HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
Received: March 18, 2013 Accepted: August 6, 2013 Published online: November 26, 2013
The Sitting Height/Height Ratio for Age in Healthy and Short Individuals and Its Potential Role in Selecting Short Children for SHOX Analysis Alexsandra C. Malaquias a, b Renata C. Scalco a, b Eveline G.P. Fontenele c Everlayny F. Costalonga d Alexandre D. Baldin e Adriana F. Braz a, b Mariana F.A. Funari b Mirian Y. Nishi b Gil Guerra-Junior e Berenice B. Mendonca b Ivo J.P. Arnhold b Alexander A.L. Jorge a, b a
Unidade de Endocrinologia-Genetica, LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), and b Laboratorio de Hormonios e Genetica Molecular, LIM/42, Unidade de Endocrinologia do Desenvolvimento, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, c Serviço de Endocrinologia e Diabetes, HUWC/UFC, Unidade de Farmacologia Clinica da Faculdade de Medicina da Universidade Federal do Ceara, Fortaleza, d Programa de Pos Graduacao em Ciencias Farmaceuticas da Universidade Vila Velha, Vila Velha, and e Laboratorio de Crescimento e Composição Corporal, Centro de Investigação em Pediatria, Faculdade de Ciências Médicas da Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil
Key Words SHOX gene · Turner syndrome · Idiopathic short stature · Léri-Weill dyschondrosteosis
Abstract Aims: To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. Methods: Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). Results: The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10–22%), which was higher than in controls (1.4%, 95% CI 0.8–1.9%, p < 0.001). The SHOX gene was evaluated in all disproportionate ISS children and defects in this gene were observed in 19%.
© 2013 S. Karger AG, Basel 1663–2818/13/0806–0449$38.00/0 E-Mail [email protected] www.karger.com/hrp
Among patients with SHOX-D, 88% of children (95% CI 75– 100%) and 96% of adults had body disproportion. In contrast, SH/H SDS >2 were less common in children (48%, 95% CI 37–59%) and in adults (28%, 95% CI 20–36%) with TS. Conclusion: Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies. © 2013 S. Karger AG, Basel
Introduction
Short stature is a multifactorial condition with an important genetic component. Among the recognized causes of short stature, SHOX gene (short stature homeobox-containing gene, MIM 312865) defects are the most Alexander A.L. Jorge Avenida Dr. Arnaldo, 455 5º andar sala 5340 Faculdade de Medicina da USP (LIM-25) CEP 01246-903 Sao Paulo, SP (Brazil) E-Mail alexj @ usp.br
frequent genetic cause. SHOX is located on the distal ends of the pseudoautosomal region of the X and Y chromosomes (PAR1) and encodes a transcription factor (highly expressed in osteogenic cells) responsible for a significant proportion of long bone growth [1, 2]. In females with Turner syndrome (TS), the partial or complete X chromosome monosomy leads to SHOX haploinsufficiency which partially explains the short stature and some skeletal features observed in these patients such as skeletal disproportions, micrognathia, cubitus valgus, higharched palate, short 4th metacarpals, genu valgum, scoliosis and Madelung wrist deformity [3, 4]. Abnormal body disproportions were observed in a substantial percentage of females with TS [5–8]. SHOX haploinsufficiency caused by heterozygous mutations or deletions in SHOX or by deletions in the downstream or upstream enhancer elements have been identified in 56–100% of Léri-Weill dyschondrosteosis (LWD, MIM 127300) cases [9]. LWD is a skeletal dysplasia affecting both sexes and is characterized by short stature, mesomelia and Madelung deformity. In addition, several groups have shown that in children who were first considered as having idiopathic short stature (ISS, MIM 300582), SHOX defects can be found in 1–16% and that the assessment of body proportions may be an important selection criterion for genetic testing [10–15]. SHOX haploinsufficiency is transmitted with a pseudoautosomal dominant inheritance pattern. The severity of short stature and the presence of LWD or ISS phenotype vary considerably even within the same family [13]. Our group demonstrated that the presence of disproportionate height, assessed by sitting height/ height ratio for age and sex (SH/H SDS), is one of the most common features of patients with SHOX defects [13]. In the present study, we assessed the SH/H SDS in a large group of children with normal growth and in children classified as ISS, as well as in children and adults with SHOX defects or TS, to establish the frequency of body disproportion in these conditions. Furthermore, we estimated the potential role of an abnormal SH/H SDS in selecting children initially considered ISS for SHOX testing. Subjects and Methods Subjects Cross-sectional data were collected on height and sitting height from 1,771 children with normal growth (height SDS >–2 and 2 above the mean for age
Malaquias et al.
8
Sitting height/height SDS
6
4
2
0
–2
Fig. 1. SH/H SDS in children with normal
growth and patients with ISS, SHOX defects and TS. The individual results are shown. Solid lines indicate mean and ±1 SD.
–4 Children with normal growth
Idiopathic short stature
SHOX defects
Turner syndrome
(n = 1,771)
(n = 128)
(n = 29)
(n = 73)
and sex [16]. We also evaluated children with disproportionate ISS and patients with SHOX defects by two previous scoring systems for selection of children for SHOX testing: the extremities/trunk ratio (Binder score) [11] and a scoring system based on various clinical features of children with SHOX defects (Rappold score) [12]. Cytogenetic and Molecular Analysis Chromosome analysis was performed in all female patients on chromosomal spreads obtained from peripheral blood lymphocyte cultures using standard karyotyping techniques with G-banding. Genomic DNA was isolated from peripheral blood leukocytes by standard methods from all disproportionate ISS patients, patients suspected of having LWD and their relatives. Defects in the SHOX gene were investigated as previously published [19]. Briefly, multiplex ligation-dependent probe amplification analysis of SHOX and PAR1 region was carried out using the commercial kits SALSA P018-C1 and P018-D1 SHOX (MCR Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. FISH analysis was performed where necessary. In patients without SHOX deletion, PCR and sequence analysis were performed for all coding exons of SHOX gene (primer sequences and amplification protocols available on request). Statistical Analysis Results were expressed as mean ± SD. Differences between groups were tested by t test or Kruskal-Wallis and χ2 or Fisher’s exact test, as appropriate. A p value 2 and were considered disproportionate, corresponding to 1.4% (95% CI 0.8–1.9%) of the total number of children with normal growth. The frequency of SH/H SDS 2 in control children (95% CI 0.5– 1.5%). SH/H SDS in Children Considered as Having ISS In total, 128 children classified as ISS aged 10 ± 3.5 years (from 4 to 17 years) had a height SDS of –2.6 ± 0.7 (fig. 1; table 1). Of these, 21 had SH/H SDS >2, which corresponds to 16.4% (95% CI 10.0–22.8%). This frequency is higher than observed in children with normal growth (1.4%, p < 0.001); 2 of the children with ISS had SH/H SDS +2 95% CI
Control
ISS
SHOX defects
Turner syndrome
882/889 7.9±1.71 0.3±0.91 0.4±1.1 –0.5±0.81 –0.4±0.91 0.1±0.9 1.4%1 0.8–1.9%
80/48 10.0±3.4 –2.6±0.7 –0.6±1.32 –3.2±0.8 –2.3±0.8 0.7±1.6 16.4% 10–23%
15/14 10.2±3.5 –2.0±1.1 0.7±0.9 –3.5±1.0 –0.9±0.93 3.7±1.63 88%5 75–100%
–/73 12.8±3.3 –2.8±1.3 0.3±1.1 –3.4±1.1 –2.4±1.4 1.9±1.64 48% 37–59%
Continuous variables are shown as the mean ± SD. 1 Children with normal growth vs. children with ISS, SHOX defects or TS, p < 0.001. 2 Children with ISS vs. children with normal growth, SHOX defects or TS, p < 0.001. 3 Children with SHOX defects vs. children with normal growth or ISS, p < 0.001. 4 Children with TS vs. children with normal growth or ISS, p < 0.001. 5 Children with SHOX defects vs. children with normal growth, ISS or TS, p < 0.001.
SH/H SDS >2 had signs of skeletal dysplasia and none of their first-degree relatives had evidence of LWD. Subsequent testing in all 21 disproportionate short children led to the detection of 4 (19%) cases with SHOX defects, a frequency higher than observed in unselected ISS children in a previous study in our group (3%, p < 0.01) [13]; 2 of these patients carried SHOX deletions and the other 2 carried previously described nonsense (p.Try35*) and missense (p.Arg147His) SHOX mutations [13]. SH/H SDS in Individuals with SHOX Defects A total of 58 patients (29 children aged 1.3–4.6 years, mean 10.6 ± 3.0 years) from 18 families had been identified with SHOX defects: 40 individuals from 15 families with SHOX gene deletion, 14 individuals from 1 family with a nonsense mutation (p.Try35*) and 4 individuals from 2 families with a missense mutation (p.Arg147His). Madelung deformity was found in 41% of children and 52% of adults with SHOX defects at the time of the first visit. Adults with SHOX defects were relatively shorter than children with SHOX defects (height SDS –2.7 ± 1.0 vs. –2.0 ± 1.1, p = 0.01). However, SH/H SDS was similar in both adults and children (3.7 ± 1.3 and 4.0 ± 1.4 in children and adults, respectively; fig. 2). The frequency of disproportionate short stature in children with SHOX defects was 88% (95% CI 75–100%) and 96% in adults (95% CI 90–100%). The mean height SDS, SH/H SDS and frequency of disproportionate short stature were similar in patients with or without features of LWD. 452
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
SH/H SDS in TS The mean age of girls with TS was 12.8 ± 3.3 years (from 5.0 to 17.6 years), their mean height SDS was –2.8 ± 1.3 and mean SH/H SDS was 1.9 ± 1.6 (fig. 1; table 1). Women with TS had a mean height SDS of –2.8 ± 1.1 and a mean SH/H SDS of 1.5 ± 1.1. Previous treatment with rhGH did not influence the SH/H SDS, but an inverse correlation between age at start of puberty (spontaneous or induced) and SH/H SDS (r = –0.2, p = 0.03) was observed. The frequency of body disproportion (SH/H SDS >2) was higher in girls than in women with TS (48 vs. 28%; p = 0.006) and lower than in patients with SHOX defects (p < 0.001; fig. 2). Only 1 girl had SH/H SDS 2, 15/19 had an abnormal Binder score, including the 4 Malaquias et al.
Fig. 2. Comparison of SH/H SDS in children and adults with isolated SHOX defects and TS: children and adults with SHOX defects had similar SH/H SDS whereas girls with TS were more disproportionate than women with TS (p = 0.006). Children and adults with SHOX defects were more affected than TS girls and women regarding body disproportion (p < 0.001). The individual results are shown. Solid lines indicate mean and ±1 SD.
Sitting height/height SDS
8
6
4
2
0
–2
–4
ISS patients with identified SHOX defects; 9 and 5 of these ISS children had a Rappold score above the cutoff of 4 and 7, respectively, and 2 patients classified as ISS with identified SHOX defects had a Rappold score of 4 (table 2).
Children
Adults
In the present study, we evaluated anthropometric measurements, mainly SH/H for age and sex, in a cohort of 1,771 children with normal growth, 128 children with ISS, 58 individuals with SHOX defects and 193 females with TS. Despite the height difference between the Dutch and Brazilian populations [17, 18], the SH/H SDS of the normal Brazilian population was similar to the reference for the Dutch population [16] (fig. 1; online suppl. fig. A, B). In children considered as ISS, body disproportion was 10 times more frequent than in children with normal growth (16.4 vs. 1.4%; table 1). Part of this difference is probably caused by the fact that short children have a higher average SH/H ratio than the general population [16], but it may also suggest that within the heterogeneous group of children with ISS there may be a subgroup in which growth impairment is associated with gene variants primarily affecting the epiphyseal growth plates. The high frequency of SHOX defects in this group of disproBody Disproportion and SHOX Defects
Adults
Turner syndrome
Table 2. Comparison between SH/H SDS and previous scores de-
scribed to select patients for SHOX studies (Binder [11] and Rappold [12] scores) in patients with SHOX defects and disproportionate ISS children SH/H SDS
Discussion
Children
SHOX defects
Binder Rappold score Rappold score score (cutoff >4) (cutoff >7)
Patients with SHOX defects Normal 3 3 Abnormal 36 36
11 23
17 17
Disproportionate ISS children Normal 4 Abnormal 19 (4) 15 (4)
10 (2) 9 (2)
14 (2) 5 (2)
The full Rappold and Binder scores were adequately calculated for 34 and 39 patients with SHOX defects, respectively, and for 19 disproportionate ISS children (including the 4 ISS children with SHOX defects). Values in parentheses represent ISS patients with SHOX defects. Abnormal, SH/H >2.
portionate ISS children (19%) in comparison to ISS children (3%) [13] is supportive for this idea. This possibility is also suggested in genome-wide association studies where several current height loci include genes involved in growth plate physiology [20]. Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
453
It has been well established that SHOX haploinsufficiency causes a wide spectrum of short stature phenotypes, including patients with TS [3], LWD [21, 22] and short stature without any specific features (ISS) [23]. The genotype-phenotype correlation in patients with SHOX defects is weak and incomplete expression in families with LWD has been demonstrated [9]. In the present study, we confirmed that SH/H SDS >2 is present in the vast majority of patients with SHOX defects (88–96%), independent of clinical phenotype (the presence or absence of features of LWD). In addition, SHOX defects were found in 19% of the children who were originally labeled as ISS, in spite of body disproportion. These observations support previous recommendations to test for SHOX defects in children with abnormal body proportions [10–15]. Although the present study was not designed to compare different strategies to select individuals for SHOX genetic tests, we compared the sensitivity of SH/H SDS, the extremities/trunk ratio (Binder score) [11] and Rappold score [12] for identifying individuals with SHOX defects (table 2). An abnormal Binder score or SH/H SDS was observed in 92% of individuals with SHOX defects and only 1 of them had both scores normal. Conversely, the Rappold score identified 68 and 50% of patients with SHOX defects using the cutoff of 4 and 7, respectively. This result might be explained by the fact that SH/H was evaluated as absolute values in the Rappold score, even though age is known to influence this ratio [16, 24]. Additionally, clinical findings related to Madelung deformity, such as bowing of forearm, short forearm and dislocation of ulna, account for an important part in this scoring system [12] and are usually absent in individuals with SHOX defects without LWD phenotype. Previous studies of children carrying SHOX defects suggested a relatively well-preserved prepubertal growth followed by a compromised pubertal growth due to premature growth plate fusion, thus causing premature growth arrest [13, 25, 26]. Indeed, we observed in our study that short stature is comparatively more severe in adults than in children with SHOX defects, while SH/H SDS was similar in both adults and children. The molecular diagnosis of patients with SHOX defects is likely to have therapeutic implications, as rhGH treatment associated or not with GnRH analogs might improve adult height [27, 28]. Girls and women with TS showed less disproportionate short stature than patients with SHOX defects, but their height SDS was lower. This suggests that in TS there 454
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
are other factors affecting bone growth, particularly spinal growth (table 1). Furthermore, SH/H SDS tends to improve with age in TS patients and this is inversely correlated with age at start of puberty, which suggests that the lack of gonadal estrogens could be an advantage in body proportion and skeletal deformity improvement in patients with TS in comparison to patients with SHOX defects. Estrogens play a pivotal role in bone mineralization regulating the pubertal growth spurt and growth plate fusion in both girls and boys. Girls with TS usually lack gonadal function and may present delayed bone age early in life. In contrast, eunuchoid body proportions, unfused epiphyses and tall stature were described in patients with aromatase deficiency. We hypothesize that the low exposure to estrogens of growth cartilage and the relatively late start of exogenous estrogens in most girls with TS protects them from early epiphyseal closure and may therefore attenuate body disproportion, allowing limbs to grow for a longer period in comparison to girls with isolated SHOX defects. In conclusion, disproportionate short stature is a common feature observed in patients with SHOX defects, more so than in females with TS. This confirms the important role of measuring body proportions in the diagnostic work-up of short children, and shows that SH/H SDS is a useful tool for selecting ISS children to undergo SHOX molecular studies. However, in most disproportionate children labeled ISS no SHOX defect could be found, suggesting that other genes involved in growth plate regulation could be responsible for growth impairment observed in these children.
Acknowledgments This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo – FAPESP (2008/50184-2, 2013/03236-5 and 2007/59555-0 to A.C.M.) and from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico – CNPq (301339/2008-9 to B.B.M.; 300982/2009-7 to I.J.P.A. and 304678/2012-0 to A.A.L.J.).
Disclosure Statement The authors declare that they have no competing financial interests.
Malaquias et al.
References 1 Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W: PHOG, a candidate gene for involvement in the short stature of turner syndrome. Hum Mol Genet 1997;6:1341–1347. 2 Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Nordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997; 16:54–63. 3 Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, Robson SC, Binder G, Glass I, Strachan T, Lindsay S, Rappold GA: The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet 2000;9:695–702. 4 Ross JL, Kowal K, Quigley CA, Blum WF, Cutler GB Jr, Crowe B, Hovanes K, Elder FF, Zinn AR: The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome. J Pediatr 2005;147:499–507. 5 Neufeld ND, Lippe BM, Kaplan SA: Disproportionate growth of the lower extremities. A major determinant of short stature in Turner’s syndrome. Am J Dis Child 1978;132:296– 298. 6 Rongen-Westerlaken C, Rikken B, Vastrick P, Jeuken AH, de Lange MY, Wit JM, van der Tweel L, Van den Brande JL: Body proportions in individuals with Turner syndrome. The Dutch growth hormone working group. Eur J Pediatr 1993;152:813–817. 7 Gravholt CH, Weis Naeraa R: Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome. Am J Med Genet 1997;72:403–408. 8 Baldin AD, Armani MC, Morcillo AM, Lemos-Marini SH, Baptista MT, MacielGuerra AT, Guerra-Junior G: Body proportions in a group of Brazilian patients with Turner syndrome. Arq Bras Endocrinol Metabol 2005;49:529–535. 9 Jorge AA, Funari MF, Nishi MY, Mendonca BB: Short stature caused by isolated SHOX gene haploinsufficiency: update on the diagnosis and treatment. Pediatr Endocrinol Rev 2010;8:79–85. 10 Ross JL, Scott C Jr, Marttila P, Kowal K, Nass A, Papenhausen P, Abboudi J, Osterman L, Kushner H, Carter P, Ezaki M, Elder F, Wei F, Chen H, Zinn AR: Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 2001;86:5674–5680. 11 Binder G, Ranke MB, Martin DD: Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in schoolage children with unexplained short stature. J Clin Endocrinol Metab 2003; 88: 4891– 4896.
Body Disproportion and SHOX Defects
12 Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA, Ross JL, Niesler B: Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007; 44: 306–313. 13 Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Liborio DC, Kim CA, Arnhold IJ, Mendonca BB: SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clin Endocrinol (Oxf) 2007;66:130–135. 14 Hirschfeldova K, Solc R, Baxova A, Zapletalova J, Kebrdlova V, Gaillyova R, Prasilova S, Soukalova J, Mihalova R, Lnenicka P, Florianova M, Stekrova J: SHOX gene defects and selected dysmorphic signs in patients of idiopathic short stature and Leri-Weill dyschondrosteosis. Gene 2012;491:123–127. 15 Kant SG, Broekman SJ, de Wit CC, Bos M, Scheltinga SA, Bakker E, Oostdijk W, van der Kamp HJ, van Zwet EW, van der Hout AH, Wit JM, Losekoot M: Phenotypic characterization of patients with deletions in the 3′-flanking SHOX region. PeerJ 2013;1:e35. 16 Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM: Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–812. 17 Kuczmarski RJ, Ogden CL, GrummerStrawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL: CDC growth charts: United States. Adv Data 2000; 314:1–27. 18 Silva DA, Pelegrini A, Petroski EL, Gaya AC: Comparison between the growth of Brazilian children and adolescents and the reference growth charts: data from a Brazilian project. J Pediatr (Rio J) 2010;86:115–120. 19 Funari MF, Jorge AA, Souza SC, Billerbeck AE, Arnhold IJ, Mendonca BB, Nishi MY: Usefulness of MLPA in the detection of SHOX deletions. Eur J Med Genet 2010;53:234–238. 20 Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tam-
mesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpelainen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Pare G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietilainen KH, Pouta A, Ridderstrale M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kahonen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimaki T, Melander O, Mosley TH Jr, Musk AW, Nieminen MS, O’Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tonjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Volzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O’Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM, Hirschhorn JN: Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010;467:832–838.
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
455
21 Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM: Mutation and deletion of the pseudoautosomal gene SHOX cause LeriWeill dyschondrosteosis. Nat Genet 1998;19: 70–73. 22 Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A, Cormier-Daire V: SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 1998;19:67–69. 23 Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, Heinrich U, Vlachopapadoupoulou E, Reinehr T, Onigata K, Ogata T: Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab 2002;87:1402–1406.
456
24 Jorge AA, Arnhold IJ: Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature. J Med Genet 2007; 44:e90, author reply e91. 25 Kosho T, Muroya K, Nagai T, Fujimoto M, Yokoya S, Sakamoto H, Hirano T, Terasaki H, Ohashi H, Nishimura G, Sato S, Matsuo N, Ogata T: Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of turner syndrome. J Clin Endocrinol Metab 1999;84:4613–4621.
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
26 Fukami M, Nishi Y, Hasegawa Y, Miyoshi Y, Okabe T, Haga N, Nagai T, Tanaka T, Ogata T: Statural growth in 31 Japanese patients with SHOX haploinsufficiency: support for a disadvantageous effect of gonadal estrogens. Endocr J 2004;51:197–200. 27 Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quigley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172. 28 Scalco RC, Melo SS, Pugliese-Pires PN, Funari MF, Nishi MY, Arnhold IJ, Mendonca BB, Jorge AA: Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency. J Clin Endocrinol Metab 2010;95:328–332.
Malaquias et al.
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
Received: March 18, 2013 Accepted: August 6, 2013 Published online: November 26, 2013
The Sitting Height/Height Ratio for Age in Healthy and Short Individuals and Its Potential Role in Selecting Short Children for SHOX Analysis Alexsandra C. Malaquias a, b Renata C. Scalco a, b Eveline G.P. Fontenele c Everlayny F. Costalonga d Alexandre D. Baldin e Adriana F. Braz a, b Mariana F.A. Funari b Mirian Y. Nishi b Gil Guerra-Junior e Berenice B. Mendonca b Ivo J.P. Arnhold b Alexander A.L. Jorge a, b a
Unidade de Endocrinologia-Genetica, LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), and b Laboratorio de Hormonios e Genetica Molecular, LIM/42, Unidade de Endocrinologia do Desenvolvimento, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, c Serviço de Endocrinologia e Diabetes, HUWC/UFC, Unidade de Farmacologia Clinica da Faculdade de Medicina da Universidade Federal do Ceara, Fortaleza, d Programa de Pos Graduacao em Ciencias Farmaceuticas da Universidade Vila Velha, Vila Velha, and e Laboratorio de Crescimento e Composição Corporal, Centro de Investigação em Pediatria, Faculdade de Ciências Médicas da Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil
Key Words SHOX gene · Turner syndrome · Idiopathic short stature · Léri-Weill dyschondrosteosis
Abstract Aims: To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. Methods: Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). Results: The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10–22%), which was higher than in controls (1.4%, 95% CI 0.8–1.9%, p < 0.001). The SHOX gene was evaluated in all disproportionate ISS children and defects in this gene were observed in 19%.
© 2013 S. Karger AG, Basel 1663–2818/13/0806–0449$38.00/0 E-Mail [email protected] www.karger.com/hrp
Among patients with SHOX-D, 88% of children (95% CI 75– 100%) and 96% of adults had body disproportion. In contrast, SH/H SDS >2 were less common in children (48%, 95% CI 37–59%) and in adults (28%, 95% CI 20–36%) with TS. Conclusion: Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies. © 2013 S. Karger AG, Basel
Introduction
Short stature is a multifactorial condition with an important genetic component. Among the recognized causes of short stature, SHOX gene (short stature homeobox-containing gene, MIM 312865) defects are the most Alexander A.L. Jorge Avenida Dr. Arnaldo, 455 5º andar sala 5340 Faculdade de Medicina da USP (LIM-25) CEP 01246-903 Sao Paulo, SP (Brazil) E-Mail alexj @ usp.br
frequent genetic cause. SHOX is located on the distal ends of the pseudoautosomal region of the X and Y chromosomes (PAR1) and encodes a transcription factor (highly expressed in osteogenic cells) responsible for a significant proportion of long bone growth [1, 2]. In females with Turner syndrome (TS), the partial or complete X chromosome monosomy leads to SHOX haploinsufficiency which partially explains the short stature and some skeletal features observed in these patients such as skeletal disproportions, micrognathia, cubitus valgus, higharched palate, short 4th metacarpals, genu valgum, scoliosis and Madelung wrist deformity [3, 4]. Abnormal body disproportions were observed in a substantial percentage of females with TS [5–8]. SHOX haploinsufficiency caused by heterozygous mutations or deletions in SHOX or by deletions in the downstream or upstream enhancer elements have been identified in 56–100% of Léri-Weill dyschondrosteosis (LWD, MIM 127300) cases [9]. LWD is a skeletal dysplasia affecting both sexes and is characterized by short stature, mesomelia and Madelung deformity. In addition, several groups have shown that in children who were first considered as having idiopathic short stature (ISS, MIM 300582), SHOX defects can be found in 1–16% and that the assessment of body proportions may be an important selection criterion for genetic testing [10–15]. SHOX haploinsufficiency is transmitted with a pseudoautosomal dominant inheritance pattern. The severity of short stature and the presence of LWD or ISS phenotype vary considerably even within the same family [13]. Our group demonstrated that the presence of disproportionate height, assessed by sitting height/ height ratio for age and sex (SH/H SDS), is one of the most common features of patients with SHOX defects [13]. In the present study, we assessed the SH/H SDS in a large group of children with normal growth and in children classified as ISS, as well as in children and adults with SHOX defects or TS, to establish the frequency of body disproportion in these conditions. Furthermore, we estimated the potential role of an abnormal SH/H SDS in selecting children initially considered ISS for SHOX testing. Subjects and Methods Subjects Cross-sectional data were collected on height and sitting height from 1,771 children with normal growth (height SDS >–2 and 2 above the mean for age
Malaquias et al.
8
Sitting height/height SDS
6
4
2
0
–2
Fig. 1. SH/H SDS in children with normal
growth and patients with ISS, SHOX defects and TS. The individual results are shown. Solid lines indicate mean and ±1 SD.
–4 Children with normal growth
Idiopathic short stature
SHOX defects
Turner syndrome
(n = 1,771)
(n = 128)
(n = 29)
(n = 73)
and sex [16]. We also evaluated children with disproportionate ISS and patients with SHOX defects by two previous scoring systems for selection of children for SHOX testing: the extremities/trunk ratio (Binder score) [11] and a scoring system based on various clinical features of children with SHOX defects (Rappold score) [12]. Cytogenetic and Molecular Analysis Chromosome analysis was performed in all female patients on chromosomal spreads obtained from peripheral blood lymphocyte cultures using standard karyotyping techniques with G-banding. Genomic DNA was isolated from peripheral blood leukocytes by standard methods from all disproportionate ISS patients, patients suspected of having LWD and their relatives. Defects in the SHOX gene were investigated as previously published [19]. Briefly, multiplex ligation-dependent probe amplification analysis of SHOX and PAR1 region was carried out using the commercial kits SALSA P018-C1 and P018-D1 SHOX (MCR Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. FISH analysis was performed where necessary. In patients without SHOX deletion, PCR and sequence analysis were performed for all coding exons of SHOX gene (primer sequences and amplification protocols available on request). Statistical Analysis Results were expressed as mean ± SD. Differences between groups were tested by t test or Kruskal-Wallis and χ2 or Fisher’s exact test, as appropriate. A p value 2 and were considered disproportionate, corresponding to 1.4% (95% CI 0.8–1.9%) of the total number of children with normal growth. The frequency of SH/H SDS 2 in control children (95% CI 0.5– 1.5%). SH/H SDS in Children Considered as Having ISS In total, 128 children classified as ISS aged 10 ± 3.5 years (from 4 to 17 years) had a height SDS of –2.6 ± 0.7 (fig. 1; table 1). Of these, 21 had SH/H SDS >2, which corresponds to 16.4% (95% CI 10.0–22.8%). This frequency is higher than observed in children with normal growth (1.4%, p < 0.001); 2 of the children with ISS had SH/H SDS +2 95% CI
Control
ISS
SHOX defects
Turner syndrome
882/889 7.9±1.71 0.3±0.91 0.4±1.1 –0.5±0.81 –0.4±0.91 0.1±0.9 1.4%1 0.8–1.9%
80/48 10.0±3.4 –2.6±0.7 –0.6±1.32 –3.2±0.8 –2.3±0.8 0.7±1.6 16.4% 10–23%
15/14 10.2±3.5 –2.0±1.1 0.7±0.9 –3.5±1.0 –0.9±0.93 3.7±1.63 88%5 75–100%
–/73 12.8±3.3 –2.8±1.3 0.3±1.1 –3.4±1.1 –2.4±1.4 1.9±1.64 48% 37–59%
Continuous variables are shown as the mean ± SD. 1 Children with normal growth vs. children with ISS, SHOX defects or TS, p < 0.001. 2 Children with ISS vs. children with normal growth, SHOX defects or TS, p < 0.001. 3 Children with SHOX defects vs. children with normal growth or ISS, p < 0.001. 4 Children with TS vs. children with normal growth or ISS, p < 0.001. 5 Children with SHOX defects vs. children with normal growth, ISS or TS, p < 0.001.
SH/H SDS >2 had signs of skeletal dysplasia and none of their first-degree relatives had evidence of LWD. Subsequent testing in all 21 disproportionate short children led to the detection of 4 (19%) cases with SHOX defects, a frequency higher than observed in unselected ISS children in a previous study in our group (3%, p < 0.01) [13]; 2 of these patients carried SHOX deletions and the other 2 carried previously described nonsense (p.Try35*) and missense (p.Arg147His) SHOX mutations [13]. SH/H SDS in Individuals with SHOX Defects A total of 58 patients (29 children aged 1.3–4.6 years, mean 10.6 ± 3.0 years) from 18 families had been identified with SHOX defects: 40 individuals from 15 families with SHOX gene deletion, 14 individuals from 1 family with a nonsense mutation (p.Try35*) and 4 individuals from 2 families with a missense mutation (p.Arg147His). Madelung deformity was found in 41% of children and 52% of adults with SHOX defects at the time of the first visit. Adults with SHOX defects were relatively shorter than children with SHOX defects (height SDS –2.7 ± 1.0 vs. –2.0 ± 1.1, p = 0.01). However, SH/H SDS was similar in both adults and children (3.7 ± 1.3 and 4.0 ± 1.4 in children and adults, respectively; fig. 2). The frequency of disproportionate short stature in children with SHOX defects was 88% (95% CI 75–100%) and 96% in adults (95% CI 90–100%). The mean height SDS, SH/H SDS and frequency of disproportionate short stature were similar in patients with or without features of LWD. 452
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
SH/H SDS in TS The mean age of girls with TS was 12.8 ± 3.3 years (from 5.0 to 17.6 years), their mean height SDS was –2.8 ± 1.3 and mean SH/H SDS was 1.9 ± 1.6 (fig. 1; table 1). Women with TS had a mean height SDS of –2.8 ± 1.1 and a mean SH/H SDS of 1.5 ± 1.1. Previous treatment with rhGH did not influence the SH/H SDS, but an inverse correlation between age at start of puberty (spontaneous or induced) and SH/H SDS (r = –0.2, p = 0.03) was observed. The frequency of body disproportion (SH/H SDS >2) was higher in girls than in women with TS (48 vs. 28%; p = 0.006) and lower than in patients with SHOX defects (p < 0.001; fig. 2). Only 1 girl had SH/H SDS 2, 15/19 had an abnormal Binder score, including the 4 Malaquias et al.
Fig. 2. Comparison of SH/H SDS in children and adults with isolated SHOX defects and TS: children and adults with SHOX defects had similar SH/H SDS whereas girls with TS were more disproportionate than women with TS (p = 0.006). Children and adults with SHOX defects were more affected than TS girls and women regarding body disproportion (p < 0.001). The individual results are shown. Solid lines indicate mean and ±1 SD.
Sitting height/height SDS
8
6
4
2
0
–2
–4
ISS patients with identified SHOX defects; 9 and 5 of these ISS children had a Rappold score above the cutoff of 4 and 7, respectively, and 2 patients classified as ISS with identified SHOX defects had a Rappold score of 4 (table 2).
Children
Adults
In the present study, we evaluated anthropometric measurements, mainly SH/H for age and sex, in a cohort of 1,771 children with normal growth, 128 children with ISS, 58 individuals with SHOX defects and 193 females with TS. Despite the height difference between the Dutch and Brazilian populations [17, 18], the SH/H SDS of the normal Brazilian population was similar to the reference for the Dutch population [16] (fig. 1; online suppl. fig. A, B). In children considered as ISS, body disproportion was 10 times more frequent than in children with normal growth (16.4 vs. 1.4%; table 1). Part of this difference is probably caused by the fact that short children have a higher average SH/H ratio than the general population [16], but it may also suggest that within the heterogeneous group of children with ISS there may be a subgroup in which growth impairment is associated with gene variants primarily affecting the epiphyseal growth plates. The high frequency of SHOX defects in this group of disproBody Disproportion and SHOX Defects
Adults
Turner syndrome
Table 2. Comparison between SH/H SDS and previous scores de-
scribed to select patients for SHOX studies (Binder [11] and Rappold [12] scores) in patients with SHOX defects and disproportionate ISS children SH/H SDS
Discussion
Children
SHOX defects
Binder Rappold score Rappold score score (cutoff >4) (cutoff >7)
Patients with SHOX defects Normal 3 3 Abnormal 36 36
11 23
17 17
Disproportionate ISS children Normal 4 Abnormal 19 (4) 15 (4)
10 (2) 9 (2)
14 (2) 5 (2)
The full Rappold and Binder scores were adequately calculated for 34 and 39 patients with SHOX defects, respectively, and for 19 disproportionate ISS children (including the 4 ISS children with SHOX defects). Values in parentheses represent ISS patients with SHOX defects. Abnormal, SH/H >2.
portionate ISS children (19%) in comparison to ISS children (3%) [13] is supportive for this idea. This possibility is also suggested in genome-wide association studies where several current height loci include genes involved in growth plate physiology [20]. Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
453
It has been well established that SHOX haploinsufficiency causes a wide spectrum of short stature phenotypes, including patients with TS [3], LWD [21, 22] and short stature without any specific features (ISS) [23]. The genotype-phenotype correlation in patients with SHOX defects is weak and incomplete expression in families with LWD has been demonstrated [9]. In the present study, we confirmed that SH/H SDS >2 is present in the vast majority of patients with SHOX defects (88–96%), independent of clinical phenotype (the presence or absence of features of LWD). In addition, SHOX defects were found in 19% of the children who were originally labeled as ISS, in spite of body disproportion. These observations support previous recommendations to test for SHOX defects in children with abnormal body proportions [10–15]. Although the present study was not designed to compare different strategies to select individuals for SHOX genetic tests, we compared the sensitivity of SH/H SDS, the extremities/trunk ratio (Binder score) [11] and Rappold score [12] for identifying individuals with SHOX defects (table 2). An abnormal Binder score or SH/H SDS was observed in 92% of individuals with SHOX defects and only 1 of them had both scores normal. Conversely, the Rappold score identified 68 and 50% of patients with SHOX defects using the cutoff of 4 and 7, respectively. This result might be explained by the fact that SH/H was evaluated as absolute values in the Rappold score, even though age is known to influence this ratio [16, 24]. Additionally, clinical findings related to Madelung deformity, such as bowing of forearm, short forearm and dislocation of ulna, account for an important part in this scoring system [12] and are usually absent in individuals with SHOX defects without LWD phenotype. Previous studies of children carrying SHOX defects suggested a relatively well-preserved prepubertal growth followed by a compromised pubertal growth due to premature growth plate fusion, thus causing premature growth arrest [13, 25, 26]. Indeed, we observed in our study that short stature is comparatively more severe in adults than in children with SHOX defects, while SH/H SDS was similar in both adults and children. The molecular diagnosis of patients with SHOX defects is likely to have therapeutic implications, as rhGH treatment associated or not with GnRH analogs might improve adult height [27, 28]. Girls and women with TS showed less disproportionate short stature than patients with SHOX defects, but their height SDS was lower. This suggests that in TS there 454
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
are other factors affecting bone growth, particularly spinal growth (table 1). Furthermore, SH/H SDS tends to improve with age in TS patients and this is inversely correlated with age at start of puberty, which suggests that the lack of gonadal estrogens could be an advantage in body proportion and skeletal deformity improvement in patients with TS in comparison to patients with SHOX defects. Estrogens play a pivotal role in bone mineralization regulating the pubertal growth spurt and growth plate fusion in both girls and boys. Girls with TS usually lack gonadal function and may present delayed bone age early in life. In contrast, eunuchoid body proportions, unfused epiphyses and tall stature were described in patients with aromatase deficiency. We hypothesize that the low exposure to estrogens of growth cartilage and the relatively late start of exogenous estrogens in most girls with TS protects them from early epiphyseal closure and may therefore attenuate body disproportion, allowing limbs to grow for a longer period in comparison to girls with isolated SHOX defects. In conclusion, disproportionate short stature is a common feature observed in patients with SHOX defects, more so than in females with TS. This confirms the important role of measuring body proportions in the diagnostic work-up of short children, and shows that SH/H SDS is a useful tool for selecting ISS children to undergo SHOX molecular studies. However, in most disproportionate children labeled ISS no SHOX defect could be found, suggesting that other genes involved in growth plate regulation could be responsible for growth impairment observed in these children.
Acknowledgments This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo – FAPESP (2008/50184-2, 2013/03236-5 and 2007/59555-0 to A.C.M.) and from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico – CNPq (301339/2008-9 to B.B.M.; 300982/2009-7 to I.J.P.A. and 304678/2012-0 to A.A.L.J.).
Disclosure Statement The authors declare that they have no competing financial interests.
Malaquias et al.
References 1 Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W: PHOG, a candidate gene for involvement in the short stature of turner syndrome. Hum Mol Genet 1997;6:1341–1347. 2 Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Nordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA: Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997; 16:54–63. 3 Clement-Jones M, Schiller S, Rao E, Blaschke RJ, Zuniga A, Zeller R, Robson SC, Binder G, Glass I, Strachan T, Lindsay S, Rappold GA: The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Hum Mol Genet 2000;9:695–702. 4 Ross JL, Kowal K, Quigley CA, Blum WF, Cutler GB Jr, Crowe B, Hovanes K, Elder FF, Zinn AR: The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome. J Pediatr 2005;147:499–507. 5 Neufeld ND, Lippe BM, Kaplan SA: Disproportionate growth of the lower extremities. A major determinant of short stature in Turner’s syndrome. Am J Dis Child 1978;132:296– 298. 6 Rongen-Westerlaken C, Rikken B, Vastrick P, Jeuken AH, de Lange MY, Wit JM, van der Tweel L, Van den Brande JL: Body proportions in individuals with Turner syndrome. The Dutch growth hormone working group. Eur J Pediatr 1993;152:813–817. 7 Gravholt CH, Weis Naeraa R: Reference values for body proportions and body composition in adult women with Ullrich-Turner syndrome. Am J Med Genet 1997;72:403–408. 8 Baldin AD, Armani MC, Morcillo AM, Lemos-Marini SH, Baptista MT, MacielGuerra AT, Guerra-Junior G: Body proportions in a group of Brazilian patients with Turner syndrome. Arq Bras Endocrinol Metabol 2005;49:529–535. 9 Jorge AA, Funari MF, Nishi MY, Mendonca BB: Short stature caused by isolated SHOX gene haploinsufficiency: update on the diagnosis and treatment. Pediatr Endocrinol Rev 2010;8:79–85. 10 Ross JL, Scott C Jr, Marttila P, Kowal K, Nass A, Papenhausen P, Abboudi J, Osterman L, Kushner H, Carter P, Ezaki M, Elder F, Wei F, Chen H, Zinn AR: Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 2001;86:5674–5680. 11 Binder G, Ranke MB, Martin DD: Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in schoolage children with unexplained short stature. J Clin Endocrinol Metab 2003; 88: 4891– 4896.
Body Disproportion and SHOX Defects
12 Rappold G, Blum WF, Shavrikova EP, Crowe BJ, Roeth R, Quigley CA, Ross JL, Niesler B: Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007; 44: 306–313. 13 Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Liborio DC, Kim CA, Arnhold IJ, Mendonca BB: SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Clin Endocrinol (Oxf) 2007;66:130–135. 14 Hirschfeldova K, Solc R, Baxova A, Zapletalova J, Kebrdlova V, Gaillyova R, Prasilova S, Soukalova J, Mihalova R, Lnenicka P, Florianova M, Stekrova J: SHOX gene defects and selected dysmorphic signs in patients of idiopathic short stature and Leri-Weill dyschondrosteosis. Gene 2012;491:123–127. 15 Kant SG, Broekman SJ, de Wit CC, Bos M, Scheltinga SA, Bakker E, Oostdijk W, van der Kamp HJ, van Zwet EW, van der Hout AH, Wit JM, Losekoot M: Phenotypic characterization of patients with deletions in the 3′-flanking SHOX region. PeerJ 2013;1:e35. 16 Fredriks AM, van Buuren S, van Heel WJ, Dijkman-Neerincx RH, Verloove-Vanhorick SP, Wit JM: Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–812. 17 Kuczmarski RJ, Ogden CL, GrummerStrawn LM, Flegal KM, Guo SS, Wei R, Mei Z, Curtin LR, Roche AF, Johnson CL: CDC growth charts: United States. Adv Data 2000; 314:1–27. 18 Silva DA, Pelegrini A, Petroski EL, Gaya AC: Comparison between the growth of Brazilian children and adolescents and the reference growth charts: data from a Brazilian project. J Pediatr (Rio J) 2010;86:115–120. 19 Funari MF, Jorge AA, Souza SC, Billerbeck AE, Arnhold IJ, Mendonca BB, Nishi MY: Usefulness of MLPA in the detection of SHOX deletions. Eur J Med Genet 2010;53:234–238. 20 Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, Willer CJ, Jackson AU, Vedantam S, Raychaudhuri S, Ferreira T, Wood AR, Weyant RJ, Segre AV, Speliotes EK, Wheeler E, Soranzo N, Park JH, Yang J, Gudbjartsson D, Heard-Costa NL, Randall JC, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid IM, Luan J, Thorleifsson G, Winkler TW, Goddard ME, Sin Lo K, Palmer C, Workalemahu T, Aulchenko YS, Johansson A, Zillikens MC, Feitosa MF, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer NL, Hayward C, Hottenga JJ, Jacobs KB, Knowles JW, Kutalik Z, Monda KL, Polasek O, Preuss M, Rayner NW, Robertson NR, Steinthorsdottir V, Tyrer JP, Voight BF, Wiklund F, Xu J, Zhao JH, Nyholt DR, Pellikka N, Perola M, Perry JR, Surakka I, Tam-
mesoo ML, Altmaier EL, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman DI, Chen C, Coin L, Cooper MN, Dixon AL, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan LM, Kettunen J, Konig IR, Kwan T, Lawrence RW, Levinson DF, Lorentzon M, McKnight B, Morris AP, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson JR, Turchin MC, Vandenput L, Verlaan DJ, Vitart V, White CC, Ziegler A, Almgren P, Balmforth AJ, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson JG, Freimer NB, Geus EJ, Glorioso N, Haiqing S, Hartikainen AL, Havulinna AS, Hicks AA, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpelainen TO, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki ML, Marusic A, Maschio A, Meitinger T, Mulas A, Pare G, Parker AN, Peden JF, Petersmann A, Pichler I, Pietilainen KH, Pouta A, Ridderstrale M, Rotter JI, Sambrook JG, Sanders AR, Schmidt CO, Sinisalo J, Smit JH, Stringham HM, Bragi Walters G, Widen E, Wild SH, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle WL, Nelis M, Peters MJ, Ripatti S, van Meurs JB, Aben KK, Ardlie KG, Beckmann JS, Beilby JP, Bergman RN, Bergmann S, Collins FS, Cusi D, den Heijer M, Eiriksdottir G, Gejman PV, Hall AS, Hamsten A, Huikuri HV, Iribarren C, Kahonen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer LJ, Lehtimaki T, Melander O, Mosley TH Jr, Musk AW, Nieminen MS, O’Donnell CJ, Ohlsson C, Oostra B, Palmer LJ, Raitakari O, Ridker PM, Rioux JD, Rissanen A, Rivolta C, Schunkert H, Shuldiner AR, Siscovick DS, Stumvoll M, Tonjes A, Tuomilehto J, van Ommen GJ, Viikari J, Heath AC, Martin NG, Montgomery GW, Province MA, Kayser M, Arnold AM, Atwood LD, Boerwinkle E, Chanock SJ, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley AT, Hengstenberg C, Hoffman W, Lathrop GM, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright AF, Assimes TL, Barroso I, Hofman A, Mohlke KL, Boomsma DI, Caulfield MJ, Cupples LA, Erdmann J, Fox CS, Gudnason V, Gyllensten U, Harris TB, Hayes RB, Jarvelin MR, Mooser V, Munroe PB, Ouwehand WH, Penninx BW, Pramstaller PP, Quertermous T, Rudan I, Samani NJ, Spector TD, Volzke H, Watkins H, Wilson JF, Groop LC, Haritunians T, Hu FB, Kaplan RC, Metspalu A, North KE, Schlessinger D, Wareham NJ, Hunter DJ, O’Connell JR, Strachan DP, Wichmann HE, Borecki IB, van Duijn CM, Schadt EE, Thorsteinsdottir U, Peltonen L, Uitterlinden AG, Visscher PM, Chatterjee N, Loos RJ, Boehnke M, McCarthy MI, Ingelsson E, Lindgren CM, Abecasis GR, Stefansson K, Frayling TM, Hirschhorn JN: Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 2010;467:832–838.
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
455
21 Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM: Mutation and deletion of the pseudoautosomal gene SHOX cause LeriWeill dyschondrosteosis. Nat Genet 1998;19: 70–73. 22 Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A, Cormier-Daire V: SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 1998;19:67–69. 23 Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, Heinrich U, Vlachopapadoupoulou E, Reinehr T, Onigata K, Ogata T: Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab 2002;87:1402–1406.
456
24 Jorge AA, Arnhold IJ: Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature. J Med Genet 2007; 44:e90, author reply e91. 25 Kosho T, Muroya K, Nagai T, Fujimoto M, Yokoya S, Sakamoto H, Hirano T, Terasaki H, Ohashi H, Nishimura G, Sato S, Matsuo N, Ogata T: Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of turner syndrome. J Clin Endocrinol Metab 1999;84:4613–4621.
Horm Res Paediatr 2013;80:449–456 DOI: 10.1159/000355411
26 Fukami M, Nishi Y, Hasegawa Y, Miyoshi Y, Okabe T, Haga N, Nagai T, Tanaka T, Ogata T: Statural growth in 31 Japanese patients with SHOX haploinsufficiency: support for a disadvantageous effect of gonadal estrogens. Endocr J 2004;51:197–200. 27 Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quigley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172. 28 Scalco RC, Melo SS, Pugliese-Pires PN, Funari MF, Nishi MY, Arnhold IJ, Mendonca BB, Jorge AA: Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency. J Clin Endocrinol Metab 2010;95:328–332.
Malaquias et al.
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
