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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4403-4408
Copyright © 2004 by The Endocrine Society

SHOX Haploinsufficiency and Leri-Weill Dyschondrosteosis: Prevalence and Growth Failure in Relation to Mutation, Sex, and Degree of Wrist Deformity

Gerhard Binder, Alexandra Renz, Alicia Martinez, Ana Keselman, Volker Hesse, Stefan W. Riedl, Gabriele Häusler, Susanne Fricke-Otto, Herwig Frisch, Juan Jorge Heinrich and Michael B. Ranke

Section of Pediatric Endocrinology (G.B., A.R., M.B.R.), University Children’s Hospital Tübingen, 72076 Tübingen, Germany; Division de Endocrinologia (A.M., A.K., J.J.H.), Centro de Investigaciones Endocrinologicas, Hospital de Ninos R. Gutierrez, 1330 Buenos Aires, Argentina; Children’s Hospital Berlin-Lichtenberg (V.H.), 10365 Berlin, Germany; Department of Pediatrics (S.W.R., G.H., H.F.), University of Vienna, 1090 Vienna, Austria; and Children’s Hospital Krefeld (S.F.-O.), 47805 Krefeld, Germany

Address all correspondence and requests for reprints to: PD Dr. Gerhard Binder, Section of Pediatric Endocrinology, University-Children’s Hospital, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany. E-mail: gdbinder{at}med.uni-tuebingen.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1–18.3), mean height SD score (SDS) (SD in parentheses) was –2.85 (1.04), and mean sitting height/height ratio SDS was +3.06 (1.09). Mean birth length SDS was –0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3–11.3) was insignificant with a mean change in height SDS of –0.10 (0.52). Mean height SDS of affected parents was –2.70 (0.85) vs. –0.91 (1.10) in unaffected parents. Height loss due to LWD was estimated calculating delta height defined by actual height SDS minus target height SDS of the unaffected parent(s). In the children, mean delta height SDS was –2.16 (1.06), the loss being greater in girls at –2.30 (1.02) than in boys at –1.72 (1.09) (P = 0.32). In patients with SHOX deletions, it was –2.14 (1.15) vs. –1.67 (0.73) for the SHOX point mutation group (P = 0.38). Mean delta height SDS was –2.26 (0.68) for the girls with early menarche (<12 yr) vs. –2.08 (0.91) for the other postmenarcheal girls (P = 0.72). Height loss in patients with radiologically severe wrist deformities in comparison with those having milder radiological signs was –2.81 (1.01) vs. –1.70 (1.04) (P = 0.03). GH treatment in five children during a median duration of 3.4 yr (range, 1.5–9.8 yr) with a median dosage of 0.23 mg/kg·wk (range, 0.14–0.25) resulted in a mean height SDS gain of +0.82 (0.34).

In conclusion, SHOX defects were the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of type of mutation, age of menarche, or sex on height were observed. The effect of GH therapy varied between individuals and needs to be examined in controlled studies.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HETEROZYGOTE MUTATIONS OF the pseudoautosomal SHOX (short stature homeobox-containing gene) (1) causing haploinsufficiency have been reported in patients with Leri-Weill dyschondrosteosis (LWD) (2, 3, 4, 5), an osteochondrodysplasia with mesomelic short stature and Madelung deformity of the wrist (6). The prevalence of this osteodysplasia due to SHOX defects has been estimated to be high (1:2000) (7, 8). The phenotype is highly variable and includes presentations without clinical signs of Madelung deformity and normal height (7, 8). SHOX is preferentially expressed in osteoblasts and can be detected in the human embryo from the second month of gestation (9). Alternative splicing generates two proteins, of which the nontruncated SHOXa was shown to induce gene transcription in vitro (10). Its exact role in the regulation of bone ontogeny, bone metabolism, and growth is unknown (11). SHOX mutations were reported to be present in 55–100% of individuals with LWD, the majority being complete deletions of the gene, whereas diverse point mutations accounted for the remainder (4, 5, 12, 13, 14). Females are more frequently affected than males (7, 12), and growth failure seems to be more severe in females than in males (6), with the underlying mechanisms still unknown.

The aim of this study was to determine the prevalence of SHOX mutations in a group of children with LWD who, in contrast to earlier studies (12, 15), were not affected by structural aberrations of sex chromosomes. We investigated the degree of growth failure in relation to the type of SHOX mutation, age, sex, degree of wrist deformity, and age of menarche. In addition, the effect of GH therapy was retrospectively analyzed in a small subgroup of children.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Individuals

In this study, children who presented with bilateral Madelung deformity and shortening of the limbs at one of the study centers during the last 7 yr were included. All parents involved agreed to participate in this study after informed consent. The total group comprised 20 families (nine from Germany, seven from Argentina, and four from Austria) with 24 affected children (18 females) and nine affected parents (seven females). A total of 20 siblings of the affected children (nine females) showed no clinical and/or radiological signs (left hand radiography) of Madelung deformity and LWD. Blood for molecular analysis was drawn from the affected children and the affected parents. DNA analysis of healthy parents was performed when microsatellite typing of the affected child was suggestive of SHOX deletion. Five children were treated with recombinant GH on the basis of individual therapeutic trials at their home center. Their auxological data were excluded when the spontaneous growth was analyzed. The children’s group contained four male-female sibling pairs. Karyotyping from blood lymphocytes was normal except in patient 8 who had a known benign variant (46,XX, 9qh+). Auxological and clinical data were collected by a structured clinical questionnaire, which was sent to each center. In addition, growth charts of the majority of patients (n = 19) were available. Auxological measurements are given in SD scores (SDSs), height and sitting height according to Prader (16), sitting/height ratio according to Gerver (17), and birth length according to Niklasson (18). The data are summarized in Table 1Go. For the sporadic cases (n = 11), the mean height SDS of both parents was taken as familial target height. For the familial cases (n = 13), target height was calculated by halving of the height SDS of the unaffected parent.


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  		TABLE 1. Clinical and genetic characteristics of the children studied

 
Radiographs of the left hand were available for analysis from 20 children (16 girls and four boys). As a measure of severity of Madelung deformity, the clear presence of radiographic radial lucency in the ulnar border of the distal radius and a severe degree of triangularization of the distal radial epiphysis were used as previously described (19).

Materials

Genomic DNA was extracted from blood lymphocytes. Two highly polymorphic microsatellite markers located on Xp22.3 around the SHOX locus were PCR amplified with fluorescent primers and separated in an automatic sequencing machine as described previously (20): the CA-SHOX repeat located directly distal to SHOX and the DXYS233 around 300 kb proximal to SHOX (21). Analysis of parental DNA was performed if only one fragment size of each of both telomeric markers was present. This analysis was informative in all cases studied and enabled us to differentiate between homozygosity (two alleles with identical size) and hemizygosity (loss of one allele).

PCR direct sequencing was performed in all cases without a SHOX deletion. For this purpose, genomic DNA was amplified by PCR and sequenced with the Thermo Sequenase cycle sequencing kit containing 7-deaza-dGTP. Exons 2–6a were amplified using primers published previously (22). The reaction was performed according to the manufacturer’s recommendations (Amersham Pharmacia Biotech, Freiburg, Germany). The sequencing primers were labeled with IR-800 fluorescent dye. The products were run and analyzed on a Li-COR DNA sequencer 4200 by DNASIS version 2.5 software (LI-COR, Lincoln, NE). Statistical analysis was performed with the Student’s t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In 14 of 20 families (70%), a SHOX mutation was detected: seven deletions (four of seven de novo) and seven point mutations (one of seven de novo) (Fig. 1Go). In the sporadic cases, SHOX deletions were most frequent (four of five) and the majority of the mutant alleles were transmitted from the father (four of five). By contrast, in the familial cases, the mutant alleles were predominantly transmitted from the affected mother (seven of nine) and point mutations were more frequent than deletions (six of nine). A novel nonsense mutation (E102X) in exon 3, which is predicted to result in truncation with total loss of the homeodomain, was found. This mutation was based on a transversion from G to T at nucleotide 304 and was found in two affected siblings and their affected father. Another novel point mutation, a transition from T to C at nucleotide 877, affected the stop codon (X293R) and is predicted to elongate the SHOX with the addition of 48 extra amino acids at the C-terminal end. This mutation was detected in an affected boy and his affected mother.



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  		FIG. 1. Schematic diagram of the SHOX mutations detected.

 
The missense mutations found comprised one known (R173H due to 518G->A) (23) and four novel missense mutations of the SHOX homeobox, which presumably cause loss of function. The four novel missense mutations were in detail. 1) A C-to-G transversion was at nucleotide 355 in exon 3, which was detected in two affected siblings and their mother. This transversion is predicted to change the charged polar amino acid arginine into the nonpolar amino acid glycine at the beginning of the homeobox (R119G). 2) A G-to-C transversion at nucleotide 401 in exon 3 was found in the affected mother and daughter. This transversion is predicted to result in a change inside the homeodomain sequence from arginine into the nonpolar amino acid proline (R134P). 3) A third missense mutation found in exon 3 was a T-to-C transition of nucleotide 482 in the affected daughter and her mother. This transition is predicted to change the nonpolar amino acid valine into the nonpolar amino acid alanine (V161A). 4) A C-to-T transition of nucleotide 502 in exon 4 was detected in the affected daughter and her mother. This mutation results in substitution of the nonpolar amino acid tryptophan for the polar amino acid arginine at the end of the homeodomain (R168W). All four novel mutations affect highly evolutionarily conserved amino acids of the homeodomain in the SHOX protein (23) and presumably cause loss of function by altering the secondary structure of the protein and interference with DNA binding. None of the above missense mutations were found in unaffected family members (n = 3) or controls (n = 4).

Median age of the 24 children studied was 13.4 yr (range, 6.1–18.3), mean height SDS (SD) –2.85 (1.04), and mean sitting height SDS –1.36 (1.29). Sitting height to height ratio was high with a mean SDS of +3.06 (1.09), indicating skeletal disproportion with shortening of the legs. Mean birth length SDS was reduced with –0.59 (1.26) (n = 17). Additional height measurements from the past years were available for 18 children, five of whom were treated with GH; at a median age of 4.5 yr (range, 2.0–14.4), mean height of the untreated children was –2.92 (1.05). During a median follow-up of 7.4 yr (range, 2.3–11.3), the mean height SDS change of these untreated children was insignificant at –0.10 (0.52). This phenomenon is also illustrated in Fig. 2AGo, which shows all available growth curves of the affected girls (n = 9) parallel to the third percentile. The growth pattern of the untreated boys was identical (data not shown). There was no difference in the mean height deficit between the affected children and the affected parents, who had a mean height SDS of –2.70 (0.85). The mean height SDS of the unaffected parents were below average with –0.91 (1.10) reflecting the phenomenon of assortative mating in the group of parents studied.



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  		FIG. 2. Growth charts showing the spontaneous growth of nine girls with LWD (A) and the growth of four girls with LWD treated with GH (B). The individual start of treatment is indicated by the arrow. The median height for age is indicated by the dotted line, and the normal variation between the third and 97th percentile by the shaded area, both according to Prader et al. (16 ).

 
For estimation of the height loss due to SHOX haploinsufficiency and LWD, actual height minus target height of the unaffected parent(s) was calculated and defined as delta height. Mean delta height SDS of the total group of affected children was –2.16 (1.06). It was –2.30 (1.02) for the girls vs. –1.72 (1.09) for the boys (P = 0.32). The comparison of the four male-female sibling pairs gave similar data, indicating a more severe growth failure in the girls with a mean delta height SDS of –2.04 vs. –1.05 of their brothers (P = 0.28). Mean delta height SDS of the adolescent girls with early menarche (≤12 yr) (n = 5) was not different from those with normal puberty (n = 6): –2.26 (0.68) vs. –2.08 (0.91) (P = 0.91). Mean delta height SDS was –1.67 (0.73) in the SHOX point mutation group vs. –2.14 (1.15) in the SHOX deletion group (P = 0.38). The Argentine children were overrepresented (four of five cases) in the SHOX mutation-negative group, which had a mean delta height SDS of –2.86 (1.03).

Mean delta height of the children with severe radiological signs of Madelung deformity (n = 9) was significantly lower at –2.81 (1.01) vs. –1.70 (1.04) in the group with milder signs (n = 11) (P = 0.03). Three of the four boys whose radiographs were available had only mild deformities of their wrist. The additional physical clinical signs of cubitus valgus, short fourth metacarpal, and high arched palate were more frequent than in normal children, the frequency of each feature was 12, 25, and 21%, respectively.

Five children (four females) who all carried a SHOX mutation had been treated with recombinant GH with a median dosage of 0.23 mg/kg·week (range, 0.14–0.25) during a median of 3.4 yr (1.5–9.8) in two of the four centers involved in this study. Mean height gain was 0.82 (0.34) SDS. Figure 2BGo shows the growth curves of the four girls treated with GH.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The molecular, clinical, and radiological characteristics of a cohort of 24 children who were selected because of the presence of bilateral Madelung deformity and shortening of the limbs defining LWD have been described. The majority (79%) of these children were short, having a height below –2.0 SDS. Molecular analysis revealed SHOX deletions in seven families (35%) and point mutations in seven families (35%), leaving LWD in six families unexplained (30%). Similar percentages of unexplained LWD (22–45%) were found by other research groups who excluded children with abnormal karyotype from their analysis (4, 5, 13, 14). Linkage studies support the existence of at least one additional gene locus contributing to LWD (5). We could not detect any significant clinical difference between the LWD individuals having SHOX point mutations, deletions, or no mutations in our analysis. Interestingly, in the SHOX mutation-negative group, the Argentineans comprised five of the six families, leaving the majority of the Argentine cases unexplained (62%). This may indicate that the prevalence of SHOX mutations that affect the coding region in LWD is different in Argentina in comparison with those in other countries. One may speculate that in these individuals, regulatory elements of SHOX or unknown genes encoding proteins involved in the regulatory pathway of SHOX are affected.

We detected six novel mutations of the SHOX: four missense mutations changing highly conserved amino acids of the homeodomain, one nonsense mutation truncating SHOX, and one mutation of the stop codon adding 45 extra amino acids to SHOX. These mutations add to the spectrum of functional SHOX mutations, which comprise structural defects of the homeodomain, C-terminal truncation, or elongation of the SHOX protein (8). In the sporadic cases, deletions of SHOX were predominant and the majority of the mutant alleles were transmitted from the father. The latter phenomenon was also observed in a previous study on SHOX mutations in unexplained short stature (7). Recently, it was shown by genotyping of single human sperms that the recombination fraction of that pseudoautosomal interval on the Y chromosome that contains SHOX is 31 times higher than the genome average (21). Such a high recombination fraction could explain a preferential instability of the SHOX locus during male meiosis.

Previous studies gave different estimates on the mean height deficit due to SHOX defects. On the basis of 21 LWD families from the United States, Ross et al. (12) estimated this deficit to be –2.20 SDS, which equalled the calculated mean height of the 42 individuals affected. Similar height deficits were reported by Grigelioniene et al. (13), who studied 28 Scandinavian individuals affected by LWD and found a mean height SDS of –2.10. The mean height SDS of our study group was lower at –2.85. However, when calculating height deficits it is crucial to take assortative mating in partnerships of short individuals into account, which implies that unaffected partners are frequently short as well. In our study, the mean height of the unaffected parents was –0.91 SDS. Therefore, delta height calculations that correct for this influencing factor seem to give a more accurate estimate of the height deficit caused by SHOX defects. Accordingly, the calculated mean height deficit caused by LWD was –2.16 SDS in this study. Taking the data of the three above studies together, the mean growth deficit caused by SHOX defects is approximately 2 SDS in height. This is the equivalent of two thirds of the height loss in Turner syndrome (24, 25). This comparison may indicate that haploinsufficiency of a second unknown gene or effects of aneuploidy may contribute to the short stature phenotype in Turner syndrome.

Influences of different parameters on growth retardation due to SHOX haploinsufficiency have been postulated, but conclusive data are missing (15). Our study shows a tendency for female sex being associated with a more severe growth failure, but the analysis did not reach statistical significance because of the low number of boys available. In contrast, we found a significant positive correlation of the degree of height deficit and the severity of wrist deformity as defined by the presence or absence of radiological signs. The presence of a clear radiological lucency of the distal radius and the severe degree of triangularization of the distal radial epiphysis (19) resulted in a poorer prognosis in comparison with individuals who had only mild radiological signs. Interestingly, most of the boys with LWD studied had only mild radiological changes. This observation is an agreement with the first descriptions of families with LWD. However, because genetic analysis was restricted to the clinically and radiologically affected children in this study, we cannot completely exclude that siblings of the affected with a milder LWD phenotype stayed undiagnosed.

According to our longitudinal data, growth failure in LWD occurred before the age of 6 yr, partly already before birth. Growth velocity after the age of six was normal with no additional height loss. The absence of a detectable additional height loss during puberty was also suggested by the fact that the mean height of the affected parents equaled those of the affected prepubertal children. Similar data were reported by Ross et al. (12). This finding is somewhat surprising because osteodysplasias affecting the long bones are frequently associated with a shortened and weakened growth spurt during puberty (26). Girls with Turner syndrome also lose more than 1.0 SD of height during induced puberty (27, 28). We cannot completely exclude that some loss of height occurred during the last 3 yr of growth in LWD because longitudinal data on this time span were sparse in this study. However, the above findings indicate that this height loss should be of minor importance. Therefore, our data suggest that the disturbance of growth during puberty is not as severe as in other osteodysplasias or in Turner syndrome. This fact may contribute to the observed height difference between adult females with LWD and females with Turner syndrome.

The clear genetic and clinical relationship between short individuals with Turner syndrome and those with LWD having SHOX haploinsufficiency has led to the use of recombinant GH for growth promotion in LWD (20, 29). The data collected here on individual therapeutic trials are the first presentation of long-term data on a GH-treated cohort. However, the children did not take part in a randomized study, and therefore, results should be interpreted with caution. The mean height gain of 0.82 SD may underestimate the therapeutic potential of recombinant GH because 1) three of the five children started GH therapy at a pubertal age, which may be too late and 2) the GH dosages used were in all five cases below the recommended ones for growth-promoting therapy in Turner syndrome.

SHOX defects were confirmed to be the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS, whereas pubertal growth seemed to be only mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of sex, type of mutation, or age of menarche on height were observed. The effect of GH therapy varied individually and needs to be further examined in controlled studies.


   Acknowledgments
 
We thank C. Urban for technical assistance in molecular analysis as well as E. Erdmann-Schwarze and C. P. Schwarze for language editing.


   Footnotes
 
Abbreviations: LWD, Leri-Weill dyschondrosteosis; SDS, SD score.

Received March 29, 2004.

Accepted June 8, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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