Nat Genet 19:7073. Sanger sequencing excluded the presence of a SHOX pathogenic coding sequence variant in all individuals. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. Analysis of a bone marrow sample from the mother would allow us to confirm this hypothesis. Heterozygous deletions or sequence variants resulting in haploinsufficiency for the short-stature homeobox-containing gene (SHOX;MIM ID # 312865) are the only known genetic cause of LWD [2, 3] and have also been reported in 1.515% of cases of idiopathic short stature (ISS; MIM ID # 300582), defined as a height below the 3rd centile or two standard deviations below the mean (2 SD) in the absence of known specific causative disorders [4,5,6,7,8]. Google Scholar, Zinn AR, Wei F, Zhang L, Elder FF, Scott CI Jr, Marttila P, Ross JL (2002) Complete SHOX deficiency causes Langer mesomelic dysplasia. This may occur through at least three possible mechanisms: 1) the extra whole or partial copy/copies disrupt the normal copy of SHOX and the inserted copy/copies is/are not functional because they lack the necessary regulatory sequences; 2) the extra copy/copies is/are present in tandem with the normal copy, either affecting SHOX regulatory sequences or modifying the distance between the gene and the enhancers or regulatory sequences; and 3) the extra copy/copies is/are localized further upstream or downstream from the normal copy, which would increase the distance between the normal copy and the regulatory regions. Clinical and molecular characterization of, Unexpected phenotype in a boy with trisomy of the. Normal peaks were classified as showing a ratio of 0.651.35, whereas duplications were classified as having a ratio greater than 1.35. All samples were reported to have a normal G-banding karyotype. To date, heterozygous deletions of two distinct regions of the pseudoautosomal region 1 (PAR1), the short-stature homeobox-containing gene (SHOX; MIM 313865) (4, 5) and the downstream enhancer region (68) or point and small insertions or deletions (indel) mutations within SHOX, have been identified in up to 60% of LWD and approximately 15% ISS patients (911). This variability is not unexpected because it is well documented that SHOX haploinsufficiency due to SHOX deletion/mutations exerts a widely variable effect on LWD patient's height (5.6 to 0.3 SDS) (3032, 3335). ISS patients with stature less than 2 SDS were ascertained using the current consensus criteria (3). The results from Patient 3 suggest an additional SHOX critical region near X:581,000, and the deletions in Patients 1 and 2 provide further evidence that the loss of CNE-3 can cause ISS. The complete SHOX duplications ranged in size from 38 to 346 kb, extending from the SHOX 5 flanking region through at least exon 6b in three ISS cases, and from the SHOX 5 flanking region through to approximately 100 kb downstream of SHOX in the single LWD case presenting with a complete gene duplication (Fig. The probands presented here were consented for SHOX analysis as part of their routine clinical care within the UK National Health Service (Patients 18) and the Switzerland Health Service (Patient 9). S. Benito-Sanz, E. Barroso, D. Heine-Suer, A. Hisado-Oliva, V. Romanelli, J. Rosell, A. Aragones, M. Caimari, J. Argente, J. L. Ross, A. R. Zinn, R. Gracia, P. Lapunzina, A. Campos-Barros, K. E. Heath, Clinical and Molecular Evaluation of SHOX/PAR1 Duplications in Lri-Weill Dyschondrosteosis (LWD) and Idiopathic Short Stature (ISS), The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 2, 1 February 2011, Pages E404E412, https://doi.org/10.1210/jc.2010-1689. 2). In contrast with deletions, the causative mechanism(s) for duplications is less clear as there is no loss of sequence material. In contrast, assignation of causality for the duplications in Patients 47 and 9 is more difficult; they were ascertained through their short stature which is a common phenotype with multiple causes. No qPCR was undertaken in proband 14 due to lack of DNA and in proband 15 because the duplicated region did not encompass any of the three amplicons. In particular cases, SHOX duplications were further delimited using an additional MLPA assay including six novel probes, located between the Xp telomere and SHOX (kindly donated by Dr. Simon Thomas, Wessex Regional Genetics Service, Wiltshire, UK). No qPCR was undertaken for proband 15 because the duplication did not include any of the analyzed regions. Although duplications flanking the SHOX gene have also been reported, their pathogenicity is more difficult to establish. 2). The most recent cis-regulatory element to be identified was ZED (Zeugopodal Enhancer Downstream of SHOX) located at X:827,128827,691 [19] which was shown to be the critical region within the common downstream 47.5kb X:780,550828,092 deletion [17, 22]. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. 2). Improved molecular diagnostics of idiopathic short stature and allied disorders: quantitative polymerase chain reaction-based copy number profiling of SHOX and pseudoautosomal region 1. Copyright 2011 by The Endocrine Society, High-risk growth trajectory related to childhood overweight/obesity and its predictive model at birth, Role of liver enzymes in the relationship between particulate matter exposure and diabetes risk: a longitudinal cohort study, TSH and FT4 reference intervals in pregnancy: a systematic review and individual participant data meta-analysis, Associations between maternal lipid blood levels at 13, Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia, The Journal of Clinical Endocrinology & Metabolism, About The Journal of Clinical Endocrinology & Metabolism, Receive exclusive offers and updates from Oxford Academic, Improved Molecular Diagnostics of Idiopathic Short Stature and Allied Disorders: Quantitative Polymerase Chain Reaction-Based Copy Number Profiling of, GH Treatment to Final Height Produces Similar Height Gains in Patients With SHOX Deficiency and Turner Syndrome: Results of a Multicenter Trial. PAR1 haplotype analysis confirmed that proband 8 had inherited the allele with the extra copies from his mother and shared the same nonduplicated paternal allele with his healthy brother, who had inherited the nonduplicated alleles form both parents. In our laboratory, the frequency of PAR1 duplications is very similar to that of SHOX point mutations and indels (15 vs. 18). on behalf of the 2007 ISS Consensus Workshop participants. Since flanking CNVs are generally associated with mild SHOX-related phenotypes, they could result in reduced expression rather than complete haploinsufficiency. DJB and NST took part in conceptualisation; DJB, JIH, PJDF, RJH, LL, NST involved in validation; DJB, EG, JIH, PJDF, RJH, MHE, PK, RVH, LL, MTCR, ZM, AG, CRH, MA took part in investigation; EG, MHE, PK, RVH, MTCR, ZM, AG, CRH, MA involved in resources; DJB and NST involved in writingoriginal draft; DJB and NST participated in writingreview & editing; NST took part in supervision. Downstream deletions have been frequently reported in patients with LeriWeill dyschondrosteosis or idiopathic short stature. We reviewed the 745 clinical subtelomeric MLPA referrals that our diagnostic unit had carried out during the last 2 yr. Only two complete SHOX duplications were detected (0.27%). Proband 15 carried a duplication located upstream of SHOX, which did not include any SHOX coding sequence (Fig. In family 15, II.3 has an inversion of chromosome 14q22-q24, and III.1 has mental retardation and premature adrenarche. However, CNVs near the SHOX gene should be interpreted with caution as the PAR1 region is highly repetitive and prone to structural rearrangements. The height SDS and SHOX copy number are shown below each individual. No SHOX haplotype was shared between these six probands. 2022 BioMed Central Ltd unless otherwise stated. Lri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm.

Partial SHOX duplications were more frequently associated with LWD (n = 8 probands) than ISS (n = 2). TAD boundary regions contain insulators that block interactions across adjacent TADs [41] and variants that disrupt TAD structures can cause malformation syndromes through de novo enhancerpromoter interactions and mis-expression [40]. All four previously reported upstream deletions involved the loss of CNE-3, plus CNE-2 and/or CNE-5 [24,25,26]. The study was approved by the local ethical committees and all participants provided informed consent. , An increased SHOX copy number (n > 2), determined by either MLPA or qPCR or by the observation of three alleles by microsatellite marker analysis. With regard to the apparent association between SHOX partial or complete duplications and LWD/ISS, we hypothesize that SHOX expression from the allele harboring the duplication is reduced or ablated, resulting in SHOX haploinsufficiency and thus clinically manifesting as LWD or ISS. Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory domain. There are three known CNEs upstream of SHOX which have transcriptional activity: CNE-5 (X:398,357398,906), CNE-3 (X:460,279460,664) and CNE-2 (516,610517,229) [23]. https://doi.org/10.1038/nature08516, Montalbano A, Juergensen L, Roeth R, Weiss B, Fukami M, Fricke-Otto S, Binder G, Ogata T, Decker E, Nuernberg G, Hassel D, Rappold GA (2016) Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency. LeriWeill dyschondrosteosis (LWD; MIM ID # 127300) [1], characterised by mesomelic disproportionate short stature and Madelung deformity of the wrist, is a pseudoautosomal dominantly inherited skeletal dysplasia. stature gene overdosage shox syndrome presented turner due tall caption Identification and characterization of different. Eur J Hum Genet 20(1):125127. SHOX mutations detected by FISH and direct sequencing in patients with short stature. Our results suggest that SHOX duplications may have an effect on human skeletal growth. We report on the largest collection of LWD or ISS cases associated with SHOX duplications or multiple copy number detected to date. The inheritance of the duplication could not be ascertained in the remaining three cases due to lack of parental DNA samples (probands 4, 9, and 10). The duplications in Patient 5 and 9 were confirmed and sized using single-nucleotide polymorphism array (SNP array) testing in external laboratories. https://doi.org/10.1016/j.gene.2017.06.034, Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Proband heights and clinical details are shown in Fig. Part of Cell 154(1):185196. The characterisation of deletions downstream of SHOX identified putative DNA elements that act as long-range enhancers [12, 13]. Four complete and 10 partial SHOX duplications as well as one duplication upstream of SHOX were detected in nine LWD and six ISS probands by MLPA and confirmed by alternative methods. Cosegregation of the duplication with the presence of short stature and Madelung deformity was apparent in three LWD families (probands 8, 11, and 12). Search for other works by this author on: Une affection congenitale et symetrique du developpement osseux: la dyschondrosteose. All patients underwent SHOX diagnostic testing, comprising sequencing of the SHOX coding exons and MLPA. There are a number of potential explanations that can be considered. 2. , The presence of a deletion in heterozygosity corresponding to MLPA probe L5101 observed in probands 6 and 8 and in homozygosity in proband 9. close to X:1,314,890) [38], although other publications describe the SHOX TAD as covering an approximate region of either X:284,6001,355,600 [25] or X:350,0011,035,000 [37]. Egyptian Journal of Medical Human Genetics Although both mother and daughter presented with LWD, they show different degrees of affectation, the mother is shorter and has a milder form of Madelung deformity compared with her daughter. The qPCR was performed in a final volume of 10 l. Secondly, the presence of additional copies of a regulatory element may act to reduce the availability of transcription factors that bind to these elements. The SHOX 3' TAD boundary has been mapped immediately upstream of the CRLF2 gene (i.e. Interestingly, three probands were observed, by MLPA and qPCR, to have multiple copies of the affected region (probands 8, 10, and 13; Table 2). Complete SHOX deficiency causes Langer mesomelic dysplasia. Furthermore, the large intra- and interfamiliar phenotypic variability observed in LWD (9, 36) is an additional hurdle for the cosegregation analysis of these patients. Article Eur J Hum Genet 18:527532. The layered H3K27Ac mark approximately 10kb upstream of the deletion in Patient 3 does not correspond to any known regulatory element. In our cohort, mental retardation and dysmorphic facies were also reported in the clinical records of ISS proband 14. 3. Nature 518:331336.

The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Homozygous or compound heterozygous SHOX mutations as well as biallelic deletions of SHOX and/or the downstream PAR1 region result in a more severe phenotype, known as Langer mesomelic dysplasia (MIM 249700) (1215). Each MLPA was repeated twice except for proband 13, which was repeated three times. An inverted tandem duplication may allow single-stranded DNA to form a quasipalindromic loop which could block any enhancers contained within the region. Pedigrees and inheritance patterns of the four families where samples from additional family members were available. We cannot rule out that the additional material is located elsewhere in the genome, and the exact location and orientation of the triplicated and duplicated segments could not be determined.

In contrast, there are only four cases in the literature of upstream deletions that remove regulatory elements. Until recently, the molecular diagnosis of LWD, Langer mesomelic dysplasia, and ISS patients was commonly undertaken by microsatellite and/or fluorescence in situ hybridization (FISH) of the SHOX encompassing PAR1 sequence (9, 10, 23). By using this website, you agree to our This technique has permitted us now to identify 14 complete or partial SHOX duplications or multiple copies (n > 3) and one duplication upstream of SHOX in nine LWD and six ISS probands. Google Scholar, Shears DJ, Guillen-Navarro E, Sempere-Miralles M, Domingo-Jimenez R, Scambler PJ, Winter RM (2002) Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. The test samples were normalized to the two copy GAPDH control gene. Centromeric probes DXZ2 and DYZ3 were used as controls. The assessment of cosegregation with the phenotype is often hampered in the absence of large families with a high number of affected and unaffected members. An increase in SHOX copy number was detected in the skin fibroblast DNA sample but absent in lymphocyte DNA, suggesting that somatic mosaicism had occurred. https://doi.org/10.1210/jc.2010-1689, Bunyan DJ, Baffico M, Capone L, Vannelli S, Iughetti L, Schmitt S, Taylor E-J, Brown SB, Herridge AA, Predieri B, Shears D, Forabosco A, Coviello DA (2016) Duplications upstream and downstream of SHOX identified as novel causes of LeriWeill dyschondrosteosis or idiopathic short stature. Growth pattern and body proportion in a female with short stature homeobox-containing gene overdosage and gonadal estrogen deficiency. All patients referred specifically for SHOX analysis were included in the cohort, regardless of the referral reason.

Rare dosage abnormalities flanking the SHOX gene. As Patient 3 had a deletion below the detection limits of aCGH, long-range PCR of the deletion region was carried out in order to define the breakpoints. Mutation and deletion of the pseudoautosomal gene. Part of the AluY sequence from the 3 deletion end of the 4959-bp deletion is present (61 bp), which aligned with the AluSc sequence from the 5 deletion end resulting in homologous recombination. Two of the deletions remove a single conserved non-coding element (CNE-3) while the third does not remove any known regulatory element but is just 4kb upstream of SHOX, and the deleted region may be important in limb bud development. The probands presented here were consented for SHOX analysis as part of their routine clinical care within the UK National Health Service (Patients 18) and the Switzerland National Health Service (Patient 9), so research ethics committee approval is not applicable for this study according to the NHS Health Research Authority guidelines (hra.nhs.uk). Nature 485:376380. Long-range PCR was also required for patient 2, but that involved a single pre-determined primer pair. 2). The two duplications in Patient 8 segregate with LWD in the proband and two other affected family members. ND, Height not documented. The homozygous deletion of the 3 enhancer of the, Trisomy of the short stature homeobox-containing gene (. The average values of the qPCR and MLPA assays are shown for proband 13. Importantly, no duplication was observed in 340 controls with normal height or 104 overgrowth referrals suggesting that they associate specifically with LWD or ISS. https://doi.org/10.1038/ejhg.2011.210, Verdin H, Fernndez-Min A, Benito-Sanz S, Janssens S, Callewaert B, De Waele K, De Schepper J, Franois I, Menten B, Heath KE, Gmez-Skarmeta JL, De Baere E (2015) Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape. Cite this article. The approximate coordinates are according to chromosome X, National Center for Biotechnology Information (Bethesda, MD) assembly GRCh37. https://doi.org/10.15252/emmm.201606623, Li Q, Barkess G, Qian H (2006) Chromatin looping and the probability of transcription. For this purpose, it would be essential to collect and document clinical and molecular data from not only the clinically affected but also their unaffected family members. Sci Rep 3(5):17667. https://doi.org/10.1038/srep17667, Shima H, Tanaka T, Kamimaki T, Dateki S, Muroya K, Horikawa R, Kanno J, Adachi M, Naiki Y, Tanaka H, Mabe H, Yagasaki H, Kure S, Matsubara Y, Tajima T, Kashimada K, Ishii T, Asakura Y, Fujiwara I, Soneda S, Nagasaki K, Hamajima T, Kanzaki S, Jinno T, Ogata T, Fukami M, SHOX The Japanese study group (2016) Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and LeriWeill dyschondrosteosis. In contrast, the deletion in Patient 3 does not contain any known regulatory elements.

This approach identified a potential additional regulatory element at approximately X:970,000 [20, 21]. PubMed Therefore, the deleted interval may be essential for normal SHOX expression. Deletions flanking the SHOX gene are an established cause of SHOX-related phenotypes. The MLPA probes are named according to kit P018D1 and are indicated by gray boxes, microsatellite markers are indicated by gray ovals, and qPCR amplicons are indicated by gray diamonds. 2). A novel class of pseudoautosomal region 1 (PAR1) deletions downstream of SHOX is associated with Lri-Weill dyschondrosteosis (LWD). The deleted region removes part of region that is acetylated at three of the four developmental stages for which data are available (E33, E41, E44 and E47 datasets) [31]. The authors have no relevant financial or non-financial interests to disclose. TADs are discrete compartments of approximately 1Mb in size, which restrict regulatory chromosomal interactions [38, 40]. 1), 12, and 13 and from both parents of proband 8 (Supplemental Fig. https://doi.org/10.1016/j.tig.2006.02.004, Kleinjan D-J, Coutinho P (2009) Cis-ruption mechanisms: disruption of cis-regulatory control as a cause of human genetic disease. SHOX phenotypic variability may also be influenced by modifier genes such as CYP26C1 [34]. We propose that the clinical manifestation associated with partial and complete SHOX duplications is dependent on the physical localization of the duplicated sequence. Recent articles have reported the detection of SHOX duplications by subtelomeric MLPA assay in clinical referrals unrelated with LWD or ISS (19, 20, 22). Multiplex ligation-dependent probe amplification, Leri A, Weill J (1929) Une affection congenitale et symetrique du developpement osseux: la dyschondrosteose. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Parallel comparative genomic studies identified multiple conserved non-coding DNA elements (CNEs) downstream of SHOX, four of which have been demonstrated to have transcriptional activity, namely CNE4 (X:714,085714,740 (hg19)), CNE5 (X:750,825751,850), CNE7 (ECR1; X:780,700781,220) and CNE9 (ECS4; X:834,746835,567) [14,15,16,17]. 1 and Table 1. No pathogenic PAR1 deletions or point or indel SHOX mutations were identified in the 15 probands. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, Wiltshire, UK, David J. Bunyan,James I. Hobbs,Philippa J. Duncan-Flavell,Rachel J. Howarth&N. Simon Thomas, School of Medicine, University of Southampton, Southampton, SO16 6YD, Hampshire, UK, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK, Department of Paediatric Endocrinology, Royal London Childrens Hospital, Whitechapel Road, Whitechapel, London, E1 1BB, UK, Department of Clinical Genetics, Guys Hospital, Borough Wing, 7th Floor, London, SE1 9RT, UK, Paediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, Switzerland, Department of Medical Genetics, University Hospitals of Geneva, Geneva, Switzerland, Roxane Van-Heurk&Maria Teresa Carminho-Rodrigues, Laboratoire de Diagnostic Molculaire et Gnomique, University Hospitals of Geneva, Geneva, Switzerland, Department of Paediatric Endocrinology and Diabetes, Birmingham Childrens Hospital, Steelhouse Lane, Birmingham, B4 6NH, West Midlands, UK, Childrens and Adolescent Services, Frimley Park Hospital, Portsmouth Road, Camberley, GU16 7UJ, Surrey, UK, Department of Paediatric Endocrinology, Evelina London Childrens Hospital, St Thomass Hospital, Westminster Bridge Road, London, SE1 7EH, UK, You can also search for this author in Huber C , Rosilio M , Munnich A , Cormier-Daire V; Chen J , Wildhardt G , Zhong Z , Rth R , Weiss B , Steinberger D , Decker J , Blum WF , Rappold G, Shears DJ , Guillen-Navarro E , Sempere-Miralles M , Domingo-Jimenez R , Scambler PJ , Winter RM, Zinn AR , Wei F , Zhang L , Elder FF , Scott Jrb CI , Marttila P , Ross JL, Campos-Barros A , Benito-Sanz S , Ross JL , Zinn AR , Heath KE, Bertorelli R , Capone L , Ambrosetti F , Garavelli L , Varriale L , Mazza V , Stanghellini I , Percesepe A , Forabosco A, Adamson KA , Cross I , Batch JA , Rappold GA , Glass IA , Ball SG, Thomas NS , Harvey JF , Bunyan DJ , Rankin J , Grigelioniene G , Bruno DL , Tan TY , Tomkins S , Hastings R, Iughetti L , Capone L , Elsedfy H , Bertorelli R , Predieri B , Bruzzi P , Forabosco A , El Kholy M, D'haene B , Hellemans J , Craen M , De Schepper J , Devriendt K , Fryns JP , Keymolen K , Debals E , de Klein A , de Jong EM , Segers K , De Paepe A , Mortier G , Vandesompele J , De Baere E, Stuppia L , Calabrese G , Gatta V , Pintor S , Morizio E , Fantasia D , Guanciali Franchi P , Rinaldi MM , Scarano G , Concolino D , Giannotti A , Petreschi F , Anzellotti MT , Pomilio M , Chiarelli F , Tumini S , Palka G, Benito-Sanz S , Gorbenko del Blanco D , Huber C , Thomas NS , Aza-Carmona M , Bunyan D , Maloney V , Argente J , Cormier-Daire V , Campos-Barros A , Heath KE, Gatta V , Antonucci I , Morizio E , Palka C , Fischetto R , Mokini V , Tumini S , Calabrese G , Stuppia L, Barroso E , Benito-Sanz S , Belinchn A , Yuste-Checa P , Gracia R , Aragones A , Campos-Barros A , Heath KE, Funari MF , Jorge AA , Souza SC , Billerbeck AE , Arnhold IJ , Mendonca BB , Nishi MY, Sobradillo B , Aguirre A , Aresti U , Bilbao A , Fernndez-Ramos C , Lizrraga A , Lorenzo H , Madariaga L , Rica I , Ruiz I , Snchez E , Santamara C , Serrano JM , Zabala A , Zurimendi B , Hernndez M, 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, Turner DJ , Miretti M , Rajan D , Fiegler H , Carter NP , Blayney ML , Beck S , Hurles ME, Grigelioniene G , Schoumans J , Neumeyer L , Ivarsson A , Eklf O , Enkvist O , Tordai P , Fosdal I , Myhre AG , Westphal O , Nilsson NO , Elfving M , Ellis I , Anderlid BM , Fransson I , Tapia-Paez I , Nordenskjld M , Hagens L , Dumanski JP, Rappold GA , Fukami M , Niesler B , Schiller S , Zumkeller W , Bettendorf M , Heinrich U , Vlachopapadoupoulou E , Reinehr T , Onigata K , Ogata T, Binder G , Renz A , Martinez A , Keselman A , Hesse V , Riedl SW , Husler G , Fricke-Otto S , Frisch H , Heinrich JJ , Ranke MB, Rappold G , Blum WF , Shavrikova EP , Crowe BJ , Roeth R , Quigley CA , Ross JL , Niesler B, Durand C , Bangs F , Signolet J , Decker E , Tickle C , Rappold G, Oxford University Press is a department of the University of Oxford. https://doi.org/10.1038/jhg.2016.18, Benito-Sanz S, Barroso E, Heine-Suer D, Hisado-Oliva A, Romanelli V, Rosell J, Aragones A, Caimari M, Argente J, Ross JL, Zinn AR, Gracia R, Lapunzina P, Campos-Barros A, Heath KE (2011) Clinical and molecular evaluation of SHOX/PAR1 duplications in LeriWeill dyschondrosteosis (LWD) and idiopathic short stature (ISS). https://doi.org/10.1086/449313, Bertorelli R, Capone L, Ambrosetti F, Garavelli L, Varriale L, Mazza V, Stanghellini I, Percesepe A, Forabosco A (2007) The homozygous deletion of the 3 enhancer of the SHOX gene causes Langer mesomelic dysplasia.