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Identification of Short Stature Caused by SHOX Defects and Therapeutic Effect of Recombinant Human Growth Hormone

University Children’s Hospital and Growth Research Center, University Tübingen, 72076 Tübingen, Germany

Address correspondence and requests for reprints to: Dr. Gerhard Binder, University Children’s Hospital, Hoppe-Seyler-Str.1, 72076 Tübingen, Germany.

	Abstract

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Point mutations or complete deletions of SHOX, the short-stature homeobox-containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3), were recently reported in one family with idiopathic short stature and in several families with Leri-Weill syndrome (dyschondrosteosis). The missing SHOX is also thought to attribute to the growth failure in Turner syndrome. For testing the frequency of defects of SHOX in unexplained growth failure and recombinant human GH (rhGH) as a possible growth-promoting agent, we selected 68 children with idiopathic short stature. These probands had heights below -2.0 SD score for age, normal target heights, no significant bone age retardations, no endocrine abnormalities, no skeletal diseases, and no other organic diseases. No mutations were detected by single-strand conformational polymorphism analysis of the PCR-amplified SHOX. The analysis of three microsatellite DNA markers of the pseudoautosomal region, including one located on the 5' untranslated region of SHOX-exon 1, identified a 15-yr-old girl who carried a mutation in the form of a complete SHOX deletion. This girl who had a normal karyotype presented with mild mesomelic shortening of the forearms and lower legs. We treated two children with short stature on the basis of a SHOX point mutation (C674T) with rhGH at a dose of 1.0 IU/kg body weight·week in accordance with the regimen used in Turner syndrome. During the first 12 months of treatment, these two children (5.9- and 8.4-yr-old) showed an excellent growth spurt with a growth rate of 9.5 and 9.4 cm/yr, respectively. Growth of the lower extremities was weaker than in the trunk and arms. Our data suggest that short stature due to SHOX deletions is not a rare entity. Growth-promoting therapy with rhGH was effective with regard to height gain, but a tendency to disproportionate growth was apparent. In cases of unexplained growth failure, especially if associated with any mild skeletal disproportions, genetic analysis of SHOX should be considered.

	Introduction

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GROWTH IS A multifactorial trait in which many genes are involved. A small percentage of growth failures are monogenic and caused by a disruption of one of the pathways involved in growth regulation (1, 2). Recently, a new gene, SHOX (short stature homeobox-containing gene), was discovered on the pseudoautosomal region of the sex chromosomes by deletion mapping using DNA from short individuals with X chromosomal deletions (3). This gene, also named PHOG for pseudoautosomal homeobox-containing osteogenic gene (4), lies on the very tip of the short arm of both sex chromosomes (3, 4). It codes for a homeobox-containing protein whose messenger RNA is alternatively spliced and highly expressed in fibroblasts (3, 4). A nonsense mutation of SHOX (C674T) was found in all affected members of one family with idiopathic short stature (3). Haploinsufficiency of SHOX was also discovered in families affected with Leri-Weill syndrome (osteochondrosteosis), caused by complete deletions of SHOX in 13 cases and by point mutations (C674T and C688G) in 2 cases (5, 6). Dyschondrosteosis is a dominantly inherited form of mesomelic dysplasia with short stature due to shortening of the forelegs and Madelung deformity of the forearm, which is characterized by bowing of the radius and dorsal dislocation of the distal ulna (7). Because all X chromosomal aberrations in Turner syndrome result in haploinsufficiency of SHOX, the missing SHOX is very likely to cause growth failure in this syndrome (3). In contrast to the Leri-Weill syndrome, however, Madelung deformity is a rare sign of the osteodysplasia of individuals affected by Turner syndrome. The aim of this study was to detect SHOX defects in children with unexplained short stature. In addition, we report for the first time on the therapeutic effect of recombinant GH in two children with short stature due to a SHOX point mutation.

	Individuals

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All 68 children with idiopathic short stature (8) were recruited in our growth research center. The following criteria were used for selection: 1) height less than -2.0 SD score (SDS) for chronological age; 2) normal basal serum levels of T₄, TSH, insulin-like growth factor (IGF)-I, and IGF binding protein (IGFBP)-3; 3) no apparent skeletal disease; 4) no evidence of organic disease; and 5) no significant bone age retardation. A subgroup (35%) was tested by at least one provocative GH test and showed normal GH secretion. Children with a short mother and short father (heights of both below -2.0 SDS) or growth retardation at birth were excluded from this study. After informed consent, 5 mL ethylenediaminetetraacetate blood was drawn from each patient for DNA extraction when routine blood analysis was performed. For exclusion of complete SHOX deletion, blood was also taken from parents and siblings in selected cases. Auxological data were transformed into SDS for comparability. The standards were taken from Prader et al. (9). SDS were calculated by dividing the difference between the patient’s value and the mean value for age- and sex-matched normal subjects by the SD value for age- and sex-matched normal subjects.

	Materials and Methods

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Mutation screening

Genomic DNA was extracted from blood leukocytes using an extraction kit (Genomix Blood Scale-Up; Talent, Triest, Italy) based on chloroform extraction after initial blood lysis.

PCR amplification of SHOX was performed with the six primer pairs published previously (3). Genomic DNA (0.3 µg) was added to a final volume of 50 µL PCR buffer containing 1.5 mmol/L MgCl₂, 100 pmol of each primer, 0.1% Triton-X-100, and 3 U Taq DNA polymerase (Qiagen, Hilden, Germany). The amplification was carried out with a Trio Thermobloc (Biometra, Göttingen, Germany) over 27–30 cycles with different programs for each primer pair: the annealing temperature for the amplification of exon 1(5') was 60 C, of exon 1(3') 62 C, of exon 2 76 C/72 C/68 C (touch-down PCR), of exon 3 65 C, of exon 4 65 C, and of exon 5a 63 C. All cycles were run at a denaturation temperature of 95 C and an extension temperature of 72 C.

Single-strand conformation analysis was carried out in an automatic Phast system electrophoresis apparatus (Pharmacia, Stockholm, Sweden) under two different conditions: each sample was run on a 20% mini acrylamide gel at 4 C and 15 C. Single strands were visualized by automatic silver staining. Genomic DNA with the C674T mutation was used as positive control in exon 4 analysis. Conformation polymorphisms of single-stranded DNA fragments were analyzed by direct sequencing as described previously (10).

DNA analysis

PCR amplification for detection of SHOX deletions was performed with the primer pairs 5'CCCAGATCGCGCCATT3' and 5'ATGGCTCTGAGGCGG3' for DXYS233 (microsatellite at 0 cM from the X-telomere), 5'TGGGAATTCGAGGCT3' and 5'TGATTTCCATCCT-GGGGT3' for DXYS234 (micosatellite at 2 cM from the X-telomere), and with two reported primers for the intragenic SHOX CA _repeat located in the 5' untranslated region of exon 1 (5). Amplification was performed in a Perkin-Elmer Corp. (Norwalk, CT) 9600 thermocycler with 35 cycles at an annealing temperature of 55 C. Paternity analysis was performed by amplification of three highly polymorphic microsatellite markers that were reported for use in personal identification applications (11). Separation and visualization of the fluorescent products were performed in the LiCor Automatic Sequencing apparatus 4200 under denaturing conditions.

Human GH (hGH) RIA

hGH levels in serum were measured by a polyclonal in-house RIA and were calibrated against the International Reference Preparation 80/505. The lower detection limit was 0.1 µg/L. The mean intra-assay coefficient of variation was 6.9%, and the mean interassay coefficient was 9.5%. Spontaneous secretion of GH was observed during a 12-h sampling period at night.

	Results

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Genetics

The single-strand conformational polymorphism (SSCP) analysis of the whole coding region of SHOX, the sequences flanking the exons, and a small part of the 5' untranslated region that was performed in all 68 patients revealed one conformation polymorphism in exon 3 in several cases. Direct sequencing of this DNA fragment demonstrated instability of single-stranded DNA conformation, but no mutation in any case. Because this method was not capable of detecting mutations in the form of complete deletions of SHOX, three microsatellite markers were amplified, which are located around (0 and 2 cM from the Xp telomere: DXYS233 and DXYS234) and in the SHOX locus (0.7 cM from the Xp telomere: SHOX-CA repeat). All previously described families with Leri-Weill syndrome due to SHOX deletions were hemizygous at the SHOX CA repeat and, in the majority of cases, also at the DXYS233 marker (5, 6). Therefore, we used these two markers to select possible candidates for SHOX deletions. Of the 68 probands, 17 individuals showed only one fragment size of the SHOX CA repeat. This result could either be explained by the presence of two alleles of identical size or by hemizygosity at this locus as a consequence of a complete SHOX deletion. For further discrimination between these two possibilities, we amplified the DXYS233 marker. Four of the 68 probands showed one fragment size of each of both markers, SHOX-CA repeat and DXYS233. Genomic DNA from parents and siblings of these 4 probands were examined. DXYS233 was not informative in any of the four families. Two of the four families were informative for the SHOX CA repeat. The analysis revealed hemizygosity due to the absence of the paternal allele in both probands (Fig. 1). Because both missing alleles were of paternal origin, we amplified three additional autosomal microsatellites. The results were not in agreement with paternity in one case, excluding this proband from analysis. The other proband, a 15-yr-old girl, was found to be heterozygous for DXYS234, suggesting the location of the breakpoint distal to DXYS234, which is located at 2 cM from the X-telomere (Fig. 1).

View larger version (34K): [in this window] [in a new window]   Figure 1. Analysis of three microsatellites at the SHOX locus in one family, indicating a deletion of the SHOX locus. The arrows indicate the amplified allele(s) of the proband who was hemizygous at the SHOX-CA repeat, but heterozygous at DXYS234. DXYS233 was not informative in this family.

The 15-yr-old girl, who was detected to carry only one SHOX, was born at 39 weeks gestation with a birth weight of 2900 g (40th percentile for gestational age) and a birth length of 49 cm (10th percentile for gestational age) (12). Her parents and two siblings were of normal height, and her target height was 166 cm. She was admitted to our hospital at the age of 13.2 yr because of nonfamilial short stature. Her height was 142.0 cm (-2.2 SDS), and her arm span was 136.0 cm (-3.5 SDS) (9). Her sitting height (81.5 cm, -0.2 SDS) (9) was augmented in relation to her standing height due to a mesomelic shortening of the lower legs. No stigmata of Turner syndrome were present. Radiographic evaluation revealed a mild triangulation of the carpal bones (Fig. 2). Bone age was 12 yr, which was in agreement with the pubertal status of the girl (breast B3 and pubes P3 according to Tanner). Her karyotype, examined by metaphase banding, was normal. Serum levels of IGF-I, IGFBP-3, T₄, TSH, and FSH were in the normal range. The 15-yr-old girl has now reached a height of 149.0 cm (-2.4 SDS) (9). The last 5 yr she had grown on the 3rd percentile growth curve for normal females, which resembles approximately the 90th percentile growth curve for Turner syndrome (13).

View larger version (83K): [in this window] [in a new window]   Figure 2. Radiography of the left hand of the girl with the SHOX deletion at the age of 13 yr showing mild triangulation of the carpal bones.

The clinical characteristics of the two children were reported previously (3). In short, both are siblings of a German nonconsanguineous family. The girl (G) was born at term by cesarean section with a birth weight of 2920 g, and her birth length was 47 cm. She developed normally, but insufficient growth was apparent at the age of 12 months [length, 67 cm (-3.0 SDS)]. At 4 yr, her height was 89.6 cm (-3.6 SDS). No dysmorphic features or dysproportions were present. Her bone age was 3.5 yr. The boy (B) was born at the 38th week of gestation by cesarean section. His birth weight was 2660 g, and his birth length was 47 cm. His developmental milestones were normal, but his growth was subnormal. At the age of 6.4 yr, he was proportionated and small (106.8 cm, -2.6 SDS) and obese (22.7 kg). His bone age was 6 yr. He grew on the 75th percentile curve as established for Turner syndrome (13), while his sister (G) grew on the 50th percentile growth curve for Turner syndrome (13). The height of the nonaffected father was 166 cm (-1.8 SDS). The height of the affected mother was only 142.3 cm (-3.8 SDS); she presented with a rhizomelic dysproportion.

Stimulation by arginine infusion resulted in GH peak serum levels of 5.3 ng/mL in the 8.4-yr-old boy (B) and 10.0 ng/mL in the 5.9-yr-old girl (G). Mean GH levels of spontaneous night secretion were low, with 1.6 ng/mL (B) and 2.7 ng/mL (G). The maximum peaks of spontaneous GH secretion were 4.3 ng/mL (B) and 9.2 ng/mL (G), respectively. However, IGF-I and IGFBP-3 serum levels were normal in both children, with 62 ng/mL and 2713 ng/mL (B) and 110 ng/mL and 2449 ng/mL (G), respectively. Both children were treated with recombinant hGH (rhGH) at a dose of 1.0 IU/kg body weight·week in accordance to the regimen used in Turner syndrome. This treatment resulted in significant acceleration of growth in the first 12 months of therapy (Fig. 3). Height increased from -3.5 SDS to -2.5 SDS (G) and from -2.5 SDS to -1.6 SDS (B), with an increase in height velocity from -2.3 SDS to +3.9 SDS (9.5 cm/yr) (G) and -2.0 SDS to +5.4 SDS (9.4 cm/yr) (B) (9). Sitting height increased from -2.6 SDS to -1.0 SDS (G) and -1.5 SDS to 0.0 SDS (B) (9). However, subischial leg length increased only weakly from -3.3 SDS to -3.1 SDS (G) and -2.9 SDS to -2.6 SDS (B) (9). The bone age of both children progressed chronologically during rhGH therapy.

View larger version (42K): [in this window] [in a new window]   Figure 3. Growth charts of the two siblings with the SHOX point mutation (C674T) treated with rhGH. Normal standards are according to Prader et al. (9 ). The shadowed area comprises the normal growth spectrum of females with Turner syndrome (±2 SD) (13 ).

	Discussion

Top Abstract Introduction Individuals Materials and Methods Results Discussion References

The discovery of complete SHOX deletions in families with Leri-Weill syndrome motivated us to extend our screening to complete deletions (5, 6). On the basis of three microsatellite markers that were located upstream and downstream of SHOX, as well as in the gene itself, we detected only one girl with a complete SHOX deletion (1.5% of all screened children). Complete SHOX deletions could be excluded in 75% of all screened children because of heterozygosity of the intragenic marker. The remaining 23.5% were either not informative at the satellite markers or could not be sufficiently studied because of missing parental DNA. The newly discovered SHOX deletion was sporadic. In contrast to her family, the affected girl exhibited mild mesomelia of arms and legs without any other dysplastic features of the Turner syndrome. Radiography of the wrist showed mild triangulation of the carpal bones, which is one of the radiological signs of the Madelung deformity.

High-dose rhGH therapy of short stature in Turner syndrome is an accepted, effective, and safe treatment, despite the absence of GH deficiency (14). The therapy is aimed at correcting one feature—short stature—of the syndrome that, like others (i.e. gonadal dysgenesis), is thought to be caused by haploinsufficiency of several genes on the sex chromosomes (15). SHOX is the first gene in Turner syndrome whose defect was associated with the specific effect of growth failure (3). On this basis, we regarded studying rhGH treatment of children with idiopathic short stature due to isolated SHOX defects as rational and promising. In the case of the newly discovered 15-yr-old girl, rhGH treatment could not be initiated because of an almost finished pubertal growth spurt. Basal levels of the GH-dependent factors were normal in her case. The evaluation of the GH axis in the two previously reported siblings with a C674T mutation of SHOX revealed a pathologically low GH night secretion profile in both and an insufficient GH maximum peak after arginine stimulation in the boy. Subnormal peak GH response to arginine was also reported in children with Leri-Weill syndrome (16). IGF-I and IGFBP-3 serum levels were, however, in the normal range in both of our children when tested subsequently. In addition, the spontaneous growth of the two children took place in parallel with the percentiles of the normal population (9). Therefore, we concluded that classical GH deficiency was not present in these two children. The 1-yr therapeutic effect of rhGH (+0.9 and +1.0 SD, respectively) was much higher than the mean response of + 0.55 SD (±0.31) observed in the British girls with Turner syndrome (14). The growth of the lower extremities was weaker than in the trunk and arms in both siblings. A similar growth pattern to rhGH treatment was observed in hypochondroplasia (17). In Turner syndrome, such effect of rhGH has not been reported as a general problem. However, in our clinical experience, a subgroup of females with Turner syndrome do exhibit a weaker growth of the lower extremities in comparison to trunk and arms before and during rhGH treatment.

The absence of Leri-Weill syndrome in most of the girls with Turner syndrome, as well as in our probands with SHOX mutations, awaits a sufficient explanation. Radiographic studies of the forearm of affected adults of our family with the SHOX point mutation (C674T), which clinically have no classic Madelung deformity, revealed a mild bowing of the radius and ulna as well as wedging of the carpal bones into a small triangular space between the distal radius and ulna in one case. These radiographic findings were not present in the prepubertal affected children (5.9- and 8.4-yr-old) of this family. The newly discovered girl with the complete SHOX deletion did exhibit mild triangulation of her carpal bones at the age of 13. Short stature in Turner syndrome is characterized by a short neck, short trunk, and occasionally disproportionately slow growth of the lower extremities (18, 19). These findings suggest that SHOX defects frequently cause short stature without the complete phenotype of Leri-Weill syndrome. Variable expression in families with Leri-Weill syndrome (6) and in individuals carrying terminal deletions of Xp (20) underline the suggestion that the genotype-phenotype correlation is weak. Modifying gene products up- or downstream of SHOX might be responsible for this phenomenon, which is not uncommon in syndromes caused by genetic haploinsufficiency (21).

In conclusion, SHOX defects in unexplained short stature are not rare and should be especially suspected in the presence of any mild disproportion of the extremities. Our data suggest that rhGH therapy in accordance to treatment in Turner syndrome may be effective in increasing final height.

	Acknowledgments

 
We thank Mrs. Christina Urban for technical assistance in applying the molecular biology techniques.

	Footnotes

 
¹ For this work, G. B. was awarded with the Jürgen-Bierich Prize (1999) from the German Society on Pediatric Endocrinology.

Received August 17, 1999.

Revised October 18, 1999.

Accepted October 21, 1999.

	References

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1. Phillips III JA, Cogan JD. 1994 Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab. 78:11–16.[CrossRef][Medline]
2. Shiang R, Thompson LM, Zhu YZ, et al. 1994 Mutation in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 78:335–342.[CrossRef][Medline]
3. Rao E, Weiss B, Fukami M, et al. 1997 Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 16:54–63.[CrossRef][Medline]
4. Ellison JW, Wardak Z, Young MF, Robey PG, Laig-Webster M, Chiong W. 1997 PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet. 6:1341–1347.[Abstract/Free Full Text]
5. Belin V, Cusin V, Viot G, et al. 1998 SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet.19:67–69.
6. Shears DJ, Vassal HJ, Goodman FR, et al. 1999 Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet. 19:70–73.
7. Léri A, Weill J. 1929 Une affection congénitale et symétrique du développement osseux: la dyschondostéose. Bull Mém Soc Med Hosp. 35:1491–1494.
8. Ranke MB. 1996 Towards a consensus on the definition of idiopathic short stature. Horm Res. 45(Suppl 2):64–66.
9. Prader A, Largo HR, Molinari L, Issler C. 1989 Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Acta Suppl. 52:3–31.
10. Binder G, Ranke MB. 1995 Screening for growth hormone gene splice site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis. J Clin Endocrinol Metab. 80:1247–1252.[Abstract]
11. Hammond HA, Jin L, Zhong Y, Caskey CT, Chakraborty R. 1994 Evaluation of 13 short tandem repeat loci for use in personal identification applications. Am J Hum Genet. 55:175–189.[Medline]
12. Gairdner D, Pearson J. 1971 A growth chart for premature and other infants. Arch Dis Child. 46:783–787.
13. Ranke MB, Pflüger H, Rosendahl W, et al. 1983 Turner syndrome: spontaneous growth in 150 cases and review of the literature. Eur J Pediatr. 141:81–88.[CrossRef][Medline]
14. Betts PR, Butler GE, Donaldson MDC, et al. 1999 A decade of growth hormone treatment in girls with Turner syndrome in the UK. Arch Dis Child. 80:221–225.[Abstract/Free Full Text]
15. Zinn AR, Page DC, Fisher EMC. 1993 Turner syndrome: the case of the missing sex chromosome. Trends Genet. 9:90–95.[CrossRef][Medline]
16. Thuestad IJ, Ivarsson S-A, Nilsson KO, Wattsgard C. 1996 Growth hormone treatment in Leri-Weill syndrome. J Pediatr Endocrinol Metab. 9:201–204.[Medline]
17. Ramaswami U, Hindmarsh PC, Brook CGD. 1999 Growth hormone therapy in hypochondroplasia. Acta Paediatr Suppl. 428:116–117.
18. Lippe BM. 1991 Turner syndrome. Endocrinol Metab Clin North Am. 20:121–152.[Medline]
19. Neufeld ND, Lippe BM, Kaplan SA. 1978 Disproportionate growth of the lower extremities: a major determinant of short stature in Turner’s syndrome. Am J Dis Child. 132:296–298.[Abstract/Free Full Text]
20. Ogata T, Petit C, Rappold G, Matsuo N, Matsumoto T, Goodfellow P. 1992 Chromosomal localization of a pseudoautosomal growth gene(s). J Med Genet. 29:624–628.[Abstract/Free Full Text]
21. Fisher E, Scambler PJ. 1994 Human haploinsufficiency—one for sorrow, two for joy. Nat Genet. 7:5–9.[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Binder, G. Articles by Ranke, M. B. Search for Related Content PubMed PubMed Citation Articles by Binder, G. Articles by Ranke, M. B.