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Deletions of the Homeobox Gene SHOX (Short Stature Homeobox) Are an Important Cause of Growth Failure in Children with Short Stature

Institute of Human Genetics (G.A.R., M.F., B.N., S.S.) and Department of Pediatrics (M.B., U.H.), University of Heidelberg, 69120 Heidelberg, Germany; Children’s University Hospital (W.Z.), 06097 Halle, Germany; Department of Growth and Development, University of Athens (E.V.), 11527 Athens, Greece; Vestische Kinderklinik, University of Witten/Herdecke (T.R.), 45711 Datteln, Germany; Department of Pediatrics, Gunma University School of Medicine (K.O.), 371-8510 Maebashi City, Japan; and Department of Pediatrics, Keio University School of Medicine and Tokyo Electric Power Co. Hospital (T.O.), 160-0016 Tokyo, Japan

Address all correspondence and requests for reprints to: Dr. Gudrun A. Rappold, Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany. E-mail: . gudrun_rappold{at}med.uni-heidelberg.de

Abstract

Short stature, with an incidence of 3 in 100, is a fairly frequent disorder in children. Idiopathic short stature refers to patients who are short due to various unknown reasons. Mutations of a human homeobox gene, SHOX (short stature homeobox), have recently been shown to be associated with the short stature phenotype in patients with Turner syndrome and most patients with Léri-Weill dyschondrosteosis. This study addresses the question of the incidence and type of SHOX mutations in patients with short stature. We analyzed the SHOX gene for intragenic mutations by single strand conformation polymorphism, followed by sequencing, in 750 patients and for complete gene deletions by fluorescence in situ hybridization in 150 patients (total, 900 patients). This is the largest group of patients with short stature studied to date for SHOX mutations. All patients had a normal karyotype, and their height for chronological age were below the third percentile or minus 2 SD of national height standards. All were without obvious skeletal features reminiscent of the Leri-Weill syndrome at the time of diagnosis.

Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype- phenotype relationship for the parents and normal control individuals. We conclude that SHOX mutations have been detected in 2.4% of children with short stature. The spectrum of SHOX mutations is biased, with the vast majority leading to complete gene deletions. The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of GH deficiency or Turner syndrome. Family studies of the children with SHOX mutations often reveal older family members with same mutation who exhibit mild skeletal features reminiscent of the Turner syndrome, such as high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, and Madelung deformity.

THE ETIOLOGY OF growth failure is unknown for many children with short stature. As a familial tendency to short stature is often present, genetic factors are presumed to explain short stature in many of these children. An unresolved question is the extent to which unrecognized monogenic disorders may underlie the growth failure in cases currently regarded as idiopathic.

During the past 4 yr the SHOX (short stature homeobox) gene, located in the pseudoautosomal region of the X and Y chromosomes, has been implicated in the short stature of Turner syndrome (1, 2) and Léri-Weill dyschondrosteosis (LWD) (3, 4). LWD is a syndrome of mesomelic short stature with a characteristic forearm skeletal abnormality termed Madelung deformity (3, 4, 5). SHOX haploinsufficiency has been found in both syndromes, in Turner syndrome most commonly due to loss of an X chromosome (45,X) and in more than 60% of LWD patients due to deletions or point mutations of the SHOX gene (3, 4, 6, 7, 8, 9, 10, 11, 12). There is an overlap in the skeletal anomalies of Turner syndrome and LWD (13), but not in the other features of Turner syndrome, such as ovarian failure, lymphedema, and heart and renal abnormalities (14).

Although involvement of SHOX deficiency in Turner syndrome and LWD is well documented, only limited data are available on the role of SHOX mutations in patients with isolated short stature. Rao et al. (1) carried out single strand conformation polymorphism (SSCP) analysis and described 1 of 91 patients who had a nonsense mutation in exon 5 of the SHOX gene that segregated with the short stature phenotype in family members. Binder et al. (15) performed fluorescence in situ hybridization (FISH) and described 1 in 68 patients with short stature and a deletion of the SHOX gene.

To obtain a more comprehensive assessment of the incidence and type of SHOX mutations in patients with short stature, we analyzed the SHOX gene region by SSCP and FISH, as the two methods have a different mutation detection range. The results of this study of 900 short children show that SHOX mutations are found in 2.4% of the patients with short stature.

Subjects and Methods

Patients

Nine hundred patients of both sexes with idiopathic short stature (ISS) were recruited using the following criteria: height for chronological age below the third percentile or minus 2 SD of national height standards; no specific known causative disorders, including skeletal dysplasia and gonadal dysgenesis; normal food intake; and normal karyotype. The patients with short stature were from 3 different countries (Japan, Germany, and Greece). From a total of 900 patients, 623 were of Japanese origin (provided by Dr. Ogata and colleagues), 249 were of German origin (provided by Drs. Zumkeller, Heinrich, Bettendorf, and Reinehr), and 28 were of Greek origin (provided by Dr. Vlachpapadopoulou). Seven hundred and fifty patients were screened by SSCP, and 150 patients were screened by FISH. This was due to the fact that some clinicians provided DNA and others metaphase spreads of chromosomes. From the population of 750 patients, 474 were male, and 276 were female. From the population of 150 patients, 79 were female, and 71 were male. Both populations were in a comparable age range. All short children were unrelated and were seen by endocrinologists. At the time of blood sampling a complete clinical history was obtained from all patients. The study was approved by institutional review boards. Informed consent was obtained from all patients and legal guardians. The DNA of 100 individuals with normal height, normal karyotype, and no specific disorders was used as a control.

Mutation analysis by SSCP

DNA was extracted from peripheral blood lymphocytes using standard protocols. PCR and SSCP analysis were performed as previously described (1, 16). Primer pairs were previously described (1, 10). In total, eight different PCR amplifications were carried out per individual patient DNA. This covers the entire protein-coding region of SHOXa as well as part of the 5'-untranslated region (exons 2–6a).

Cloning and sequencing of PCR products

PCR products were cloned into pCR2.1-TOPO vector (Invitrogen, San Diego, CA). Sequencing of three independent clones for each allele was carried out by the cycle sequencing method (ThermoSequenase Kit, Pharmacia Biotech, Piscataway, NJ) and analyzed on an ALFexpress automated sequencer (Pharmacia Biotech) as previously described (1).

FISH analysis

Biotinylated cosmid DNA of cosmid LLNOYCO3'M'34F5 was hybridized to metaphase chromosomes from stimulated lymphocytes of patients under conditions previously described (17). The hybridized probe was detected via avidin-conjugated fluorescein isothiocyanate.

Results

Seven hundred and fifty patients with short stature were screened for intragenic mutations in the SHOXa-coding gene region, which extends over 5 exons (exons 2–6a). Novel mutations were identified in exons 2 (A-337G, C37T, and C64G) and 6a (G761A), which encodes an A224T substitution, and delC776-G787, which produces deletion of 4 amino acids, H229–L232. These mutations (except for A-337G) were not seen in 100 control individuals with normal height. The mutations were confirmed by digestion of the respective PCR products with AluI (in the case of A-337G), Hin6I (C37T), SmaI (C64G), and DdeI (C674T), whereas a native AccII restriction site was destroyed in the G761A mutation. All mutations in female patients (A-337G, C37T, C674T, and G761A) were heterozygous for the different mutations. The previously identified mutation C674T (R195X) was found in 2 individuals with ISS (see Table 1). Based upon the genotype-phenotype relationships for the parents, at least 3 functional intragenic mutations were found by studying 750 patients using SSCP (0.4%). We assigned functionality of a mutation based upon genotype-phenotype correlation among patient and parents and control individuals with normal height. Both parents were not available in all cases. However, 4 of the 6 mutations resided in the noncoding part of the gene and were not translated into protein. The 2 mutations in exon 6a were also detected in individuals with normal height. Therefore, there is good reason to assume that 6 of the mutations are indeed nonfunctional polymorphisms.

Compiling these data with data from our and other laboratories on the mutation spectrum detected in patients with LWD, additional, more general features emerge (see Table 2). The phenotype of the children with complete SHOX deletion does not differ from the phenotype of patients with point mutations. There is no noticeably increased frequency of mutations in the homeobox region compared with the rest of the gene. Instead, mutations seem to be spread across the entire gene. Mutations within the SH3 domain binding site or orthopedia aristaless rax domain coding regions have not been found to date (Fig. 1). In addition, nonsense mutations leading to protein truncation are the prevailing intragenic mutation type and are found in about two thirds of the cases (Table 2). The C674T mutation is the most frequent point mutation, leading to the codon R195X and a protein chain termination, and was seen in four patients with ISS and LWD (Fig. 1 and Table 2).

View larger version (15K): [in this window] [in a new window]   Figure 1. Summary of the presently known SHOX point mutations in patients with ISS and LWD. The coding region of SHOXa consists of five exons and is indicated in gray; the untranslated regions are hatched. The homeodomain, the SH3 domain binding site, and the orthopedia aristaless rax (OAR) domain encoding regions are indicated in light, middle, and dark gray, respectively. The introns are not drawn to scale. Functional mutations are marked by filled symbols, and polymorphisms by open symbols. Data are from this report (A-337G, C37T, C64G, C674T, G761A, del C776-G787) and those of Rao et al. (1 ) (C674T), Belin et al. (3 ) (C674T), Shears et al. (4 ) (C688G), Clement-Jones et al. (13 ) (C674T), Grigelioniene et al. (11 ) (272delG, C485G, G549T), Flanagan et al. (29 ) (GT-IVS-AG, C674T), and Huber et al. (12 ) (197–198delCG, C425T, G536T, 572insGT, C608T).

The SHOX gene belongs to a family of transcriptional regulators that are major controllers of developmental processes. Orthologs of SHOX are present in chicken (Blaschke and Rappold, unpublished observations), fish (18), and other vertebrates (13), suggesting that this gene plays a fundamental role in development. In human embryos the earliest evidence of SHOX gene expression was in the developing limbs from 32 d postconception onward (13).

The SHOX gene has been shown to escape X inactivation, and both alleles are expressed on the active and inactive X and Y chromosomes (1, 2). Over the last few years it has become clear that SHOX haploinsufficiency results in the dominant phenotype of short stature and sometimes in other skeletal abnormalities, such as the Madelung deformity (19). Inter- and intrafamilial heterogeneities are frequent findings, and phenotypic manifestations of disease are generally more frequent and more severe in females. Because the underlying principle in haploinsufficiency syndromes is the disturbance of a delicately balanced temporal and spatial expression, variations in the expression level may explain the variable severity in the manifestations of SHOX mutations. The observation that an identical mutation in SHOX can give rise to either the LWD syndrome or the ISS phenotype also suggests complex genetic and phenotypic heterogeneity in the SHOX phenotype. Modifier genes, epigenetic interactions, and stochastic effects are hypothesized to explain these phenomena.

Although SHOX mutations are found in 60–100% of patients with signs of LWD, our study has demonstrated that 2.4% of short patients free from obvious skeletal deformity also present a functional SHOX mutation. Of these 2.4%, 2.0% were complete gene deletions, and 0.4% were intragenic mutations. How does the prevalence of SHOX mutations compare with that of other established causes of growth failure? The presence of SHOX mutations in 2.4% of ISS patients would imply a population prevalence of at least 1 in 2000 children. By contrast, classic GH deficiency is established to be present in 1 in 3500 children, and Turner syndrome in 1 in 2500 girls or 1 in 5000 children (14). Thus, the prevalence of short stature due to SHOX gene deletion among children with ISS appears to be similar to that of GH deficiency or Turner syndrome.

We are aware that a certain proportion of cases with mutations might have escaped detection by our analysis. For SSCP, the sensitivity to detect mutations is estimated to be 80%. Moreover, it may not always be the transcription unit that bears the defect. Clearly, the spectrum of SHOX mutations in patients with ISS and LWD is highly biased, with the majority leading to large complete gene deletions (3, 4, 7, 10, 20). Although large deletions in chromosomal DNA are generally rare, the high incidence of SHOX deletions is easily comprehended from the preponderance of tandem or interspersed repeats in the pseudoautosomal region (21).

Interestingly, the prevalence of skeletal abnormalities in SHOX haploinsufficiency seems to increase with age. One of the patients (J451), for example, was without skeletal features at 7 yr of age, but presented a borderline cubitus valgus and Madelung deformity 4 yr later during puberty. This is consistent with the hypothesis that gonadal estrogens accentuate deformity by unbalanced premature fusion of growth plates in patients with SHOX haploinsufficiency. This effect may facilitate skeletal lesions in a female-dominant and pubertal tempo-influenced fashion (7).

A significant conclusion from the data presented here and previous reports is the lack of correlation between the type and position of a mutation within the gene and the resulting phenotype. Similarly, entire gene deletions or intragenic SHOX-null mutations manifest no phenotypic differences. The molecular basis of SHOX-associated short stature is therefore caused by the loss of function of one allele, resulting in a 50% reduction of overall activity (haploinsufficiency). Moreover, homozygous SHOX mutations lead to the striking phenotype of Langer dwarfism (3, 4), whereas SHOX overdosage in, for example, Klinefelter syndrome has been suggested to cause or contribute to the long limbs and tall stature (22).

Over the past 10 yr, clinical studies have demonstrated that recombinant GH is effective and generally safe in increasing the final height of children with Turner syndrome (23, 24, 25, 26, 27). The major cause of short stature in Turner syndrome and other patients with SHOX defects with or without skeletal dysplasia is haploinsufficiency of the SHOX gene. As GH is effective in the treatment of children with ISS (28) and Turner syndrome (24, 25, 26, 27, 28), it has been hypothesized that GH therapy may also improve the growth rate and final height of children with a SHOX defect without Turner syndrome (1, 15, 28). A formal clinical trial with a concurrent randomized untreated control group to provide a rigorous test of this assumption is now in progress.

Acknowledgments

An interactive SHOX mutation database web page will be established at the Institute of Human Genetics in Heidelberg.

We are grateful to the following clinicians for providing DNA: Dr. Yukihiro Hasegawa, Division of Endocrinology and Metabolism, Kiose Children’s Hospital; Dr. Masanori Adachi, Division of Endocrinology and Metabolism, Kanagawa Children’s Medical Center; Dr. Masayuki Kaji, Division of Endocrinology and Metabolism, Shizuoka Children’s Medical Center; and Dr. Nobutake Matsuo, Department of Pediatrics, Keio University School of Medicine. We thank Dr. Gordon Cutler for valuable comments, and Prof. Claus Bartram for his continuous support.

Footnotes

This work was supported by a grant from Eli Lilly \|[amp ]\| Co.

Abbreviations: FISH, Fluorescence in situ hybridization; ISS, idiopathic short stature; LWD, Léri-Weill dyschondrosteosis; SHOX, short stature homeobox; SSCP, single strand conformation polymorphism.

Received September 20, 2001.

Accepted December 3, 2001.

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