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Departments of Pediatrics (J.L.R., C.S., K.K., A.N.) and Orthopedic Surgery (J.A., L.O.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; Alfred I. DuPont Hospital for Children (J.L.R., C.S.), Wilmington, Delaware 19803; Molecular Endocrinology, Research and Development (P.M.), Esoterix Endocrinology, Calabasas Hills, California 91301; Laboratory Corporation of America (P.P.), Research Triangle Park, North Carolina 27709; Biomedical Computing (H.K.), Philadelphia, Pennsylvania 19115; Texas Scottish Rite Hospital for Children (P.C., M.E.), Dallas, Texas 75219; Department of Pathology (F.E.), The University of Texas Southwestern Medical School, Dallas, Texas 75219; and Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine (F.W., H.C., A.R.Z.), The University of Texas Southwestern Medical School, Dallas, Texas 75390
Address all correspondence and requests for reprints to: Judith L. Ross, M.D., Thomas Jefferson University, Department of Pediatrics, 1025 Walnut Street, Philadelphia, Pennsylvania 19107. E-mail: Judith.Ross@mail.tju.edu (or Andrew.Zinn{at}UTSouthwestern.edu)
Abstract
Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3–56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype.
SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean ± SD = -2.2 ± 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations.
In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.
LERI-WEILL DYSCHONDROSTEOSIS (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia first described in 1929 (1). The phenotype includes Madelung’s deformity of the wrist, mesomelia, and short stature. Madelung wrist deformity likely originates with disorganized growth of part of the radial epiphysis, leading to radial bowing, premature fusion of that epiphysis, dorsal dislocation of the ulna, and wedged carpal bones (2).
The molecular basis for LWD was recently described (3, 4, 5).
A gene on the distal part of the pseudoautosomal region, SHOX (short
stature homeobox-containing gene), was cloned (6) and
related to the short stature that is nearly universal in 45,X Turner
syndrome (TS, monosomy X). SHOX is expressed by both sex chromosomes in
males and females and is thought to play a role in bone growth and
development. The importance of SHOX in TS linear growth was supported
by the finding of similar growth patterns in 1 of 91 idiopathic short
stature patients with a SHOX nonsense mutation (
1%) and TS females
(6). Haploinsufficiency for the SHOX gene is also
associated with LWD (3, 7); SHOX deletions or mutations
were found in 60–100% of LWD cases (4, 8).
The discovery that SHOX deficiency causes LWD prompted reexamination of its role in TS. Clement-Jones et al. (9) found robust SHOX expression in early human embryos in the mid-portions of the developing limbs as well as the first and second pharyngeal arches. They hypothesized that SHOX haploinsufficiency causes TS skeletal features such as cubitus valgus and short fourth metacarpals, as well as TS craniofacial abnormalities such as high arched palate and micrognathia. Retrospective clinical examination of subjects with known SHOX mutations (without TS) revealed cubitus valgus, short fourth metacarpals, short neck, and scoliosis in some individuals (9). These individuals did not have TS but shared some skeletal features of TS, presumably due to SHOX haploinsufficiency. Thus, TS and LWD share both SHOX haploinsufficiency and associated phenotypic features such as short stature and skeletal anomalies. However, TS is distinguished from LWD by its additional growth deficit, ovarian failure, and extra-skeletal features.
We have prospectively studied 21 LWD families to investigate the relationship between SHOX deficiency and other TS skeletal features (short stature, mesomelia, Madelung deformity, increased carrying angle, and palate morphology). Our study included precise molecular description of the SHOX abnormalities and detailed phenotypic descriptions. We compared the phenotype of LWD patients with SHOX point mutations vs. larger deletions encompassing SHOX (but limited to Xp22.3) to determine whether contiguous genes play a role in the LWD phenotype. We also examined the effects of age, gender, and puberty (estrogen) on the phenotype. The comprehensive evaluation of these LWD subjects sheds light on the normal role of SHOX in bone growth and development and the contribution of SHOX haploinsufficiency to Turner syndrome.
Subjects and Methods
Methods
SHOX deletions were detected by fluorescence in situ hybridization (FISH) using cosmid probe LLNOYCO3'M'34F5 as previously described (10). At least five metaphases were scored for each sample.
SHOX mutations were detected by denaturing HPLC (DHPLC) using the Transgenomic WAVE system. Primers and DHPLC conditions will be described elsewhere (Marttila, P., J. Ross, M. Stene, S. Blakely, J. Sernberger, and A. Zinn, manuscript in preparation). Mutations were confirmed by direct sequencing of genomic PCR products.
Parental origin of deletions was inferred from pedigrees or from parental karyotypes for deletions due to unbalanced translocations.
Karyotypes were obtained from subjects when possible. For purposes of differentiating LWD and TS, LWD cases with an abnormal karyotype were defined as LWD only if the karyotype result was a nonmosaic deletion encompassing distal Xp22.3 only.
Subjects
Subjects were generally referred for short stature or Madelung deformity. The study was approved by the Human Studies Committee at Thomas Jefferson University and The University of Texas Southwestern Medical School, and informed consent or assent was obtained in all cases. None of the patients had received GH treatment. The clinical assessment included measurement of height, lower segment, arm span, and forearm length. High arched palate, increased carrying angle of the arms, and scoliosis were evaluated as previously described (11). Arm span was measured as the distance from right to left third finger tips with patients facing the wall, with outstretched arms held parallel to the ground. Results were converted to z-scores where possible using age- and gender-specific norms (12, 13, 14). Pubertal development was assessed according to standard methods (15). Age of onset of menarche in females was recorded.
Metacarpal-phalangeal profiles measured from hand x-rays were used to determine the presence of short fourth or fifth metacarpals (16). Age- and gender-specific height z-scores were calculated from National Center for Health Statistics (12). Z-scores for right radial length and ratio of upper to lower segment were calculated from published norms (14). A positive z-score means the ratio (upper to lower segment) was greater than normal, indicating relatively short legs.
Radial length was measured from the olecranon to the radial prominence by physical examination. The presence of Madelung deformity was assessed by the following defined measurements on AP and lateral wrist x-rays. Carpal wedging was defined as the age- and gender-specific z-score of the angle between the tangents of the proximal scapholunate and lunotriquetral surfaces (13). Radial lucency was defined as the presence of radiographic lucency, particularly in the ulnar border of the radius measured relative to metaphyseal width, in line with the ulnar corner and perpendicular to the long axis of the radius. Ulnar variance was defined as the distance between the perpendicular to the long axis of the ulna at the tip of the ulnar head and the ulnar corner of the radius. The third metacarpal radial angle was defined as the angle between the long axis of the third metacarpal and the long axis of the radius. Subluxation of the ulnar head was defined as the relative percentage of ulnar head dorsal to radius, compared with the width of the ulnar head. Control x-rays from anonymous normal individuals were used for comparison purposes. Bone age was calculated according to the method of Greulich and Pyle (17).
Heights from 25 women with 45,X Turner syndrome who had received no growth-promoting treatment were used in the comparisons with LWD adults.
Statistics
Continuous variables were compared by unpaired t
test, and dichotomous variables were compared by
2 analysis. Pearson correlations were
calculated to examine the relationship of the variables with age. We
applied a Bonferroni correction for multiple comparisons. Only results
for which the P value was less than 0.001 were considered
statistically significant. However, all observed, unadjusted
P values are presented. Some comparisons with P
values greater than 0.001 would have been significant if they were the
primary endpoints alone.
Results
Molecular analysis of SHOX deletions and mutations
SHOX abnormalities were identified
in all 21 LWD families (Table 1
). Complete gene deletion was
detected by FISH (Fig. 1) in 33 subjects
from 17 unrelated families. Nine of these kindreds had probands with
karyotypic abnormalities, which were the basis for ascertainment for
this study. Five families had probands with normal karyotypes. No
karyotype results were available from three families. One of these
three families had an undiagnosed X;autosome translocation
determined by FISH that was balanced in the mother and unbalanced in
the proband.
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) were
identified in four families by DHPLC and confirmed by DNA sequencing.
Three mutations were novel. One was a frameshift due to deletion of a
single base pair at nucleotide 358, numbering from the translation
start site (Fig. 2, del358A). The frameshift results in a
predicted protein of 128 amino acids lacking the homeodomain. The
mutation was present in a father and daughter (SW386 and SW387) who
both had LWD. Another family had a transversion from A to T at
nucleotide 383, resulting in substitution of leucine for an
evolutionarily conserved glutamine at amino acid 128 within the
homeodomain (Fig. 2, Q128L). This mutation was present in a father with
LWD (SW427) and two affected daughters (SW391, SW425). Another missense
mutation was a transition from T to C at nucleotide 461, which replaces
leucine at residue 154 with proline, also within the homeodomain (Fig. 2, L154P). This substitution would likely alter the secondary structure
of the protein and interfere with DNA binding. This mutation was
present in a mother with LWD (SW343) and her affected daughter (SW344).
The fourth mutation was a nonsense mutation at codon 195 (Fig. 2, R195X), present in a mother with LWD (SW435) and two affected
daughters (SW366, SW367). None of the SHOX point mutations that we
identified were found in unaffected family members or in more than 100
control chromosomes.
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Analyses include examination of the effects of age, gender,
pubertal status (Tanner 1 vs. Tanner 5), and parent of
origin on the LWD phenotype. The clinical features of 43 LWD subjects
(32 females and 11 males) are shown in Table 1
. Phenotypes examined
were height, Madelung deformity, and other TS skeletal features: high
arched palate, increased carrying angle, and scoliosis. Results are
presented as z-scores if age- and gender-specific norms were available.
Numbers are specified for each analysis because evaluations have not
been completed for all subjects. Ages ranged from 3 to 56 yr. Most were
Caucasian, two were African-American, and four were Hispanic. Of 16
adult LWD females, one with a translocation had secondary amenorrhea
and premature ovarian failure. The mean age for onset of menarche in
the postpubertal females was 12.5 ± 1.5 yr. Ten of the adult
women had one or more children.
Analysis of physical features
Height. Age- and gender-specific height z-scores for the LWD subjects ranged from -4.6 to +0.6 SD (mean = -2.2 ± 1.0 SD). Twenty-one subjects (49%) had heights within the normal range (±2 SD). Mean z-score for the ratio of upper segment to lower segment was 2.0 ± 3.3, suggesting short lower limbs. Mean arm span z-score was -2.9 ± 1.0, and the mean height minus arm span was 6.1 ± 4.5 cm, indicating relatively short arms. The mean z-score (age- and gender-adjusted) for right radius length was -2.6 ± 1.0, indicating mesomelia.
The results did not demonstrate any effects of age, gender, pubertal
status, or parental origin of SHOX mutations on height z-score. There
was no correlation between height z-score and chronologic age (r =
0.08; P = 0.63) (Fig. 3).
Thus, height deficits were similar in children and adults. The height
deficits of affected parents and children within the same family were
compared by subtracting the child’s height z-score from the affected
parent’s height z-score. Five families with more than one affected
child were included in the calculations. There was no significant
difference in parents’ and children’s relative heights within
families. The mean difference was -0.3 ± 1.5
SD (n = 19 parent-child pairs),
demonstrating no apparent age effect within families.
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Height deficits were compared for 25 subjects with SHOX abnormalities of known parental origin. The height z-score of subjects with maternally vs. paternally inherited SHOX abnormalities was -2.2 ± 1.0 (n = 17) vs. -1.8 ± 0.6 SD(n = 8), respectively (P = 0.36). The overrepresentation of maternally inherited SHOX abnormalities may reflect cases due to cytogenetic abnormalities that are only transmitted maternally because they are lethal or cause severe developmental delay in males.
Height deficits of LWD subjects with unbalanced translocations (-2.2 ± 1.1 SD; n = 9) were compared with the other LWD subjects (-2.2 ± 1.0 SD; n = 34), and no differences were found (P = 0.90). Lastly, the height deficit in adult LWD females (-2.2 ± 1.1 SD; n = 18) was less than that of untreated adult TS females (-3.1 ± 1.0 SD; n = 25; P = 0.01).
Madelung wrist deformity. Madelung deformity was diagnosed
clinically or radiographically in 32 of 43 (74%) LWD subjects. Results
demonstrated effects of gender, age, and pubertal status on the
severity but not the initial development of the deformity. Wrist x-rays
(Fig. 4) were assessed for the presence
of radial lucency, subluxation of the ulnar head, z-score for carpal
wedging, third metacarpal/radial angle, lunate fossa index, and
SD score of the length of the fourth and fifth metacarpals
(see Subjects and Methods). Results are shown for the LWD
group compared with normal controls, LWD females compared with LWD
males, and Tanner 1 LWD females compared with Tanner 5 LWD females
(Table 2). Multiple measurements differed
between LWD patients and controls, including the presence of
radial lucency (P < 0.02), subluxation of the ulnar
head (P < 0.02), carpal wedging z-score
(P < 0.001), third metacarpal/radial angle
(P < 0.05), and lunate fossa index (P
< 0.008). Radial lucencies were seen in 19 of 39 LWD subjects
vs. 0 of 16 control subjects (P = 0.02). The
relative length (z-score) of the fourth and fifth metacarpals was
similar in LWD and control subjects (Table 2).
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). Radial lucencies were present in 3 of 10 males
vs. 16 of 29 females (P = 0.61). Third
metacarpal/radial angle differed between females and males, suggesting
greater severity of Madelung deformity in females. By contrast, the
fourth and fifth metacarpals were shorter in males. We also examined the relationship of Madelung deformity to pubertal status and, by inference, age because the two are directly related. We compared the measurements in prepubertal Tanner 1 (no breast development) LWD girls vs. mature, Tanner 5 LWD females. The incidence of radial lucencies was similar in children and adults. These results indicate that certain features of Madelung deformity, such as radial lucencies, carpal wedging, and subluxation of the ulnar head, are present in children before puberty, whereas other features, such as lunate fossa index, may progress with pubertal development and increasing age. The number of LWD males was too small to make similar comparisons according to pubertal status of males. Too few x-rays were available for parent of origin analyses for either gender.
The bone ages of LWD patients were assessed. All adults had achieved bone ages of more than 18 yr, indicating epiphyseal fusion. The mean differences in chronologic age minus bone age for girls (n = 13) and boys (n = 6) with bone ages less than 18 yr were 0.3 ± 1.0 and 0.7 ± 0.9 yr, respectively. The numbers were too small to assess developmental changes throughout the childhood years.
Other TS physical features. We also looked at the frequency of other TS-associated features including high arched palate, increased carrying angle, and scoliosis in relation to gender, age, and parent of origin of the SHOX abnormality. The frequency of each respective feature in the LWD population was 59% (24 of 41), 71% (29 of 41), and 22% (9 of 41). High arched palate was present in 55% (17 of 31) of females vs. 70% (7 of 10) of males (P = 0.90). Increased carrying angle was noted in 77% (24 of 31) of females vs. 50% (5 of 10) of males (P = 0.67). Scoliosis was noted in 26% (8 of 31) of females vs. 10% (1 of 10) of males, (P = 0.67). The frequency of these features in LWD females was similar to that of a population of 196 TS (45,X) children and adults (high arched palate, 96%; increased carrying angle, 84%; and scoliosis, 19%; Ross, J. L., unpublished observations). Thus, no significant gender differences were noted for these features. In addition, with the possible exception of high arched palate, the prevalence of these features was similar in LWD and TS.
We compared the occurrence of the above TS-associated features in prepubertal (Tanner 1) LWD children vs. postpubertal (Tanner 2–5) LWD adolescents and adults. Males and females were combined for this analysis because no significant gender differences were seen. High arched palate was present in 12 of 17 prepubertal children vs. 12 of 24 adolescents and adults (P = 0.68). Increased carrying angle was present in 10 of 17 prepubertal children vs. 19 of 24 adolescents and adults (P = 0.73). Scoliosis was present in 0 of 17 prepubertal children vs. 9 of 24 adolescents and adults (P = 0.05). The occurrence of the above features was also compared in parent-prepubertal child pairs. For the three features, six of nine pairs were concordant (both parent and child had or did not have the feature). Three of the adults and none of their prepubertal children had scoliosis. Thus, the developmental trajectory of scoliosis in LWD appears to be similar to that of idiopathic scoliosis.
The occurrence of the above features was also compared in the subjects with a maternally vs. paternally derived SHOX deletion or mutation. High arched palate was noted in 77% (13 of 17) of the maternal group vs. 50% (4 of 8) of the paternal group (P = 0.80). Increased carrying angle was noted in 53% (9 of 17) of the maternal group vs. 50% (4 of 8) of the paternal group (P = 0.77). Scoliosis was noted in 24% (4 of 17) of the maternal group vs. 0% (0 of 8) of the paternal group (P = 0.47). Thus, no significant parent of origin differences were noted for these features, although there was a trend toward more frequent occurrence of high arched palate and scoliosis in subjects with maternal SHOX abnormalities.
Comparison of SHOX point mutations and deletions
Height z-scores of LWD subjects with SHOX point mutations vs. deletions were similar (-2.4 ± 0.8 SD and -2.1 ± 1.1 SD, respectively). Madelung deformity was clinically apparent in 9 of 10 LWD subjects with SHOX mutations vs. 22 of 32 subjects with SHOX deletions. The upper to lower segment ratio z-score was also similar in the two groups (1.1 ± 0.2 SD vs. 1.0 ± 0.2 SD). Height minus arm span was similar (5.3 ± 3.7 vs. 6.1 ± 4.8 cm). The incidence of high arched palate, scoliosis, and increased carrying angle was similar in the two groups.
Discussion
SHOX deletions or mutations were identified in all of our 21 LWD families. We noted mutations in 4 families and deletions in 17 families, similar to the 37.5% mutations and 62.5% deletions recently reported in 16 European LWD families (18). The proportion of families with SHOX abnormalities (100%) was greater than that found by some other studies. This difference may reflect the sensitivity of DHPLC and DNA sequencing to identify point mutations that may have been missed by investigators using other methods such as single-strand conformation polymorphism analysis. One of the mutations (R195X) found in our families was reported by Rao et al. (6) in a subject with idiopathic short stature and also by Clement-Jones et al. (9) and Belin et al. (3) in unrelated LWD patients; thus, it appears to represent a mutational hot spot. SHOX haploinsufficiency alone appears to be responsible for the LWD height deficit as well as the other physical features of LWD because the SHOX point mutations we identified caused similar phenotypes as did complete gene deletions. Conversely, the similarity of the phenotypes suggests that the point mutations are likely loss of function mutations, although a dominant negative effect of R195X cannot be ruled out (19).
We also investigated the potential impact of gender, age, and parent of origin on height of LWD patients and found no significant effects. Interestingly, unlike height, the metacarpals were relatively shorter in LWD men than women, suggesting that gender differences in proportions may be accentuated by SHOX deficiency. The role of imprinting in TS is controversial. Skuse et al. (20) reported differences in the social skills of 45,X TS girls depending upon the parental origin of the single X chromosome. Most researchers have not found imprinting of any TS physical features such as stature. Likewise, we did not detect statistically significant parent of origin effects on the LWD phenotype.
These results are based on a relatively small population subject to ascertainment bias and may not be conclusive. Short stature was found in most subjects, including prepubertal children, but nearly half had heights within the normal range (±2 SD), indicating that severe short stature is not universal. The mean height deficit (-2.2 SD) was less than the height deficit generally observed in TS (-3.2 SD) (11, 21), suggesting that SHOX haploinsufficiency is responsible for approximately two thirds of the height deficit (SD) observed in TS. This would imply that other loci also contribute to the growth impairment in TS. We previously found evidence for a TS height locus in Xp11.2-p22.1, proximal to the pseudoautosomal region (11).
The ratio of females to males in our population was 3:1, demonstrating the female preponderance of LWD. Surprisingly, males and females had similar height deficits, although the Madelung deformity appeared to be more frequent and severe in females. These preliminary results must be interpreted with caution and could be due to under-diagnosis of LWD males or other ascertainment bias. Our results contrast with a previous report that patients with SHOX deficiency and overt dyschondrosteosis show worsening height deficits after puberty (22). Others have suggested that estrogen action is important in the development of dyschondrosteosis (7, 22). Consistent with this hypothesis, there is a reported 4:1 female to male predominance of dyschondrosteosis, and within families, dyschondrosteosis appears to be more common and severe in females (2). Recently, estrogen has been shown to accelerate the programmed senescence of the growth plate, causing earlier fusion (23). Estrogen could have asymmetric effects on the growth plate by interacting with specific SHOX deficient areas.
Madelung deformity was common but not universal in LWD subjects. Curiously, Madelung deformity is relatively uncommon (7%) in TS (24), although virtually all TS females have SHOX haploinsufficiency and short stature. The reasons for the low prevalence of Madelung deformity in TS are not clear. One explanation may be that estrogen exposure influences the development of Madelung deformity. TS girls could be protected from developing Madelung deformity by their sex steroid deficiency, whereas LWD females generally have normal ovarian function. Evidence against this hypothesis is the fact that Madelung deformity was found in some of our prepubertal female and male LWD patients. Radial lucencies, which appear to be an antecedent of the Madelung deformity, were detected in females and males as young as age 3 yr. Furthermore, the deformity does not seem to develop in TS females treated with estrogen before epiphyseal closure (Ross, J. L., unpublished observations). Finally, the SHOX gene is expressed in limbs during early fetal development (9), at which time there is a relatively high circulating estrogen level, but dyschondrosteosis is usually not clinically apparent until adolescence.
An alternative hypothesis to explain the paucity of Madelung deformity in 45,X TS is that modifying effects of loss of nonpseudoautosomal growth genes ameliorate the asymmetric radial growth abnormality that gives rise to Madelung deformity (7). It would be interesting to determine the incidence of radiographic changes such as radial lucency in 45,X TS. Comparisons of the incidence of Madelung deformity and radiographic forme frustes in TS subjects according to karyotype or spontaneous puberty may also help establish the importance of genetic vs. hormonal factors in the etiology of this abnormality.
Our data demonstrated clinical overlap between TS and LWD, consistent with SHOX haploinsufficiency in both disorders. The frequency of skeletal features such as high arched palate, increased carrying angle, and scoliosis was similar in the two groups. Even within these groups, there is considerable phenotypic variability, for unknown reasons. Unfortunately, there is no mouse model for SHOX haploinsufficiency. Thus, humans represent the best system for understanding the role of SHOX in normal and abnormal growth and development.
There are several prevailing notions about LWD phenotypic variability and SHOX deficiency that require further scrutiny. They include: 1) LWD is sex limited, i.e. more common and more severe in females; and 2) puberty or adolescence somehow accentuates LWD features such as Madelung deformity. Our data would confirm that LWD is more common in females, but the males were just as short as the females. This would suggest that males are underdiagnosed and may be part of the idiopathic short stature population in childhood. Careful anthropometric measurements would perhaps permit earlier diagnosis of LWD in affected males. Jackson (25) previously reported that an abnormally low ratio of forearm to upper arm length may be a valuable diagnostic clue. Family history would also provide a clue to the diagnosis because all of the SHOX abnormalities that we observed in males were familial. Second, estrogen may impact on the severity of the Madelung deformity, but its antecedents are present very early in childhood, in both males and females. Most likely, estrogen exposure accentuates the dynamic bony malformation that occurs. Longitudinal studies of a larger population that includes presymptomatic carriers will clarify these issues. In summary, SHOX haploinsufficiency gives rise to LWD and a subset of features of TS. Similarities and contrasts between these two disorders provide insight into the roles of X-linked genes and estrogen on normal bone growth and development.
Acknowledgments
Footnotes
This study was supported in part by NIH Grants NS35554, NS32531, and NS42777.
Abbreviations: DHPLC, Denaturing HPLC; FISH, fluorescence in situ hybridization; LWD, Leri-Weill dyschondrosteosis; SHOX, short stature homeobox-containing gene; TS, Turner syndrome.
Received May 3, 2001.
Accepted July 18, 2001.
References
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M. Roubicek, M. C. Arriazu, and G. Isaac SHOX Deficiency Phenotypes J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 4004 - 4004. [Full Text]
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R. G. Rosenfeld Author's Response: SHOX--A Geneticist's View J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1912 - 1912. [Full Text] [PDF]
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G. Rappold SHOX: A Geneticist's View J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1911 - 1912. [Full Text] [PDF]
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R. G. Rosenfeld EDITORIAL: A SHOX to the System J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5672 - 5673. [Full Text] [PDF]
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