Mosaic compound heterozygosity of SHOX resulting in Leri-Weill dyschondrosteosis with marked short stature: implications for disease mechanisms and recurrence risks.
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 identified 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 considered 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.
Reish
Orit
O
Genetics Institute, Assaf Harofeh Medical Center, Zerifin, Israel. oreish@post.tau.ac.il
Huber
Céline
C
Altarescu
Gheona
G
Chapman-Shimshoni
Daphne
D
Levy-Lahad
Ephrat
E
Renbaum
Paul
P
Mashevich
Maya
M
Munnich
Arnold
A
Cormier-Daire
Valérie
V
D000293:Adolescent; D000328:Adult; D041321:Chromosomes, Human, X; D004392:Dwarfism; D005190:Family; D005260:Female; D006130:Growth Disorders / Q000209:etiology / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009006:Monosomy; D009030:Mosaicism; D010009:Osteochondrodysplasias / Q000209:etiology / Q000235:genetics / Q000473:pathology; D012008:Recurrence; D012306:Risk; D017384:Sequence Deletion; D000074122:Short Stature Homeobox Protein; D014424:Turner Syndrome / Q000235:genetics; D055815:Young Adult
D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein