RESEARCH ARTICLE Mosaic Compound Heterozygosity of SHOX Resulting in Leri–Weill Dyschondrosteosis With Marked Short Stature: Implications for Disease Mechanisms and Recurrence Risks Orit Reish, 1,2 *C eline Huber, 3 Gheona Altarescu, 4,5 Daphne Chapman-Shimshoni, 1 Ephrat Levy-Lahad, 4,5 Paul Renbaum, 4 Maya Mashevich, 1 Arnold Munnich, 3 and Val  erie Cormier-Daire 3 1 Genetics Institute, Assaf Harofeh Medical Center, Zerifin, Israel 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3 INSERM U781 and D epartement de G en etique, Universit e Paris Descartes, H^ opital Necker-Enfants Malades, Paris, France 4 Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel 5 Hebrew University Hadassah School of Medicine, Jerusalem, Israel Received 20 December 2009; Accepted 22 May 2010 Mutations or deletions in the SHOX gene cause Leri–Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD) when present in heterozygous or homozygous form, respectively. A new class of enhancer deletions was identi- fied 30–250 kb downstream of SHOX. We identified a female patient with marked short stature, mosaic for monosomy X in 31% of her lymphocytes, and findings consistent with LWD. Additional molecular studies demonstrated segregation of 17 polymorphic markers flanking and including the SHOX locus, spanning 328 kb of pseudoautosomal region 1 (PAR1) region. A deletion up to 10 kb residing 197 kb downstream of SHOX gene was detected, which was germinally transmitted from her clinically unaffected father. This was associated with post- zygotic mosaic loss of the normal maternal X-chromosome, evidenced by fluorescent fragment analysis. Since most patients with LMD with deletions downstream of SHOX gene also have SHOX mutations in trans, it may suggest these deletions are associated with a milder phenotype. Further studies are required to elucidate the role of the former region in disease etiology. Mutations should be sought in clinically non- affected family members because of the variable expressivity in hemizygous carriers, and cytogenetic evaluation should be con- sidered to detect possible X-chromosome rearrangements underlying the haploinsufficiency for the PAR1 when deletion is detected by molecular analysis. Similarly, when LWD and marked short stature occur in a patient with mosaic Turner syndrome, the possibility of mutations in SHOX and the downstream of SHOX gene should be considered. Ó 2010 Wiley-Liss, Inc. Key words: Leri–Weill dyschondrosteosis (LWD); X-chromo- some monosomy; mosaicism; downstream of SHOX deletion; post-zygotic INTRODUCTION Mutations or deletions in the short-stature homeobox gene (SHOX; OMIM# 312865) cause growth retardation associated with Turner, Leri–Weill dyschondrosteosis (LWD), and idiopathic short stature (ISS) syndromes when present in heterozygous form, and with Langer mesomelic dysplasia (LMD) syndrome when homozygous. LWD comprises short stature, mesomelia, and Madelung deformity that includes deformities of the distal radii, ulnae, and carpal bones [Langer, 1965; Jones, 2006]. C eline Huber and Gheona Altarescu contributed equally to this work. *Correspondence to: Orit Reish, M.D., Director, Genetics Institute, Assaf Harofeh Medical Center, Zerifin 70300, Israel. E-mail: oreish@post.tau.ac.il Published online 3 August 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ajmg.a.33563 How to Cite this Article: Reish O, Huber C, Altarescu G, Chapman-Shimshoni D, Levy-Lahad E, Renbaum P, Mashevich M, Munnich A, Cormier-Daire V. 2010. Mosaic compound heterozygosity of SHOX resulting in Leri–Weill dyschondrosteosis with marked short stature: Implications for disease mechanisms and recurrence risks. Am J Med Genet Part A 152A:2230–2235. Ó 2010 Wiley-Liss, Inc. 2230