Author's Response: The Apparent Paradox of Tall Stature with ...

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The Journal of Clinical Endocrinology & Metabolism 88(8):4001– 4004 Copyright © 2003 by The Endocrine Society

LETTERS TO THE EDITOR DHEA Replacement in Adrenal Insufficiency To the editor:

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Recent double-blind, randomized crossover studies have demonstrated significant beneficial effects of dehydroepiandrosterone (DHEA) replacement on mood, sexuality, and health-related quality of life (HRQoL) in patients with adrenal insufficiency (1, 2). HRQoL in patients with both primary and secondary adrenal insufficiency is significantly impaired (3, 4). In a cohort of 88 Addison patients, Lovas et al. (3) found significantly impaired HRQoL scores, similar to those usually seen in chronic heart failure, with a significant impact on the incidence of disablement pensions (41% in Addison’s vs. only 17% in the general population for ages 40 – 67 yr; P ⬍ 0.001). In the March issue of the JCEM, Lovas et al. (5) have published the results of a 9-month, randomized, parallel group clinical trial investigating the effects of DHEA replacement in women with adrenal failure, failing to find significant improvements in HRQoL during DHEA administration. However, this outcome could have been easily predicted because their study is severely underpowered. Statistical power calculations show that a parallel study aiming to obtain significant effects similar to those reported by recent crossover studies (1, 2), which used 24 –39 patients, would require the inclusion of at least 100 patients to ascertain adequate statistical power. Power calculations are of particular importance for parallel studies using HRQoL measurements, because HRQoL scores generally show broad interindividual variability. In addition, the study presented by Lovas et al. (5) is the result of a multicenter approach, reporting the results of DHEA treatment in 15 patients from five different centers. For a reliable power calculation, this would push the number needed to treat beyond even 100 because a multicenter study necessarily shows a greater variability in results, again, in particular with regard to HRQoL scores. Results from underpowered studies are definitely noteworthy if they show significant effects, like the recent study by Johannsson et al. (6) on DHEA replacement in women with secondary adrenal failure. However, negative results from an underpowered study like the paper by Lovas et al. (5) do not contribute to furthering our knowledge in this field. By contrast, this paper may adversely affect it because it will be cited as negative evidence against DHEA replacement in adrenal insufficiency, despite its lack of statistical power. Results from an adequately powered parallel trial on DHEA replacement including 106 patients with primary adrenal insufficiency will hopefully be available soon; preliminary results published in abstract form (7, 8) reported significant improvements in HRQoL scores in both men and women with primary adrenal failure. The scientific community needs the results from well-designed, adequately powered, larger scale studies to securely establish the role of DHEA in the standard replacement regimen for adrenal insufficiency. Wiebke Arlt and Bruno Allolio Department of Medicine, Endocrine and Diabetes Unit (B.A.), University of Wuerzburg, D-97080 Germany; and Division of Medical Sciences (W.A.), University of Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2TH, United Kingdom

References 1. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B 1999 Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 341:1013–1020 2. Hunt PJ, Gurnell EM, Huppert FA, Richards C, Prevost AT, Wass JA, Herbert J, Chatterjee VK 2000 Improvement in mood and fatigue after dehydroepi-

Received March 27, 2003. Address correspondence to: Dr. Wiebke Arlt, M.D., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom. E-mail [email protected].

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androsterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 85:4650 – 4656 Lovas K, Loge JH, Husebye ES 2002 Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf) 56:581–588 Rosen T, Wiren L, Wilhelmsen L, Wiklund I, Bengtsson BA 1994 Decreased psychological well-being in adult patients with growth hormone deficiency. Clin Endocrinol (Oxf) 40:111–116 Lovas K, Gebre-Medhin G, Trovik T, Fougner KJ, Uhlving S, Nedrebo BG, Myking OL, Kampe O, Husebye ES 2003 Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 88:1112–1118 Johannsson G, Burman P, Wiren L, Engstrom BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA 2002 Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebocontrolled trial. J Clin Endocrinol Metab 87:2046 –2052 Gurnell EM, Hunt PJ, Curran SE, Conway CL, Huppert FA, Herbert J, Chatterjee VK, A long term trial of DHEA replacement in Addison’s disease. Program of the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, 2002, p 33 (Abstract S19-2) Gurnell EM, Hunt PJ, Curran SE, Conway CL, Huppert FA, Herbert J, Chatterjee VK, A longer term trial of DHEA replacement in Addison’s disease. Proc of the 193rd Meeting of the Society for Endocrinology, London, 2002; Endocrine Abstracts 4:OC24 (Abstract)

doi: 10.1210/jc.2003-030534

Authors’ Response: DHEA Replacement in Adrenal Insufficiency To the editor: We recently published the results of a randomized parallel-group clinical trial of dehydroepiandrosterone (DHEA) replacement in adrenal failure, in which we found no benefit for subjective health status and sexuality (1). We agree with Arlt and Allolio (2) that low statistical power infers risk of excluding true benefit (type 2 statistical error). However, statistical power is not only a matter of study size. It also depends on treatment variability and definitions of clinically relevant treatment responses. The wide variation in treatment responses was not known or anticipated at the time of our trial. It seems reasonable that clinically relevant treatment responses should at least exceed the range of measurement variability. The confidence intervals of treatment effects illustrate that there may be true benefit of DHEA replacement, although we did not find any statistically significant difference in effects between DHEA and placebo in our study population (1). Information provided by confidence intervals overcomes the limitations of presenting trial results simply as positive or negative. In fact, our results are consistent with those of Johannsson et al. (3), who did not find significant effects on subjective health status or sexuality (confidence intervals not given). Moreover, if only studies demonstrating significant effects are published, the conclusion of benefit may be severely biased (publication bias). We do not agree with the use of crossover trials (1), because this design is very vulnerable to unblinding, particularly when psychological outcome measures are used (4). Such design is at high risk of reporting statistically significant effects that are not clinically relevant. For instance, we questioned the clinical relevance of negative placebo effects in the two previous crossover trials (5, 6). Taken together, we agree with Arlt and Allolio (2) that larger parallel group studies are required, and we await the conclusions of the larger clinical trial by Gurnell and co-workers (7). Received April 15, 2003. Address correspondence to: Kristian Løvås, M.D., Division of Endocrinology, Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail: kristian.lovas@ med.uib.no.

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Kristian Løvås, Olle Ka¨ mpe, and Eystein S. Husebye Division of Endocrinology (K.L., E.S.H.), Institute of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway; and Department of Clinical Sciences (O.K.), Uppsala University, S-751 85 Uppsala, Sweden

References 1. Løvås K, Gebre-Medhin G, Trovik TS, Fougner KJ, Uhlving S, Nedrebø BG, Myking OL, Ka¨mpe O, Husebye ES 2003 Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 88:1112–1118 2. Arlt W, Allolio B 2003 Letter: DHEA replacement in adrenal insufficiency. J Clin Endocrinol Metab 88:4001 3. Johannsson G, Burman P, Wiren L, Engstrøm BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA 2002 Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebocontrolled trial. J Clin Endocrinol Metab 87:2046 –2052 4. Woods JR, Williams JG, Tavel M 1989 The two-period crossover design in medical research. Ann Intern Med 110:560 –566 5. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B 1999 Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 341:1013–1020 6. Hunt PJ, Gurnell EM, Huppert FA, Richards C, Prevost AT, Wass JA, Herbert J, Chatterjee VK 2000 Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 85:4650 – 4656 7. Gurnell EM, Hunt PJ, Curran SE, Conway CL, Huppert FA, Herbert J, Chatterjee VK, A long term trial of DHEA replacement in Addison’s disease. Program of the 84th Annual Meeting of The Endocrine Society, San Francisco, CA, 2002, p 33 (Abstract S19-2) doi: 10.1210/jc.2003-030638

The Apparent Paradox of Tall Stature with Hypopituitarism: New Insights from an Old Story To the editor: Reading the article by den Ouden et al. (1) evoked some questions and remarks. First, the intriguing history of gigantism with hypopituitarism warrants some comment. In their review of the literature, the authors state that “to date, six adult untreated panhypopituitarism patients have been described.” Of these, only three attained normal or tall stature, in addition to their patient. To our knowledge, other six adult patients have been reported in the medical literature (2– 6). In 1963, a 32-yr-old man with evidence of hypopituitarism, eunuchoid habitus and proportions, tall stature (height, 195.5 cm; weight, 85.35 kg; body mass index, 22.3 kg/m2), slipped epiphyses, and continuing linear growth was described (2). At the time, pituitary gigantism associated with a deficiency of other pituitary hormones was suggested, but a subsequent revaluation with specific tests of GH reserve led to the definitive diagnosis of panhypopituitarism (3). In 1964, Sarver et al. (4) reported three other patients with hypopituitarism and tall or normal stature. Again, Sarver et al. tried to explain the phenotype with a kind of “fractional hypopituitarism” coupled with pituitary gigantism. In 1967, two other similar cases were reported, but insulininduced hypoglycemia produced no significant increase in GH concentrations, providing evidence for the diagnosis of panhypopituitarism (5). Notably, at that time physicians widely ignored the skeletal effects of estrogen, a finding that has recently led to a radical change in our thinking. Second, we are aware that a lack of estrogenic effect on the skeleton may have had a crucial role in the patient’s pattern of growth, which reminds the authors of the growth curve depicted in men with congenital estrogen deficiency. By contrast, other patients with untreated hypopituitarism have short adult height without evidence of continuing linear growth. A possible explanation of these differences, as the authors point out, is the involvement of factors other than GH and Received April 8, 2003. Address correspondence to: Marco FaustiniFustini, M.D., Department of Internal Medicine (Endocrine Unit), Ospedale Bellaria-Padiglione “Tinozzi,” Via Altura, 3, 40139 Bologna, Italy. E-mail: [email protected].

Letters to the Editor

IGF-I (such as insulin, differences in insulin sensitivity, and unknown growth factor). There is also another possibility. Still unknown is the amount of estrogen necessary for epiphyseal closure, although it has been established that estrogens are effective on growth plate even at serum levels not detectable by conventional commercial kits (7). Perhaps, a complete estrogen deficiency cannot be applied to all the patients with untreated hypopituitarism. Such a hypothesis, however, cannot be demonstrated to date because ultrasensitive assays of serum estradiol are far from being commonly used in clinical practice. There is also evidence for a role of paracrine/autocrine/intracrine mechanisms in the physiology of bone and cartilaginous growth plate. Aromatase, as well as estrogen receptors, is expressed in human bone. Like other extragonadal sites of estrogen biosynthesis, however, bone is dependent on circulating C19 precursors. Furthermore, findings in animals and humans support the notion that local estrogen production is of physiological significance in bone (7). If so, then individual differences in the amount of locally produced estrogen could play a part in the variable pattern of linear growth in adults with untreated hypopituitarism. Accordingly, in severe male hypogonadism, two groups of untreated adult men with similar circulating sex steroids have been identified, the former with a complete epiphyseal closure at 19 yr of age, and the latter with open epiphyses and delayed bone age at more than 19 yr (8). Another experiment of nature may help us with this issue. In 17␣-hydroxylase deficiency, impaired production of sex hormones leads to abnormalities of sexual development, eunuchoid skeleton, bone age retardation, and osteoporosis. Interestingly, tall stature may occur, but only in sporadic cases with severe enzyme deficiency (9). Again, in these cases, the amount of C19 precursors might be too low for adequate estrogen biosynthesis. Finally, surprisingly, the patient reported by den Ouden et al. (1) seems to have no evidence of decreased bone mineral density (BMD). We have some concerns about this finding. Previous studies of patients with hypogonadotropic hypogonadism, estrogen insensitivity, or aromatase deficiency have shown that a prolonged lack of estrogen results in eunuchoid skeletal proportions and reduced BMD (7). More recently, in the attempt to enhance linear growth by delaying epiphyseal closure, a group of adolescents with normally timed puberty and short stature was treated with an LH releasing hormone agonist for 3.5 yr (10). As a result, adult height increased by 0.6 sd to the detriment of their BMD (⫺1.6 below the population mean). Marco Faustini-Fustini, Antonio Balestrieri, Vincenzo Rochira, and Cesare Carani Department of Internal Medicine, Endocrine Unit, Bellaria Hospital (M.F.-F.), 40139 Bologna, Italy; and Department of Internal Medicine, University of Modena and Reggio Emilia (A.B., V.R., C.C.), 41100 Modena, Italy

References 1. den Ouden DT, Kroon M, Hoogland PH, Geelhoed-Duijvestijn PHLM, Wit JM 2002 A 43-year-old male with untreated panhypopituitarism due to absence of the pituitary stalk: from dwarf to giant. J Clin Endocrinol Metab 87:5430 –5434 2. Goldman JK, Cahill GH, Thorn GW 1963 Gigantism with hypopituitarism. Am J Med 34:407– 416 3. Baumann G, Cain JP, Dingman JF 1972 Gigantism with hypopituitarism. A reevaluation. Am J Med 53:805– 810 4. Sarver ME, Sabeh G, Fetterman GH, Wald N, Danowski TS 1964 Fractional hypopituitarism with giantism and normal sella turcica. N Engl J Med 271: 1286 –1289 5. Zimmerman TS, White MG, Doughaday Wh, Goetz FC 1967 Hypopituitarism with normal or increased height. Am J Med 42:146 –150 6. Ihara C, Shimatsu A, Tanoh T, Harada M, Nakamura T, Imura H 1992 A case of panhypopituitarism with normal height manifesting the transection of the pituitary stalk and the formation of the ectopic and eutopic posterior lobes. Nippon Naibunpi Gakkai Zasshi 68:81– 88 7. Riggs BL, Khosla S, Melton J 2002 Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279 –302 8. Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, Crowley WF 1987 Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann Intern Med 106:354 –361 9. Mayer EIE, Homoki J, Ranke MB 1999 Spontaneous growth and bone age development in a patient with 17␣-hydroxylase deficiency: evidence of the role of sexual steroids in prepubertal bone maturation. J Pediatr 134: 371–375


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10. Yanovski JA, Rose SR, Municchi G, Pescovitz OH, Hill SC, Cassorla FG, Cutler Jr GB 2003 Treatment with luteinizing hormone-releasing hormone agonist in adolescents with short stature. N Engl J Med 348:908 –917 doi: 10.1210/jc.2003-030603

Author’s Response: The Apparent Paradox of Tall Stature with Hypopituitarism: New Insights from an Old Story To the editor: The letter of Dr. Faustini-Fustini and colleagues (1) in response to our recent article (2) in JCEM makes three interesting points. First, some additional cases with similar phenotypes are mentioned, which illustrates that the pattern of continuing growth in adulthood—in some cases resulting in gigantism—in panhypopituitary patients may be not as rare as has been previously believed. Second, an additional hypothesis is put forward to explain why some untreated patients with multiple pituitary deficiency continue to grow, whereas others do not. In addition to variability in insulin secretion and sensitivity, and sex steroid sensitivity, the authors suggest that there may also be an interindividual variation of local aromatase activity and, thus, local availability of estrogen. We agree that, indeed, this is a plausible hypothesis; however, it will be virtually impossible to prove or disprove any of these hypotheses. The third point is the unexpected finding of a low bone mineral density, despite the known effects of sex steroid deficiency on bone mineral density. We believe that the patient’s recent humerus fracture and the thoracic kyphoscoliosis indicate a decreased bone strength, whereas the normal bone mineral density indicates a normal amount of calcified bone. We hypothesize that this apparent contradiction can be explained by a slow bone turnover and remodeling that has resulted in a bone with an apparently normal bone mineral density but with a decreased strength. This is consistent with the observations that, in patients with GH deficiency, bone mineral density is not far below the mean for age when corrected for body size (3), while both osteoclastic and osteoblastic activity are decreased (4, 5). The findings in our patient may suggest that sex hormone deficiency may only result in low bone density in the presence of a normal GH secretion. D. T. den Ouden, M. Kroon, P. H. Hoogland, P. H. L. M. Geelhoed-Duijvestijn, and J. M. Wit Leiden University Hospital, Department of Internal Medicine, Leiden, The Netherlands 2300 RC

References 1. Faustini-Fustini M, Balestrieri A, Rochira V, Carani C 2003 The apparent paradox of tall stature with hypopituitarism: new insights from an old story. J Clin Endocrinol Metab 88:4002 (Letters) 2. Den Ouden DT, Kroon M, Hoogland PH, Geelhoed-Duijvestijn PHLM, Wit JM 2002 A 43-year-old male with untreated panhypopituitarism due to absence of the pituitary stalk: from dwarf to giant. J Clin Endocrinol Metab 87:5430 –5434 3. de Boer H, Blok GJ, van Lingen A, Teule GJ, Lips P, van der Veen EA 1994 Consequences of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res 9:1319 –26 4. Bravenboer N, Holzmann P, de Boer H, Blok GJ, Lips P 1996 Histomorphometric analysis of bone mass and bone metabolism in growth hormone deficient adult men. Bone 18:551–557 5. Bravenboer N, Holzmann P, de Boer H, Roos JC, van der Veen EA, Lips P 1997 The effect of growth hormone (GH) on histomorphometric indices of bone structure and bone turnover in GH-deficient men. J Clin Endocrinol Metab 82:1818 –22 doi: 10.1210/jc.2003-030836

Received May 13, 2003. Address correspondence to: Dr. Danielle T. den Ouden, Leiden University Hospital, Department of Internal Medicine, C1/R P.O. Box 9600, Leiden, The Netherlands 2300 RC. E-mail: [email protected].

Commercial Radioimmunoassays Do Not Measure Urinary Free Cortisol Accurately and Should Not Be Used for Physiological Studiesa To the editor: In their recent article, Legro et al. (1) claim to have studied urinary free cortisol (UFC) in adolescent females using “established RIA methods that employ methanol extraction before assay.” They provide data for reproducibility (8%) and sensitivity (5 ␮g/24 h) and minimal data for cross-reactivity. No references are provided. It is not clear what the methanol extraction step consisted of or was meant to accomplish. The assays used are presumably commercial RIAs, none of which has been shown to measure UFC accurately. Such assays are validated only for serum or plasma cortisol and give values that are much too high for UFC, as shown more than 20 yr ago and many times since when compared with data obtained after HPLC or other extensive chromatography (2), or more recently by liquid chromatography-tandem mass spectrometry (3). The values obtained by RIA are usually about three or more times higher than the true values, due to competition by large amounts of metabolites or other forms of interference. Although such RIA methods may have some clinical use in determining excessive cortisol production, they are unsuitable for physiological studies if one wishes to measure cortisol itself. The nature of the interference has been poorly documented, so that one would not know if the same substances are responsible for interference in different samples or using different antibodies. We are not told how many different antibodies were used, but each antibody has its own set of crossreactivities, and no two are identical. This makes it impossible to interpret data such as those shown by Legro et al. (1). For example, changes in metabolism resulting in different competing metabolites and, thus, differences in the amount of interference would not be apparent. Mean or median values in healthy female adults obtained after extensive chromatography are approximately 20 ␮g/24 h (range, ⬃3– 43 ␮g/24 h), approximately one third of the mean and range (67 ⫾ 44 sd ␮g/24 h) reported here. Thus, approximately two thirds of the material measured is not cortisol. It is, therefore, obviously incorrect to refer to the material measured as UFC and, therefore, impossible to interpret their data. Beverley E. Pearson Murphy Departments of Medicine, Obstetrics and Gynecology, and Psychiatry McGill University Montreal H3G 1A4, Canada

References 1. Legro RS, Lin HM, Demers LM, Lloyd T 2003 Urinary free cortisol increases in adolescent Caucasian females during perimenarche. J Clin Endocrinol Metab 88:215–219 2. Murphy BEP 2002 Urinary free cortisol determinations—what they measure. The Endocrinologist 12:143–150 3. Taylor RL, Machacek F, Singh RJ 2002 Validation of a high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem 48:1511–1519 doi: 10.1210/jc.2003-030715

Authors’ Response: Urine Free Cortisol Assayb To the editor: Urine assays for cortisol in our laboratory have been appropriately validated for accuracy, recovery and precision according to National Committee for Clinical Laboratory Standards guidelines along with comparison studies to an HPLC method. We also participate in the American College of Pathologists proficiency survey program that tracks urine cortisol results across a range of methods from different laboratories throughout the United States. The antibody used for our a Received April 22, 2003. Address correspondence to: Dr. Beverley E. Pearson Murphy, Division of Endocrinology, Montreal General Hospital, 1650 Cedar, Montreal 83G IA4, Canada. E-mail: bev.murphy@ mcgill.ca. b Received May 19, 2003. Address correspondence to: Richard S. Legro, M.D., Department of Obstetrics and Gynecology, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033.

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cortisol assay shows minimal cross-reactivity (⬍1%) with other possible interferents including corticosterone, cortisone, and 11-deocycortisone, and none of the individual subjects in this study were on steroid therapy including prednisone to suggest a chemical interference in our urinary free cortisol results. Our method uses a methylene chloride extraction step before RIA. We have no reason to believe that our results are not accurate or reproducible using our RIA method. Laurence M. Demers and Richard S. Legro Department of Pathology (L.M.D.), and Department of Obstetrics and Gynecology (R.S.L.) The Milton S. Hershey Medical Center Hershey, Pennsylvania 17033 doi: 10.1210/jc.2003-030857

SHOX Deficiency Phenotypes To the editor: We enjoyed reading the very interesting report by Judith L. Ross and colleagues on SHOX deficiency phenotypes in the December 2001 issue of JCEM (1) and the accompanying editorial by Ron G. Rosenfeld (2). We wish to share with you and your readers some caveats referring to both reports. 1. In the third paragraph of the editorial, Leri-Weill dyschondrosteosis is described as “an autosomal dominant form of mesomelic dysplasia. . . . ” If, in fact, the SHOX gene, whose abnormalities have been shown to be causally related to the dysplasia, has been located in the pseudoautosomal region of the sex chromosomes (as mentioned in the second paragraph of the editorial), then the correct term for the type of hereditary transmission should be a “pseudoautosomal dominant,” a “sex chromosomal dominant,” or a “gonosomal dominant” form of mesomelic dysplasia, and the genetics literature should be corrected acReceived February 22, 2003. Address correspondence to: Dr. Martin Roubicek, M.D., Servicio de Endocrinologia, Hospital Privado de Comunidad, Co´ rdoba 4545, 7600 Mar del Plata, Argentina. E-mail: [email protected].


cordingly. The On-line Mendelian Inheritance in Man entry for LeriWeill dyschondrosteosis (http://www.ncbi.nlm.nih.gov/Omim/ entry 127300), although still listed among dominant mutations, makes the distinction clear in its first paragraphs. 2. In the last paragraph of the same editorial, on page 5673, it is stated that “Part of the female to male preponderance can be explained . . . by the fact that females can obtain an abnormal SHOX gene from either their mother or father, whereas males can only receive an abnormal SHOX gene from their mothers.” This statement would be correct for an Xlinked dominant condition, such as familial hypophosphatemic rickets. But when the causal abnormal gene is located in the pseudoautosomal region, it can also be found on the Y chromosomal pseudoautosomal region, and thus be transmitted from father to son. This is beautifully illustrated by family 10 in the study by J. L. Ross et al. (1). As may be seen in Ross et al.’s Table 1 (page 5676), in that family the deletion was present in the male proband on his X chromosome, in his mother and sister (obviously) on their X, but in his son on the Y chromosome, implying that a crossover had occurred between the X and Y chromosomes in the proband’s spermatogenesis. Incidentally, this occurrence was not emphasized in the article in question, although it is a beautiful example of a genetic disease previously thought to be autosomal dominant, being in fact a pseudoautosomal or sex chromosomal dominant, with a potentially more severe phenotypic expression in the hemizygote males than in the heterozygote females. This type of inheritance would not explain the female preponderance of affected persons, thus favoring some of the other possible explanations mentioned by Dr. Rosenfeld. Martin Roubicek, Maria Cristina Arriazu, and Gabriel Isaac Endocrinology and Genetics, Hospital Privado de Comunidad 7600 Mar del Plata, Argentina

References 1. Ross JL, Scott Jr C, Marttila P, Kowal K, Nass A, Papenhausen P, Abboudi J, Osterman L, Kushner H, Carter P, Ezaki M, Elder F, Wei F, Chen H, Zinn AR 2001 Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 86:5674 –5680 2. Rosenfeld RG 2001 A SHOX to the system. J Clin Endocrinol Metab 86: 5672–5673 doi: 10.1210/jc.2002-020285