The Journal of Pediatrics
Volume 143, Issue 1 , Pages 9-10, July 2003

Precocious puberty: McCune-Albright syndrome and beyond

  • Paul Saenger, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Paul Saenger, MD, Division of Pediatric Endocrinology, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 2100th St, The Bronx, NY 10467-2490.
    • ,
  • Marielisa Rincon, MD

Division of Pediatric Endocrinology, Children's Hospital at Montefiore Medical Center, Albert Einstein College of Medicine, The Bronx, NY 10467-2490, USA

See related article, p 61.

Article Outline

Abbreviations: LHRH, Luteinizing hormone-releasing hormone

 

As a rule, the first signs of puberty appear in girls between the ages of 8 and 11 years and in boys between 9 and 12. If signs of puberty appear at an earlier age, the pediatrician should consider the possibility of precocious puberty, should seek information about family history, and should consider referring the patient to a pediatric endocrinologist.1., 2.

The age at menarche has not changed over the last several decades and is pegged at 12.6 years in white girls and 12.0 years in African American girls.1 These long held views on the definition of puberty were called into question in a 1997 report by the Pediatric Research in Office Settings program in which 17,077 girls, 3 to 12 years of age, were evaluated for the age of onset of secondary sexual development. The authors concluded that girls “across the US are developing pubertal characteristics at a younger age than currently used norms.” The study focused on premature thelarche and premature adrenarche, both characterized by only one sign of puberty.3 On the basis of that single report, which was marred by ascertainment bias because the girls were self-referred, the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society stated, perhaps prematurely: “In most cases, evaluation of girls with early breast and/or pubic hair development to look for a pathologic etiology of precocious puberty need not be performed for white girls older than 7 years and African American girls older than 6 years of age”.4 Several endocrinologists warned that liberation of the definition of “normal” carries with it the risk of overlooking pathologic features,5 and the topic even made it onto the front page of The New York Times.6

In a very thorough recent study, Midyett et al asked the simple question: Are pubertal changes in girls before eight benign?7 They found that of 1570 6- to 8-year-old girls seen at their clinic in Kansas City during a 5-year period, 223 were referred solely for signs of puberty. Indeed, 47.1% had true precocious puberty and 12.3% overall also had diagnoses of other treatable conditions, including congenital adrenal hyperplasia, growth hormone deficiency, hypothyroidism, hyperinsulinism, pituitary adenoma, neurofibromatosis and, yes, two girls had McCune-Albright syndrome. In 35% of the girls with precocious puberty, they found a bone age advancement of >3 SD, clearly indicating a markedly diminished growth potential for these girls had they gone untreated. Obesity was not a mitigating factor and equal attention should therefore be paid to obese and nonobese girls with signs of early pubertal development.

The inescapable conclusion of these findings is that signs of puberty in 6- to 8-year-old girls should not be considered normal or benign (16/25 patients with McCune-Albright syndrome in the study by Eugster et al were <8 years8). These children should be seen by a pediatric endocrinologist and have, at a minimum observation of statural growth, a physical examination and a bone age evaluation. True precocious puberty (characterized by breast and pubic hair development in girls, or testicular enlargement in boys) occurs in approximately 1 in 5000 children and is five to six times more common in girls than boys. In most affected girls (80–90%), but in only half of the affected boys, precocious puberty is gonadotropin-dependent and idiopathic in nature. Central nervous system tumors or lesions are much more common in boys. These CNS lesions may be hamartomas, pineal, dysgerminomas, and neurofibromatosis. Less commonly precocious puberty is gonadotropin independent and may include testotoxicosis (male limited with premature Leydig and germ cell maturation), gonadal, or adrenal steroid-producing tumors, and McCune-Albright syndrome.

Affected tissues in patients with McCune-Albright syndrome have a mutation of the G3α subunit of the G3 protein that activates adenylate cyclase.9 This activating mutation leads to continued stimulation of endocrine function, eg, precocious puberty. Mutations have also been found in other organs, such as the liver, associated with hepatitis, gastrointestinal tract associated with intestinal polyps, and the heart associated with arrhythmias. Other autonomous function may lead to gigantism, Cushing's syndrome, adrenal hyperplasia, and thyrothoxicoxis. Germline mutations of this type would be lethal, and somatic mutations may explain the great phenotypic variability.9., 10., 11.

To date, therapy of the symptoms of precocious puberty associated with McCune-Albright syndrome has been rather disappointing, and safe and effective drug therapy has so far remained elusive. It is likely that the therapeutic intervention studied by Eugster et al in a multicenter study trial will become the standard of care.8 The data presented in this issue of The Journal of Pediatrics indicate that anti-estrogen therapy with Tamoxifen (Noraldex, AstraZeneca Pharmaceuticals, Wilmington, Del)—approved for treatment of estrogen-sensitive breast cancer—in McCune-Albright syndrome results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation. Tamoxifen therapy should be considered the therapy of choice.7 The fibrous dysplasia of bone, causing bone pain and increased fractures, appears to improve with the biphosphonate pamidronate.12 The introduction of Tamoxifen for this form of gonadotropin-independent precocious puberty widens considerably the therapeutic possibilities in precocious puberty.

Uterine volume as well as ovarian volume may increase during Tamoxifen therapy. Periodic pelvic ultrasounds are therefore recommended.

For the more common gonadotropin-dependent central forms of precocious puberty, Lupron Depot (TAP Pharmaceuticals, Lake Forest, Ill) given every month, or with a newer formulation even only every 3 months, provides effective and safe treatment.13., 14. These modes of therapy provide a steady release of luteinizing hormone-releasing hormone (LHRH) analogue between injections (either subcutaneous or intramuscular). Long-term results are now available that have shown that they restore height potential negatively affected by central precocious puberty, and that they improve the quality of life by normalizing the timing of puberty. The efficacy of the treatment can easily be monitored by measuring the drop in luteinizing hormone levels 30 minutes after the injection of the LHRH dose.15 Secondary activation of central precocious puberty may also occur in McCune-Albright syndrome in patients treated with Tamoxifen. As stressed by Eugster et al, adjuvant treatment with a LHRH analogue may then be required in addition.8

Children with central precocious puberty who are already close to the age of normal puberty or who have a very slowly progressive variant of precocious puberty may not require treatment at all. If their height prediction is above 150 cm and anticipated social problems are minor because sexual maturation occurs close to normal age, a more conservative approach may be warranted under the guidance of a pediatric endocrinologist.16

Back to Article Outline

References 

  1. Rosenfield RL. Normal and almost normal variants of precocious puberty: premature pubarche and premature thelarche revisited. Horm Res. 1994;41:7
  2. Lee PA. Central precocious puberty. An overview of diagnosis, treatment, and outcome. Endocrinol Metab Clin North Am. 1999;28:901–918
  3. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, et al.  Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Setting network. Pediatrics. 1997;99:505–512
  4. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implication for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins pediatric Endocrine Society. Pediatrics. 1999;104:936–941
  5. Rosenfield RL, Bachrach LK, Chemausek SD, Gertner JM, Gottschalk M, Hardin DS, et al.  Current age of onset of puberty. Pediatrics. 2000;106:622–623
  6. New York Times. Doubters fault theory finding earlier puberty. February 20, 2001; A1, A16.
  7. Midyett LK, Moore WV, Jacobson JD. Are pubertal changes in girls before age 8 benign?. Pediatrics. 2003;111:47–51
  8. Eugster E, Rubin S, Reiter E, Plourde P, Jou H, Pescovitz O. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr. 2003;143:61–67
  9. Schwindinger WF, Francomano CA, Levine MA. Identification of a mutation in the gene encoding the α subunit of the stimulatory G protein of adenyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci U S A. 1992;89:5152
  10. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Eng J Med. 1991;325:1688
  11. Styne DM. The testes. In:  Sperling MA editors. Disorders of sexual differentiation and puberty in the male. Pediatric endocrinology. Philadelphia: Saunders; 2002;p. 611
  12. Lala R, Matarazzo P, Bertelloni S, Buzzi F, Rigon F, de Sanctis C. Pamidronate treatment of fibrous dysplasia in nine children with McCune-Albright syndrome. Acta Paediatr. 2000;89:88–92
  13. Kappy MS, Stuart TE, Perelman AH, Clemons RD. Supression of gonadotropin secretion by a long-acting gonadotropin–releasing hormone analog (leuprolide acetate, Lupron Depo) in children with precocious puberty. J Clin Endocrinol Metab. 1989;87:1087–1089
  14. Carel J, Lahlou N, Jaramillo O, Montauban V, Tenturier C, Colle M, et al.  Treatment of central precocious puberty by subcutaneous injection of Leuprorelin 3-month Depo (11.25 mg). J Clin Endocrinol Metab. 2002;87:4111–4116
  15. Bhatia S, Neely K, Wilson D. Serum luteinizing hormone rises within minutes after Depo Leuprolide injection: implications for monitoring therapy. Pediatrics. 2002;109:1–6
  16. Bar A, Linder B, Sobel EH, Saenger P, DiMartino-Nardi J. Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height. J Pediatr. 1995;126:955–958

PII: S0022-3476(03)00272-5

doi:10.1016/S0022-3476(03)00272-5

The Journal of Pediatrics
Volume 143, Issue 1 , Pages 9-10, July 2003

Article Tools