The
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tered. Were these studies to show an effect on the Lawrence G. Raisz, M.D. incidence of fracture, a prospective add-on trial University of Connecticut Health Center Farmington, CT 06032 would certainly be desirable.
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Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child to the editor: Schuelke et al. (June 24 issue)1 de- ing usually, but not always, causes growth suppres-
scribe a child with muscle hypertrophy in association with a mutation in the myostatin gene. Another possible case of a myostatin mutation in an exceptionally strong child was described more than 2500 years ago in Greek mythology, in the story about Hercules. As an infant, Hercules strangled a snake in each hand when the goddess Hera tried to kill him. His legendary strength was obvious from the time of his birth, and it was not the result of any exercise program. Branimir ∑atipovi´c, M.D. Department of Veteran Affairs Mason City, IA 50401
[email protected] 1. Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation as-
sociated with gross muscle hypertrophy in a child. N Engl J Med 2004;350:2682-8.
sion.3 In the case reported by Schuelke et al., maternal isodisomy of chromosome 2 should be ruled out as a possible cause of the muscle hypertrophy. Marc S. Williams, M.D. Gundersen Lutheran Medical Center La Crosse, WI 54601
[email protected] 1. University of Chicago. Human imprinting map. (Accessed Au-
gust 13, 2004, at http://www.genes.uchicago.edu/upd/upd.html.) 2. Webb AL, Sturgiss S, Warwicker P, Robson SC, Goodship JA,
Wolstenholme J. Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation. Prenat Diagn 1996;16:958-62. 3. Butler MG. Imprinting disorders: non-Mendelian mechanisms affecting growth. J Pediatr Endocrinol Metab 2002;15:Suppl 5: 1279-88. 4. OMIM, Online Mendelian Inheritance in Man. Baltimore: Johns Hopkins University. (Accessed August 13, 2004, at http://www. ncbi.nlm.nih.gov/omim/.)
to the editor: Schuelke et al. report a case of dr. schuelke and colleagues reply: Williams rais-
muscle hypertrophy associated with a mutation in the myostatin gene. The patient was homozygous for a guanine-to-adenine transition at nucleotide g.IVS1+5 — a mutation that may lead to missplicing. The mother was heterozygous for this mutation, and the father was unavailable. The authors hypothesize that the muscular hypertrophy was due to lack of myostatin. Although this hypothesis is attractive, another possibility was not addressed. The myostatin gene (GDF8) maps to chromosome 2q32.1 in humans. Maternal isodisomy of chromosome 2 could explain the homozygosity of the described mutation. All or part of chromosome 2 may be subject to maternal imprinting.1,2 Abnormal imprinting can lead to growth abnormalities and tissue hypertrophy.3 For example, patients with the Beckwith–Wiedemann syndrome, a paternal imprinting disorder, may have macroglossia, hemihypertrophy (including muscle hemihypertrophy), and organomegaly; embryonal rhabdomyosarcoma has also been observed.4 Abnormal maternal imprint-
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es the question of whether the increased muscle mass in the child we describe might be due to an imprinting disorder and suggests that maternal isodisomy should be ruled out. Here we provide data to rule out uniparental isodisomy of chromosome 2 on the basis of microsatellite-marker analysis of specimens from the patient and his mother. We detected a founder haplotype for which the patient was homozygous in a 20-cM segment around the myostatin gene (Fig. 1). Thus, the mode of inheritance in this child seems most likely to have been autosomal recessive, as it is in myostatin knockout mice1 and double-muscled cattle.2 There is additional evidence against an imprinting disorder: the effect of the myostatin splice-site mutation could be demonstrated in vitro after a genomic myostatin construct was transfected into mammalian cells. In this system, myostatin transcription is regulated by a cytomegalovirus promoter in which imprinting does not play a role.1 Most children with imprinting disorders have multiple-organ involve-
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correspondence
Figure 1. Results of Haplotype Analysis. Haplotype analysis of specimens from the patient and his mother was carried out with informative markers (deCODE) on chromosome 2 and reconstruction of the father’s allele. The analysis revealed a founder haplotype (black bar) for which the patient was homozygous at the myostatin-gene locus. The numbers flanking the chromosomes depict the lengths (in base pairs) of the microsatellite markers from the maternal and the paternal alleles. Because the father’s chromosome was reconstructed from the child’s haplotypes, only one chromosome shows the numbers that refer to the length of the microsatellite markers. All codes beginning with D2 designate the names of the microsatellite markers from the deCODE marker set; D2 indicates that the markers are located on chromosome 2. The genetic distance between the markers is shown in centimorgans.
ment and dysmorphic features,3,4 which was not the case with our patient. Birgit Uhlenberg, M.D. Barbara Lucke Markus Schuelke, M.D.
Genetic Distance Father D2S2976 D2S2952 D2S1360 D2S405 D2S1346 D2S441 D2S410 D2S1334 D2S2177 D2S326 D2S1391 D2S116 D2S1384 D2S434 D2S427 D2S2968
211 185 142 254 257 140 176 298 128 109 113 155 146 271 252 186
Mother ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
241 189 146 246 260 156 166 286 120 111 117 147 150 263 244 178
203 189 162 254 260 136 172 294 120 109 113 155 154 275 256 182
Patient 2,97 cM 19,64 cM 39,96 cM 51,48 cM 77,97 cM 90,50 cM 127,38 cM 149,00 cM 176,30 cM 178,40 cM 189,15 cM 198,66 cM 201,34 cM 216,01 cM 238,22 cM 249,60 cM
Charité University Medical Center 13353 Berlin, Germany
[email protected] 1. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal mus-
cle mass in mice by a new TGF-beta superfamily member. Nature 1997;387:83-90. 2. Grobet L, Martin LJ, Poncelet D, et al. A deletion in the bovine myostatin gene causes the double-muscled phenotype in cattle. Nat Genet 1997;17:71-4. 3. Buntinx IM, Hennekam RC, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56: 176-83. 4. Engstrom W, Lindham S, Schofield P. Wiedemann-Beckwith syndrome. Eur J Pediatr 1988;147:450-7.
D2S2976 D2S2952 D2S1360 D2S405 D2S1346 D2S441 D2S410 D2S1334 D2S2177 D2S326 D2S1391 D2S116 D2S1384 D2S434 D2S427 D2S2968
211 185 142 254 257 140 176 298 128 109 113 155 146 271 252 186
203 189 162 254 260 136 172 294 120 109 113 155 154 275 256 182
Myostatin gene
Plan B — The FDA and Emergency Contraception to the editor: Dr. Steinbrook (June 3 issue)1 joins tion that the patient will have rapid access to Plan B
the American College of Obstetricians and Gynecologists in urging “all obstetrician-gynecologists to provide advance prescriptions for emergency contraception to all women of reproductive age at every office visit.” It should be noted, however, that all physicians who care for women of reproductive age have the ability to contribute to this effort. Multiple well-designed studies have shown that advance provision of emergency contraception increases timely, appropriate use without adversely affecting routine contraception and sexual risk-taking behavior.2-4 Any physician who recommends that a patient use condoms should ensure with a prescrip-
n engl j med 351;10
should the condom break. In addition, physicians (such as internists, family practitioners, dermatologists, psychiatrists, and neurologists) who prescribe teratogenic medications to women of reproductive age have a particular responsibility to ensure that their patients are prepared for contraceptive emergencies, by routinely discussing and providing prescriptions for Plan B. Eleanor B. Schwarz, M.D. University of California, San Francisco San Francisco, CA 94121
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