Turner syndrome and Xp deletions: Clinical and molecular studies in 47 patients

Although clinical features of Turner syndrome have primarily been explained by the dosage effects of SHOX (short stature homeobox-containing gene) and the putative lymphogenic gene together with chromosomal effects leading to nonspecific features, several matters remain to be determined, including m odifying factors for the effects of SHOX haploinsufficiency, chromosomal lo cation of the lymphogenic gene, and genetic factors for miscellaneous featu res such as multiple pigmented nevi. To clarify such unresolved issues, we examined clinical findings in 47 patients with molecularly defined Xp delet ion chromosomes accompanied by the breakpoints on Xp21-22 (group 1; n = 19) , those accompanied by the breakpoints on Xp11 (group 2; n = 16), i(Xq) or idic(X)(p11) chromosomes (group 3; n = 8), and interstitial Xp deletion chr omosomes (group 4; n = 4). The deletion size of each patient was determined by fluorescence in situ hybridization and microsatellite analyses for 38 X p loci including SHOX, which was deleted in groups 1-3 and preserved in gro up 4. The mean GH-untreated adult height was -2.2 SD in group 1 and -2.7 SD in group 2 (GH-untreated adult heights were scanty in group 3). The preval ence of spontaneous breast development in patients kaged 12.8 yr or more (m ean +/- 2 SD for B2 stage) was 11 of 11 in group 1, 7 of 12 in group 2, and 1 of 7 in group 3. The prevalence of wrist abnormality suggestive of Madel ung deformity was 8 of 18 in group 1 and 2 of 23 in groups 2 and 3, and 9 o f 18 in patients with spontaneous puberty and 1 of 23 in those without spon taneous puberty. The prevalence of short neck was 1 of 19 in group 1 and 7 of 24 in groups 2 and 3. Soft tissue and visceral anomalies were absent in group 1 preserving the region proximal to Duchenne muscular dystrophy and w ere often present in groups 2 and 3 missing the region distal to monoamine oxidase A (MAOA). Multiple pigmented nevi were observed in groups 1-3, with the prevalence of 0 of 7 in patients less than 10 yr of age and 15 of 36 i n those 10 yr or older regardless of the presence or absence of spontaneous puberty. Turner phenotype was absent in group 4, including a fetus aborted at 21 wk gestation who preserved the region distal to MAOA. The results provide further support for the idea that clinical features in X chromosome aberrations are primarily explained by haploinsufficiency of S HOX and the lymphogenic gene and by the extent of chromosome imbalance in m itotic cells and pairing failure in meiotic cells. Furthermore, it is sugge sted that 1) expressivity of SHOX haploinsufficiency in the limb and facioc ervical regions is primarily influenced by gonadal function status and the presence or absence of the lymphogenic gene, respectively; 2) the lymphogen ic gene for soft tissue and visceral stigmata is located between Duchenne m uscular dystrophy and MAOA; and 3) multiple pigmented nevi may primarily be ascribed to cooperation between a hitherto unknown genetic factor and an a ge-dependent factor other than gonadal E.