Correspondence
Case 31-2006: A Girl with Severe Obesity
N Engl J Med 2007; 356:194-196January 11, 2007
- Article
To the Editor:
The Case Record discussed by Hoppin et al. (Oct. 12 issue),1 which describes the condition of a severely obese 15-year-old girl, concludes with a diagnosis of “severe childhood obesity with obstructive sleep apnea, hypertension, impaired glucose tolerance progressing to type 2 diabetes mellitus, the polycystic ovary syndrome, and nonalcoholic steatohepatitis.” However, this case seems to present an unsolved medical problem. A number of the clinical signs may have been the consequence of an unexplained metabolic syndrome, probably related to the severe obesity. Why was this child so severely obese by the age of 3 years that she had clinical signs of type 2 diabetes by the age of 6?
Because of the wide phenotypical variability of the Prader–Willi syndrome,2 in which severe obesity, childhood polyphagia, sleep apnea, and hyperinsulinemia have been reported,3 molecular testing to rule out the syndrome would have been useful or, probably, mandatory.
3 ReferencesLuigi Titomanlio, M.D.
Alain Verloes, M.D.
Jean-Christophe Mercier, M.D.
University Hospital R. Debré, 75019 Paris, France
luigi.titomanlio@rdb. aphp. fr 1
Case Records of the Massachusetts General Hospital (Case 31-2006). N Engl J Med 2006;355:1593-1602
Full Text | Web of Science | Medline2
Wattendorf DJ ,Muenke M . Prader-Willi syndrome. Am Fam Physician 2005;72:827-830
Web of Science | Medline3
Talebizadeh Z ,Butler MG . Insulin resistance and obesity-related factors in Prader-Willi syndrome: comparison with obese subjects. Clin Genet 2005;67:230-239
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To the Editor:
The 15-year-old girl under discussion had lifelong, severe obesity, and numerous obesity-related diseases developed. On the basis of appropriate laboratory tests, the discussants exclude the possibility that her obesity was caused by leptin deficiency or a mutation in the melanocortin 4 receptor (MC4R) gene. They also state that she did not have the stigmata of the Prader–Willi syndrome, the Bardet–Biedl syndrome, or a single-minded homologue (SIM-1) haploinsufficiency. The discussants note that the patient had hyperpigmentation of the thighs at the age of 8 years, a finding that should have raised the specter of adrenocorticotropic hormone-dependent Cushing's syndrome. Did the patient undergo screening with a low-dose dexamethasone suppression test, measurement of 24-hour urinary cortisol excretion, or an assay of the nadir salivary cortisol level in the evening?1
1 ReferencesAmnon Schlegel, M.D., Ph.D.
University of California, San Francisco, San Francisco, CA 94121
amnon.schlegel@ucsf. edu 1
Raff H ,Findling JW . A physiologic approach to diagnosis of Cushing syndrome. Ann Intern Med 2003;138:980-991
Web of Science | Medline
To the Editor:
We are concerned that the diagnosis of the polycystic ovary syndrome may not be appropriate for the patient described by Hoppin et al. Polycystic ovaries, in the absence of anovulation or hyperandrogenism, do not constitute a diagnosis of the polycystic ovary syndrome.1 This patient had a normal testosterone level at 15 years of age and had no hirsutism. The isolated elevation in the free testosterone level at 13 years of age can be explained by the profound suppression of sex hormone–binding globulin due to hyperinsulinemia and secondary to obesity.2,3 Moreover, obesity has been associated with hyperandrogenism in adults as well as in peripubertal girls4 and is not among the diagnostic criteria for the polycystic ovary syndrome. Although this disorder is common, obesity is considerably more prevalent. A diagnosis of the polycystic ovary syndrome is not necessary to explain this obese patient's presentation, and her regular menstrual periods argue strongly against it.
4 ReferencesAlex J. Polotsky, M.D.
Jessica Rieder, M.D.
Nanette Santoro, M.D.
Albert Einstein College of Medicine, Bronx, NY 104611
Ehrmann DA . Polycystic ovary syndrome. N Engl J Med 2005;352:1223-1236
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Grenman S ,Ronnemaa T ,Irjala K ,Kaihola HL ,Gronroos M . Sex steroid, gonadotropin, cortisol, and prolactin levels in healthy, massively obese women: correlation with abdominal fat cell size and effect of weight reduction. J Clin Endocrinol Metab 1986;63:1257-1261
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Santoro N ,Torrens J ,Crawford S , et al. Correlates of circulating androgens in mid-life women: the study of women's health across the nation. J Clin Endocrinol Metab 2005;90:4836-4845
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McCartney CR ,Prendergast KA ,Chhabra S , et al. The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism. J Clin Endocrinol Metab 2006;91:1714-1722
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Author/Editor Response
With regard to the comments by Titomanlio et al. about the Prader–Willi syndrome: molecular testing for this disorder is highly sensitive but expensive, so selection of patients for testing is currently limited to those with characteristic clinical features, including global developmental delay and infantile hypotonia, which are present in more than 97% of patients with this condition.1 Our patient had normal intelligence, speech patterns, and stature and did not have a history of neonatal hypotonia or hypogonadism. Obesity and acanthosis nigricans had developed by the time she was 6 years old, but she did not meet the clinical criteria for type 2 diabetes until late adolescence.
Schlegel suggests that the patient may have had Cushing's syndrome, which is always a consideration in patients with obesity and insulin resistance. The symptoms and signs of Cushing's syndrome, including insulin resistance, striae, and hypertension, are nonspecific and common in all forms of obesity. Clinical and laboratory evidence of hypercortisolism can occur in the setting of severe obesity, leading to “pseudo–Cushing's syndrome.” In patients with Cushing's syndrome who present during childhood, cortisol excess typically impairs linear growth.2 Our patient had early-onset obesity, but her height and height velocity were consistently normal, even after insulin resistance and hypertension developed. As a result, we and the pediatric endocrinologists who evaluated her had a low suspicion for Cushing's syndrome.
We agree with the skepticism expressed by Polotsky et al. about the diagnosis of the polycystic ovary syndrome in this patient. The 2003 Rotterdam criteria for the diagnosis of the polycystic ovary syndrome require two of the following criteria: the presence of polycystic ovaries, biochemical or clinical evidence of hyperandrogenism, and ovulatory dysfunction.3 On the basis of the elevated free testosterone level and the percentage of free testosterone at age 13, the android hair pattern, and the polycystic ovaries detected on laparoscopy, the patient fulfilled the criteria for the polycystic ovary syndrome. Her marked hyperinsulinism and central obesity support the diagnosis. Abnormal menstrual cycles are not required for the diagnosis; in one study, polycystic ovaries were detected in 87% of women presenting with hirsutism and normal menses.4 Clinical definitions have not been established for the polycystic ovary syndrome in adolescents, in whom anovulatory cycles and multifollicular ovaries are common. We agree that the laboratory measurement of free testosterone is not an accurate measure of androgen excess, particularly in view of the patient's known low level of sex hormone–binding globulin. Androgen levels are generally higher during the period of anovulatory cycles after the onset of menarche, so this finding may have been caused by a transient phenomenon in this patient.5 We will never know whether convincing evidence of the polycystic ovary syndrome would have developed if the patient had not begun to receive oral contraceptives, which were continued until she underwent gastric bypass surgery at the age of 19 years.
The patient is doing very well 4 months postoperatively. Thus far, she has lost almost 50 lb (23 kg), or 50% of her excess body weight. The hypertension, type 2 diabetes, and laboratory evidence of fatty liver disease have all resolved, and the dyslipidemia is now very mild.
5 ReferencesAlison G. Hoppin, M.D.
Lee M. Kaplan, M.D., Ph.D.
Massachusetts General Hospital, Boston, MA 021141
Gunay-Aygun M ,Schwartz S ,Heeger S ,O'Riordan MA ,Cassidy SB . The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 2001;108:E92-E92
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Magiakou MA ,Mastorakos G ,Oldfield EH , et al. Cushing's syndrome in children and adolescents: presentation, diagnosis, and therapy. N Engl J Med 1994;331:629-636
Full Text | Web of Science | Medline3
The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
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Franks S . Polycystic ovary syndrome: a changing perspective. Clin Endocrinol (Oxf) 1989;31:87-120
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Venturoli S ,Porcu E ,Fabbri R , et al. Menstrual irregularities in adolescents: hormonal pattern and ovarian morphology. Horm Res 1986;24:269-279
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