, Kenigsberg D, Pescovitz OH. Treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med 1989; 320 : 498-502.
8. Leschek EW, Jones J, Barnes KM et al. Six year results of spironolactone ans testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84(1) : 175-178.(Rajput R, Bhansali Anil, )
Abstract
Gonadotropins independent precocious puberty (GIPP) in male is characterized by early appearance of sexual hairs and phallic growth but without testicular enlargement. We report a case of GIPP with testicular enlargement who was diagnosed to have testotoxicosis and successfully managed with spironolactone.
Keywords: Precocious pseudopuberty; Testotoxicosis
Puberty is the process of physical maturation manifested by an increase in growth rate and appearance of secondary sexual characteristics. Puberty is said to be precocious if it occurs in boys younger than 9 years of age, while in girls, less than 7 years of age, and in African American girls younger than 6 years of age.[1] Precocious puberty can be divided into two categories. The first category is gonadotropins dependent precocious puberty (GDPP) or true precocious puberty, which involves the premature activation of hypothalamic-pituitary-gonadal axis and characterized by appearance of axillary and pubic hairs along with testicular enlargement. The second category is gonadotropins independent precocious puberty (GIPP) or precocious pseudopuberty in which the increase in sex steroids is independent of pituitary gonadotropins release, and axillary and pubic hairs appear along with phallic enlargement but without associated testicular enlargement.[1], [2]
We describe a case of a five and a half year old boy who presented with precocious pseudopuberty with testicular enlargement.
Case Report
A five and a half-year-old boy presented with progressive phallic enlargement, development of axillary and pubic hairs, aggressive behavior and rapid increase in height over the last two years. The child was born of a non-consanguineous marriage and had no family history of precocious puberty. He had no history of central nervous system infections, head injury, neoplasm or prior radiation and exposure to exogenous sex steroids. On examination, his height was 128 cm (90th percentile) and weight was 23.4 kg, with target height of 165.3cm. He had no cafι-au-lait spots and bony swellings. Systemic examination was unremarkable. Genital examination revealed a stretched penile length (SPL) of 6 cm and testicular volume of 6 ml bilaterally (Prader's orchidometer). Both testes were firm, symmetrical and non-tender Figure1. Axillary and pubic hairs were Tanner stage 2 and had no gynecomastia. Investigations revealed a bone age of 10 years. Basal serum lentiaisling hormone (LH) was <0.07 mIU/ml (prepubertal N<1.56mIU/ml); follicle stimulating hormene (FSH) was 0.45 mIU/ml (prepubertal N< 1.25mIU/ml); and serum testosterone was 64.2 ng/dl (prepubertal N 10-30 ng/dl). LH stimulation with 100mg IV bolus GnRH had a flat response. Serum 17OHP, thyroid function test, b-hCG and α-fetoprotein (AFP) were normal. Ultrasonography examination of the abdomen and testes was unremarkable. MRI of head and contrast enhanced computed tomography of the chest and abdomen did not reveal any pathology. Fine needle aspiration cytology from the testis showed matured Sertoli cells More Details and few spermatids and spermatozoa. Therefore, the diagnosis of testotoxicosis was considered and he was successfully treated with spironolactone 4mg/kg PO in two divided doses.
Discussion
Clinically, this young boy seems to have true precocious puberty in view of his testicular enlargement and early appearance of axillary and pubic hair. The various causes of GIPP with symmetrical testicular enlargement include male-limited precocious puberty or testotoxicosis, adrenal rest tumor due to untreated congenital adrenal hyperplasia, b-hCG secreting tumors and juvenile hypothyroidism.[3] Since the patient's 17-OHP levels were within normal limits and there was no evidence of adrenal tumor on CT scan of the abdomen, congenital adrenal hyperplasia (CAH) and adrenal tumors are unlikely. Also, negative imaging of the brain, chest, abdomen and testis, normal b-hCG and normal thyroid function tests exclude most of the causes of precocious pseudopuberty with testicular enlargement. Therefore, male-limited precocious puberty or testotoxicosis is the likely cause in this case.
The diagnosis of testotoxicosis is made in the presence of following clinical and laboratory characteristics including (a) sex-limited autosomal dominant inheritance, (b) early onset of sexual precocity in boys with bilateral testicular enlargement, (c) prepubertal LH response to GnRH, (d) concentration of plasma testosterone in pubertal range, (e) premature Leyding cell maturation, (f) no CNS, adrenal, or testicular abnormality demonstrable by radiologic or hormonal studies.[4] This case fulfills all criteria for making a diagnosis of testotoxicosis in this case except the absence of family history. Since the patients investigative work-up was negative for all other mentioned causes of precocious pseudopuberty, so even though we are not able to demonstrate the activating mutation of LH receptor in this case, his history, clinical and hormonal workup is consistent with diagnosis of testotoxicosis. Also, the documentation of spermatogenesis with flat gonadotropin response to GnRH further substantiates this diagnosis, as increase in intratesticular testosterone concentration induces spermatogenesis.
Testotoxicosis, also known as familial male-limited precocious puberty, is inherited as autosomal dominant trait with more than 90% penetrance. However, denovo mutations may arise; therefore it should be considered even in cases without a clear family history of precocious puberty. It is caused by the activating mutation in LH receptor gene that results in constitutive activation in the absence of either LH or hCG.[5] The LH receptor is an 80 to 90 Kd glycoprotein encoded by a gene on chromosome 2p21. The gene spans at least 70 kb and contains 11 exons separated by 10 introns. Till now, thirteen constitutively activating heterozygous missense mutations, all residing within exon 11, in over 60 patients have been reported.[5],[6] Six involves the transmembrane helix VI; two involves the flanking third cytoplasmic loop, and one each in helix V and II. Less commonly, there are mutations in the first transmembrane helix.[5], [6]
Since the underlying pathophysiology in testotoxicosis is autonomous functioning of Leyding cells, GnRH agonistic analogs are not effective in the management of such cases. The available treatment options for such instances include steroid synthesis inhibitors like ketoconazole, antiandrogens like spironolactone, and aromatous inhibitors like letrazole.[7] Ketoconazole inhibits several enzymes including 17, 20 desmolase involved in the cortisol and androgen biosynthesis. The successful use of ketoconazole is limited in patients whose bone age has reached the normal pubertal range, since the ketoconazole-induced blockade of testosterone synthesis is overridden by pubertal increase in gonadotropins secretion. Antiandrogens like spironolactone and aromatase inhibitors like letrazole, either alone or in combination, can be used in the treatment of testotoxicosis. However, the combination of both is better than either drug alone. The patient reported was treated with spironolactone, and at 6 months follow-up there was no further progression of secondary sexual characters, and his aggressive behaviour has settled down with both parents and child feeling better psychologically. If testotoxicosis is not recognized early and treatment is delayed, then secondary true precocious puberty often occurs, when bone age advances or has already reached pubertal stage (usually around 11.5 years). In such cases addition of GnRH agonistic analogs is helpful in arresting the further progression of puberty.[8] Thus, the present case highlights the importance of having high index of suspicion for testotoxicosis in male patients with gonadotropins-independent precocious puberty.
References
1. Kaplowit PB, Oberfield SE. Reexamination of age limit for defining when puberty is precocious in girls in United States: implications for evaluation and treatment. Drug and Therapeutic and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics 1999; 104 : 936-941.
2. Marke DP, Cutler GB Jr. Evaluation and management of Precocious puberty. Arch Dis Child 1996: 296-371.
3. Low LC, Wang Q: Gonadotropin indepaendent precocious puberty. J Pediatr Endocrinol Metab 1998: 497-507.
4. Melvin M Grumbach, Dennis M Styne. Puberty: Ontogeny, meuroendocronology, physiology and disorders. In Larsen, Kronenberg, Metmed, polonsky, eds. Williams's textbook of Endocrinology. Phialdelphia; WB Saunders, 2003; 1219-1221.
5. Egli CA, Rosenthal SM, Grumbach MM et al. Pituitiary gonadotropin-independent male-limited autosomal domonant sexual precocity in nine generations: familial testotoxicosis. Arch Pathol Lab Med 1985; 109 : 990-995.
6. Shenker A, Laue L, kosugi S et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993; 365: 652-654.
7. Laue L, Kenigsberg D, Pescovitz OH. Treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med 1989; 320 : 498-502.
8. Leschek EW, Jones J, Barnes KM et al. Six year results of spironolactone ans testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84(1) : 175-178.(Rajput R, Bhansali Anil, )