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Growth abnormalities resulting in short stature in genetic syndromes.


Lena Dain, M.D., Stavit A. Shalev, M.D. 
Haemek Genetic Institute, HaEmek Medical Center, Afula, Israel


Corresponding Author:     Lena Dain, M.D.
                                             Haemek Genetic Institute 
                                             Haemek Medical Center
                                             21 Itzhak Rabin St., Afula 18101, Israel
                                             Tel: +972-506265842, Fax: +972-46494425
                                             Email: lena2303@gmail.com
Abstract:

Short stature is a common problem in children and adolescents, and has been reported in a wide variety of genetic syndromes. In this article, we provide an overview of clinical features typical to handful genetic syndromes in which short stature is a cardinal feature, and for which there is a well based core data. These disorders include chromosomal abnormalities such as Down and Turner syndromes, monogenic syndromes (Noonan syndrome and other selected  syndromes caused by RAS/MAPK pathway genes, Cornelia de Lange syndrome and SHOX gene abnormalities) and epigenetic mechanism abnormalities, including Silver Russell syndrome and Prader-Willi syndrome. In addition, the article discusses potential mechanisms for abnormal growth in various genetic syndromes. Early diagnosis of the cause of short stature in some of these disorders allows for earlier treatment, and has the potential for a better outcome in children with growth abnormality.

Introduction

Various classifications of growth abnormalities leading to short stature have been proposed in the literature, mainly based on clinical grounds. These include the distinction of pre-natal (small for gestational age, SGA) and post-natal short stature, implying that most congenital hormonal errors are manifested after birth. Another widely accepted classification sorts the short statured individuals to proportionate versus disproportionate, assuming that most inborn errors are of cartilage or bone formation; hence most of skeletal syndromes will be manifested as the latter. Although generally useful, these classifications, like others, have limited accuracy, since many cases are overlapping, and unusual cases are commonly observed in the clinical arena. 

Large numbers of genetic conditions associated with short stature have been described. Of these, over 500 have well-characterized phenotype with known genetic basis, and about 150 are Mendelian phenotypes whose molecular basis is unknown. The list also includes almost 200 phenotypes for which the Mendelian basis is only suspected (OMIM). The following chapter delineates clinical features typical to handful genetic syndromes in which short stature is a cardinal feature, and for which there is a well based core data. Naturally, many other syndromes and genetic conditions known to date, or others yet to be deciphered, will not be reviewed.

Chromosomal abnormalities

Down syndrome: 
Phenotypic characteristics: 
The phenotype is complex and varies both in terms of the presenting features and of their severity. Down syndrome (DS) is characterized by cognitive impairment, craniofacial alterations and muscle hypotonia, occasional heart and/or gut malformations and leukemia. The more common physical features are hypotonia, small brachycephalic head, epicanthic folds, flat nasal bridge, upward slanting palpebral fissures, Brushfield spots, small mouth and ears, excessive skin of neck, single transverse palmar crease, and short fifth finger with clinodactyly. The degree of cognitive impairment is variable, ranging from mild to only occasionally severe.  There are increased risks for other medical problems, including congenital heart defects (50%), leukemia (less than 1%), hearing loss (75%), otitis media (50-75%), Hirschsprung disease (less than 1%), gastrointestinal atresia (12%), eye disease (60%) including cataract (15%) and severe refractive errors (50%), hip dislocation (6%), obstructive sleep apnea (50-75%) and thyroid disease (15%)  ADDIN EN.CITE <EndNote><Cite><Year>2001</Year><RecNum>129</RecNum><DisplayText>[1]</DisplayText><record><rec-number>129</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>American Academy of Pediatrics: Health supervision for children with Down syndrome</title><secondary-title>Pediatrics</secondary-title><alt-title>Pediatrics</alt-title></titles><periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></periodical><alt-periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></alt-periodical><pages>442-9</pages><volume>107</volume><number>2</number><edition>2001/02/07</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Body Height</keyword><keyword>Body Weight</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>*Down Syndrome/physiopathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Male</keyword><keyword>Patient Care/methods/*standards</keyword><keyword>Reference Values</keyword></keywords><dates><year>2001</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1098-4275 (Electronic)&#xD;0031-4005 (Linking)</isbn><accession-num>11158488</accession-num><work-type>Guideline&#xD;Practice Guideline</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11158488</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_1" \o ", 2001 #129" 1]. 
Genetic etiology:
DS is caused by an extra copy of chromosome 21. In approximately 95% of children with DS, the condition is caused by non-familial trisomy 21. In approximately 3-4% of affected individuals, the extra chromosomal material is the result of an unbalanced translocation between chromosome 21 and another acrocentric chromosome, usually chromosome 14. About 75% of these unbalanced translocations appear de novo, and one forth is the result of familial translocation. In the remaining 1-2% of persons with the DS phenotype two cell lines are present: one is normal, and the other is trisomy 21, namely, mosaicism (American Academy of Pediatrics, 2001). The prevailing hypothesis for the patho-mechanism is that individual phenotypes are caused by an extra copy of one or more of approximately 310 genes present on chromosome 21, described as being dosage-sensitive  ADDIN EN.CITE <EndNote><Cite><Author>Lana-Elola</Author><Year>2011</Year><RecNum>28</RecNum><DisplayText>[2]</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lana-Elola, E.</author><author>Watson-Scales, S. D.</author><author>Fisher, E. M.</author><author>Tybulewicz, V. L.</author></authors></contributors><auth-address>MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK.</auth-address><titles><title>Down syndrome: searching for the genetic culprits</title><secondary-title>Dis Model Mech</secondary-title><alt-title>Disease models &amp; mechanisms</alt-title></titles><periodical><full-title>Dis Model Mech</full-title><abbr-1>Disease models &amp; mechanisms</abbr-1></periodical><alt-periodical><full-title>Dis Model Mech</full-title><abbr-1>Disease models &amp; mechanisms</abbr-1></alt-periodical><pages>586-95</pages><volume>4</volume><number>5</number><edition>2011/09/01</edition><keywords><keyword>Brain/growth &amp; development/physiopathology</keyword><keyword>Down Syndrome/complications/*genetics/physiopathology</keyword><keyword>Humans</keyword><keyword>Memory/physiology</keyword><keyword>Motor Activity/physiology</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1754-8411 (Electronic)&#xD;1754-8403 (Linking)</isbn><accession-num>21878459</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21878459</url></related-urls></urls><custom2>3180222</custom2><electronic-resource-num>10.1242/dmm.008078</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_2" \o "Lana-Elola, 2011 #28" 2]. 
Growth:
Except for the primary chromosomal abnormality, which is directly related to an abnormal growth, some of the medical conditions strongly associated with DS might also have significant contribution to growth disturbances. Among the prominent disorders are hypothyroidism, celiac disease and congenital heart defects. Medical interventions intended to treat those disturbances may have an effect on the natural history of growth. For an example, children with severe heart defects were found to show growth retardation during their first year of life, while after this period they had growth velocities similar to the healthy children with DS  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Van Gameren-Oosterom, 2012 #29" 3].
Among otherwise healthy individuals with DS, retarded growth is apparent during pregnancy. Throughout the first three years of life they show slower height gain compared to the general population. The gap stays relatively constant during the first 3-12 years. Later, a further deflection in growth is observed, a pattern which is similar among boys and girls. Thus, children with DS show growth retardation during the critical periods of growth, in which the highest growth velocity occurs (infancy and puberty). In puberty, an early or short growth spurt also limits final growth, leading to a substantial difference in final height - 20.4 cm in boys and 18.9 cm in girls  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Van Gameren-Oosterom, 2012 #29" 3].

Turner syndrome
Phenotypic characteristics:
The syndrome is usually associated with reduced adult height and gonadal dysgenesis, which results in insufficient circulating levels of female sex steroids leading to premature ovarian failure and infertility. The most frequent congenital anomalies detected by ultrasound examinations during pregnancy are cystic hygroma (59.5%), hydrops fetalis (19%) and congenital heart defects (7.8%), the most frequent being aortic coarctation [3].
Genetic etiology:
Turner syndrome (TS) is associated with abnormalities of the X chromosome.
The genetic background is highly variable, and mosaicism (presence of two or more cell lines) frequently occurs. Classically, the karyotype 45,X was considered the prime etiology, but it has been observed in only about 50% of TS individuals, whereas the remaining cases comprise mosaic karyotypes (cells with 45,X and cells with 46XX), karyotypes with an isochromosome of X (i.e. duplication of one arm of chromosomes X's arm, such as i(Xq) or i(Xp)), deletions of the short or long arm of the X chromosome (Xp- or Xq-), ring chromosome X (rX), or karyotypes with presence of entire or part of chromosome Y [3, 4].  Haploinsufficiency of the SHOX gene, located on chromosome X, seems to explain the reduction of final height and other features associated with the syndrome. Effects of SHOX gene mutations will be discussed later in this chapter. 
Growth:
Short stature affects 95-99% of girls with TS [5]. Growth retardation is already present in-utero, with birth weight of about 1 Standard Deviation (SD) below the mean. This delay aggravates during infancy and childhood, reaching a height which is about 2 SD below the mean. Later, around the age of 14 years, following the lack of pubertal growth spurt, the height is about - 4 SD below the mean. The growth phase is prolonged, achieving a spontaneous final height of � 2.6 SD or about 20 cm below the normal height [6]. Despite the fact that growth hormone (GH) deficiency is not apparent in TS, the GH-IGF-I-IGFBP-3 axis is disturbed, and increased levels of IGFBP-3 proteolytic activity have been described in adults with TS in association with low circulating levels of IGD-L. Significant gain in height over predicted adult height following GH therapy and sex steroid replacement therapy has been reported [7, 8].


Monogenic syndromes

Noonan syndrome and other selected  syndromes caused by RAS/MAPK pathway genes
Phenotypic characteristics:
Noonan syndrome (NS) is a spectrum of clinically and genetically heterogeneous conditions, characterized by distinctive facial features, short stature, chest deformity, congenital heart disease and other abnormalities. Facial appearance changes with time, and is most characteristic in childhood. Typical features include large head and small face, widely spaced (hyperteloric) and prominent eyes with epicanthal folds, ptosis, and horizontal or down-slanting palpebral fissures. The nose is short and broad with a depressed root and full tip. The ears are low set, posteriorly rotated, with thickening of the helix. The lips are full, and upper lip is distinctive, exhibiting a deeply grooved philtrum with high, wide peaks to the vermillion. The neck is short with excess skin and low posterior hairline  ADDIN EN.CITE <EndNote><Cite><Author>Romano</Author><Year>2010</Year><RecNum>53</RecNum><DisplayText>[4]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Romano, A. A.</author><author>Allanson, J. E.</author><author>Dahlgren, J.</author><author>Gelb, B. D.</author><author>Hall, B.</author><author>Pierpont, M. E.</author><author>Roberts, A. E.</author><author>Robinson, W.</author><author>Takemoto, C. M.</author><author>Noonan, J. A.</author></authors></contributors><auth-address>Department of Pediatrics, Munger Pavilion, Room 123, New York Medical College, Valhalla, NY 10595, USA. alicia.romano@mac.com</auth-address><titles><title>Noonan syndrome: clinical features, diagnosis, and management guidelines</title><secondary-title>Pediatrics</secondary-title><alt-title>Pediatrics</alt-title></titles><periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></periodical><alt-periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></alt-periodical><pages>746-59</pages><volume>126</volume><number>4</number><edition>2010/09/30</edition><keywords><keyword>Humans</keyword><keyword>*Noonan Syndrome/diagnosis/genetics/therapy</keyword></keywords><dates><year>2010</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1098-4275 (Electronic)&#xD;0031-4005 (Linking)</isbn><accession-num>20876176</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20876176</url></related-urls></urls><electronic-resource-num>10.1542/peds.2009-3207</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "Romano, 2010 #53" 4]. A characteristic pectus deformity of the chest, with pectus carinatum superiorly and pectus excavatum inferiorly, is seen in most individuals. In 50-80% of the affected individuals heart defects are found, most typical of which include valvular pulmonary stenosis, often associated with valve dysplasia, hypertrophic cardiomyopathy and atrioventricular septal defect  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Romano, 2010 #53" 4,  HYPERLINK \l "_ENREF_5" \o "Allanson, 1987 #54" 5].

LEOPARD syndrome is an acronym for lentigines, electrocardiographic anomalies, ocular hypertelorism, pulmonary stenosis, abnormal genitalia and deafness.

Cardio-Facio-Cutaneous syndrome (CFC) shares the major clinical features of NS  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Zenker, 2009 #60" 6], but is differed mainly by the high frequency of ectodermal anomalies, including hyperkeratotic skin changes, hair which is thin, curly and friable, and more severe cognitive impairment  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Roberts, 2006 #59" 7]. 

Patients with Costello syndrome usually show severe feeding problems in infancy. During childhood, patients develop coarser facial features than those usually seen in NS. The skin is soft and redundant with deep palmar and plantar creases. Hair is sparse in early childhood and curly. Epidermal warts and papillomas may occur. Cognitive impairment is typically at the level of mild to moderate mental retardation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Axelrad, 2009 #61" 8]. Costello syndrome is associated with an increased risk of malignancy (15-25%), with embryonal rhadomyosarcoma, bladder carcinoma, and neuroblastoma representing the most common tumors  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Gripp, 2006 #63" 9].



Genetic etiology:
Gene mutations identified in individuals with NS phenotype involve the RAS/MAPK (mitogen-activated protein kinase) pathway (Figure 1). RAS proteins (HRAS, KRAS and NRAS) and the MAPKs (RAF, MEK and ERK) are important mediators in a ubiquitous signaling pathway that relays signals from receptor tyrosine kinases, such as growth factor receptors, to the nucleus  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Gripp, 2006 #63" 9]. The first gene to be discovered was PTPN11 (protein tyrosine phosphatase non-receptor type 11 gene), responsible for about 40-50% of NS cases. Its revelation was followed by the discovery of KRAS (1-3% of cases), SOS1 (approximately 10-15%), RAF1 (around 5%), BRAF (0.8%), SHOC2 (1.7%) and NRAS (0.2%), reaching 61% of clinically diagnosed individuals  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Romano, 2010 #53" 4,  HYPERLINK \l "_ENREF_9" \o "Gripp, 2006 #63" 9]. 
Mutations of PTPN11 account for approximately 90% of LEOPARD cases, and specific mutations, particularly Y259C and T468M, are prevalent only in LEOPARD syndrome  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Legius, 2002 #69" 10]. 
Four different RAS/MAPK genes were found to be mutated in CFC: BRAF (50-60%), MEK1 (5-10%), MEK2 (5-10%), and KRAS (3-5%)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_11" \o "Niihori, 2006 #75" 11,  HYPERLINK \l "_ENREF_12" \o "Rodriguez-Viciana, 2006 #76" 12].
HRAS mutations were shown to cause Costello syndrome, with a tendency to cluster in codon 12 or 13 of the protein product  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_9" \o "Gripp, 2006 #63" 9].
Of note is the fact that abnormal RAS-MAPK signaling has long been known to be involved in tumorigenesis. Constitutively activating somatic mutations of the RAS genes belong to the most common genetic events found in a broad spectrum of tumors  ADDIN EN.CITE <EndNote><Cite><Author>Bos</Author><Year>1989</Year><RecNum>77</RecNum><DisplayText>[13]</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">77</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bos, J. L.</author></authors></contributors><auth-address>Laboratory for Molecular Carcinogenesis, Sylvius Laboratory, Leiden, The Netherlands.</auth-address><titles><title>ras oncogenes in human cancer: a review</title><secondary-title>Cancer Res</secondary-title><alt-title>Cancer research</alt-title></titles><periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></periodical><alt-periodical><full-title>Cancer Res</full-title><abbr-1>Cancer research</abbr-1></alt-periodical><pages>4682-9</pages><volume>49</volume><number>17</number><edition>1989/09/01</edition><keywords><keyword>Carcinoma, Non-Small-Cell Lung/genetics</keyword><keyword>Colonic Neoplasms/genetics</keyword><keyword>*Genes, ras</keyword><keyword>Humans</keyword><keyword>Leukemia/genetics</keyword><keyword>Lung Neoplasms/genetics</keyword><keyword>Lymphoma/genetics</keyword><keyword>Melanoma/genetics</keyword><keyword>Mutation</keyword><keyword>Myelodysplastic Syndromes/genetics</keyword><keyword>Neoplasms/*genetics</keyword><keyword>Pancreatic Neoplasms/genetics</keyword><keyword>Thyroid Neoplasms/genetics</keyword></keywords><dates><year>1989</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>0008-5472 (Print)&#xD;0008-5472 (Linking)</isbn><accession-num>2547513</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/2547513</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_13" \o "Bos, 1989 #77" 13].
Principally, the syndromes discussed above are inherited as an autosomal dominant trait with (almost) complete penetrance. However, more than half of the individuals with NS and virtually all the affected CFC and Costello syndrome patients represent sporadic cases due to de novo mutations. It has been demonstrated that de novo mutations predominantly occur on the paternally inherited allele and show a paternal age effect, indicating that these mutations may accumulate in sperm during life. On the contrary, familial cases with NS are more often transmitted by the mother. This may reflect reduced productive fitness of males affected by NS  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Zenker, 2009 #60" 6,  HYPERLINK \l "_ENREF_14" \o "Tartaglia, 2004 #78" 14]. 
Growth:
Referring to the group at general, severe feeding difficulties and failure to thrive are common in the first year. As childhood progresses, short stature with relative macrocephaly, learning disability and skin abnormalities may be the presenting features  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_15" \o "Wright, 2010 #79" 15]. 
Short stature is noted in about 50-70% of individuals with NS. Although decreased height is a main characteristic feature of NS, some of the affected patients have normal growth and stature. Birth weight and length are typically normal or slightly abnormal, thus short stature is of postnatal onset. After birth, there is subsequent deceleration of height and weight to the third percentile or less, leading to proportionate and usually of the mild to moderate degree short stature  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Romano, 2010 #53" 4,  HYPERLINK \l "_ENREF_6" \o "Zenker, 2009 #60" 6,  HYPERLINK \l "_ENREF_16" \o "Zenker, 2011 #64" 16]. Mean adult height of European individuals with NS has been reported as 153 cm for women and 162.5-167.4 cm for men  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_17" \o "Ranke, 1988 #80" 17,  HYPERLINK \l "_ENREF_18" \o "Shaw, 2007 #81" 18]. Adult height of North American individuals with NS is less than the third percentile in 54.5% of women (lower than 151 cm) and 38% of men (lower than 163.2 cm). 30% of the individuals have heights above the 10th percentile  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_19" \o "Noonan, 2003 #82" 19,  HYPERLINK \l "_ENREF_20" \o "Kuczmarski, 2002 #83" 20]. Overall, mean adult height is about -2 SD  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Shaw, 2007 #81" 18]. Higher prevalence of short stature has been found in PTPN11 mutations-positive subjects compared to mutation-negative subjects, and lower prevalence of short stature has been described for those with SOS1-assoicated NS  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Zenker, 2004 #84" 21,  HYPERLINK \l "_ENREF_22" \o "Ko, 2008 #85" 22]. Short stature is not usually seen in LEOPARD syndrome  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_15" \o "Wright, 2010 #79" 15].  
Costello syndrome is characterized by slightly increased birth weight and relative macrocephaly, followed by severe postnatal failure to thrive and short stature  ADDIN EN.CITE <EndNote><Cite><Author>Gripp</Author><Year>2005</Year><RecNum>87</RecNum><DisplayText>[23]</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gripp, K. W.</author></authors></contributors><auth-address>Thomas Jefferson Medical College, Philadelphia, Pennsylvania, USA. kgripp@nemours.org</auth-address><titles><title>Tumor predisposition in Costello syndrome</title><secondary-title>Am J Med Genet C Semin Med Genet</secondary-title><alt-title>American journal of medical genetics. Part C, Seminars in medical genetics</alt-title></titles><periodical><full-title>Am J Med Genet C Semin Med Genet</full-title><abbr-1>American journal of medical genetics. Part C, Seminars in medical genetics</abbr-1></periodical><alt-periodical><full-title>Am J Med Genet C Semin Med Genet</full-title><abbr-1>American journal of medical genetics. Part C, Seminars in medical genetics</abbr-1></alt-periodical><pages>72-7</pages><volume>137C</volume><number>1</number><edition>2005/07/13</edition><keywords><keyword>*Abnormalities, Multiple/diagnosis/therapy</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Growth Disorders/complications/diagnosis/therapy</keyword><keyword>Humans</keyword><keyword>Neoplasms/complications/diagnosis</keyword><keyword>Syndrome</keyword></keywords><dates><year>2005</year><pub-dates><date>Aug 15</date></pub-dates></dates><isbn>1552-4868 (Print)&#xD;1552-4868 (Linking)</isbn><accession-num>16010679</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16010679</url></related-urls></urls><electronic-resource-num>10.1002/ajmg.c.30065</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Gripp, 2005 #87" 23]. 
Most of the evidence for the effect of growth hormone therapy on growth in NS has been obtained from observational studies in small numbers of subjects, without randomization or control groups. Decreased levels of IGF-I have been noted in children with NS who carried PTPN11 mutations, suggesting mild GH insensitivity. The short-term responsiveness to GH therapy in PTPN11-related NS has been shown to be mildly reduced  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_24" \o "Kappelgaard, 2011 #52" 24]. 

Cornelia de Lange syndrome
Phenotypic characteristics:
Cornelia de Lange (CdLS) is a multi-system syndrome, most commonly exhibiting neurodevelopmental, craniofacial, gastrointestinal and musculoskeletal abnormalities.  Typical facial features include synophris and arched eyebrows, thick and long eyelashes and generalized hirsutism, most noticeable on the face, back and extremities. Midface is flattened, and nose is short, with anteverted nares. Philtrum tends to be long and prominent, and mouth typically exhibits thin-upper-lip and down-turned corners, with micrognathia  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_25" \o "Kline, 2007 #88" 25]. Upper extremity malformations are noted in nearly one third of the patients, ranging from oligodactyly to ulnar deficiency, to absent forearm, with digits present just distal to the elbow. Lower extremities are less frequently involved  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_25" \o "Kline, 2007 #88" 25]. Severe-to-profound pervasive developmental delay characterizes the classical CdLS syndrome, the overall IQ in CdLS ranges from below 30 to 102, with an average IQ of 53  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_26" \o "Kline, 1993 #89" 26]. A milder  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/" phenotype that retains many of the characteristic facial features but with less severe cognitive and limb involvement has been consistently described  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_27" \o "Deardorff, 2007 #90" 27].
Genetic etiology: 
Three genes, NIPBL, SMC1A and SMC3, have been found to be associated with CdLS  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_27" \o "Deardorff, 2007 #90" 27-30]. NIPBL-related Cornelia de Lange syndrome (CdLS) and SMC3-related CdLS are inherited in an  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/autosomal-dominant/" autosomal dominant manner. SMC1A-related CdLS is inherited in an X-linked manner. NIPBL mutations are evenly distributed throughout the coding sequence, and are found in approximately 60% of individuals with CdLS. The majority of  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/" affected patients have a de novo NIPBL  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/" mutation. Sequence analysis has identified a SMC1A  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/" mutation in approximately 5% of affected individuals, particularly those with milder features. Whereas patients with classic findings of CdLS, including characteristic facial features and limb anomalies, are likely to have a  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/" mutation in NIPBL, these mutations have been also found in individuals with both mild and severe phenotypes. Individuals with a SMC1A or SMC3  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/mutation/" mutation typically have fewer structural anomalies than those with NIPBL mutations. However, they have significant intellectual disability that can range from moderate to severe  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_27" \o "Deardorff, 2007 #90" 27-30]. 
Growth: 
Proportionate small stature occurs throughout life, starting in the prenatal period. Birth parameters tend to be below the 10th percentiles, with average length of 45.5 cm. Growth parallels the standard growth curves, but by early childhood tends to fall below the 5th percentiles. Mean adult parameters are 156 cm (males) and 131 cm (females)  ADDIN EN.CITE <EndNote><Cite><Author>Kline</Author><Year>1993</Year><RecNum>96</RecNum><DisplayText>[31]</DisplayText><record><rec-number>96</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">96</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kline, A. D.</author><author>Barr, M.</author><author>Jackson, L. G.</author></authors></contributors><auth-address>Division of Medical Genetics, Jefferson Medical College, Philadelphia, Pennsylvania.</auth-address><titles><title>Growth manifestations in the Brachmann-de Lange syndrome</title><secondary-title>Am J Med Genet</secondary-title><alt-title>American journal of medical genetics</alt-title></titles><periodical><full-title>Am J Med Genet</full-title><abbr-1>American journal of medical genetics</abbr-1></periodical><alt-periodical><full-title>Am J Med Genet</full-title><abbr-1>American journal of medical genetics</abbr-1></alt-periodical><pages>1042-9</pages><volume>47</volume><number>7</number><edition>1993/11/15</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Anthropometry</keyword><keyword>Body Height</keyword><keyword>Body Weight</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>De Lange Syndrome/*pathology</keyword><keyword>Female</keyword><keyword>Growth Disorders/*pathology</keyword><keyword>Head/pathology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Male</keyword></keywords><dates><year>1993</year><pub-dates><date>Nov 15</date></pub-dates></dates><isbn>0148-7299 (Print)&#xD;0148-7299 (Linking)</isbn><accession-num>8291521</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8291521</url></related-urls></urls><electronic-resource-num>10.1002/ajmg.1320470722</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_31" \o "Kline, 1993 #96" 31]. Adult patients may have truncal obesity. Growth hormone deficiency is rare  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_25" \o "Kline, 2007 #88" 25].



SHOX gene abnormalities 
Phenotypic characteristics:
The clinical spectrum associated with SHOX gene abnormalities is wide, varying from short stature with no specific findings (also called "idiopathic short stature"), to short stature with subtle radiological findings, to the full picture of Leri-Weill syndrome (osteochondrosteosis)  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. Leri-Weill syndrome is characterized by a triad of short stature, mesomelia (shortness of the middle part of the limb, the most frequent clinical finding) and Madelung deformity, in which there is abnormal alignment of the radius, ulna, and carpal bones at the wrist. Mesomelic disproportion of the limbs and Madelung deformity of the forearm develop over time. These features rarely present before 6 years of age (and in some boys above 6 years of age), and appear during the second decade of life, or never develop. Characteristic signs are more frequent and more severe in females  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32-35]. Other features associated with SHOX abnormality include shortening of the 4th and 5th metacarpal bones, high arched palate, increased carrying angle of the elbow, scoliosis and micrognathia, and muscular hypertrophy of the calves  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_34" \o "Rappold, 2007 #99" 34].
Genetic etiology:
SHOX (the short stature homebox-containing gene) is located on the very tips of the short arms of both sex chromosomes X and Y, inside the telomeric part of pseudoautosomal region 1 (PAR1). This region contains genes which escape X inactivation, leading to bi-allelic expression, i.e. SHOX is expressed on both sex chromosomes  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. The initial discovery of the gene SHOX was promoted by the known association of short stature with deletions of the short arm of the X chromosome or small terminal deletions of the short arm of the Y chromosome  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. SHOX gene function is dosage dependent: the loss-of-function mutation of one SHOX copy (haploinsufficiency) results in the disorder of SHOX deficiency leading to growth failure. The protein is located in the nucleus and acts as a transcriptional activator  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_36" \o "Rao, 2001 #102" 36].
The most frequent SHOX mutations are gene deletions of varying size, which encompass the SHOX gene itself or a regulatory enhancer region, located 50-250kb downstream of the coding region. These deletions account for around 80% of all mutations  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_37" \o "Schiller, 2000 #103" 37,  HYPERLINK \l "_ENREF_38" \o "Sabherwal, 2007 #104" 38]. Other SHOX defects include missense and nonsense mutations, predicted to cause inactivation of the protein, and chromosomal rearrangements disrupting the gene expression  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. Turner syndrome is almost always associated with loss of one SHOX gene secondary to the numerical or structural abnormalities of the X chromosome  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. 
SHOX (X) deletions have been more frequently reported than SHOX (Y) deletions, finding that may indicate that the SHOX on the X chromosome is more prone to getting deleted than the SHOX on the Y  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. 
Growth:
Birth length in SHOX deficiency is only mildly reduced, but height deficit is already present at preschool age, suggesting that early childhood is the phase of growth failure. Longitudinal data suggest the absence of catch-up growth  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_35" \o "Binder, 2003 #100" 35,  HYPERLINK \l "_ENREF_39" \o "Ross, 2001 #105" 39]. Of note is the mesomelic shortening of limbs, highly characteristic of the syndrome, hence, more detailed measurements of length of body parts are needed in order to have a better clinical judgment  ADDIN EN.CITE <EndNote><Cite><Author>Binder</Author><Year>2011</Year><RecNum>97</RecNum><DisplayText>[32]</DisplayText><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Binder, G.</author></authors></contributors><auth-address>University Children&apos;s Hospital, Pediatric Endocrinology and Diabetology, Tubingen, Germany. gerhard.binder @ med.uni-tuebingen.de</auth-address><titles><title>Short stature due to SHOX deficiency: genotype, phenotype, and therapy</title><secondary-title>Horm Res Paediatr</secondary-title><alt-title>Hormone research in paediatrics</alt-title></titles><periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></periodical><alt-periodical><full-title>Horm Res Paediatr</full-title><abbr-1>Hormone research in paediatrics</abbr-1></alt-periodical><pages>81-9</pages><volume>75</volume><number>2</number><edition>2011/02/18</edition><keywords><keyword>Body Height/genetics</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Genotype</keyword><keyword>Growth Disorders/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Homeodomain Proteins/*genetics</keyword><keyword>Human Growth Hormone/therapeutic use</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Osteochondrodysplasias/diagnosis/drug therapy/*genetics/radiography</keyword><keyword>Phenotype</keyword><keyword>Turner Syndrome/genetics</keyword><keyword>Wrist/abnormalities</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1663-2826 (Electronic)</isbn><accession-num>21325865</accession-num><work-type>Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21325865</url></related-urls></urls><electronic-resource-num>10.1159/000324105</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_32" \o "Binder, 2011 #97" 32]. 
Loss of both SHOX alleles causes a more severe phenotype of osteodysplasia, the Langer syndrome  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_40" \o "Zinn, 2002 #106" 40]. 
Duplications (gain of one or two additional copies of SHOX gene) have variable effect on stature: height appears to be elevated in some carriers, particularly in those with the largest duplications, but is still within the normal range  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_41" \o "Thomas, 2009 #107" 41]. 

Epigenetic mechanism abnormalities
Epigenetics refers to heritable but reversible regulation of various genetic functions, including gene expression, which is influenced by environmental factors. Nearly all imprinted genes have a CpG-rich differentially methylated region, which usually relates to allele repression. Methylation of cytokine bases occurring in the CpG dinucleotides involves key regulatory gene elements. Defects in the imprinting center controlling the activity of imprinted genes originate from either parent and can lead to different clinical syndromes. About 1% of mammalian genes is imprinted and frequently affects growth, development and viability. Genomic imprinting is an epigenetic phenomenon, whereby the phenotype is modified depending on the sex of the parent contributing the gene allele. It arises from epigenetic changes which influence gene expression without changing the DNA sequence. Regulation of gene expression is usually carried through DNA methylation. The control of imprinted genes expression is dependent on the parent of origin, with mono-allelic gene expression of either the maternal or paternal allele for a particular imprinted locus or gene  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_42" \o "Hanel, 2001 #108" 42,  HYPERLINK \l "_ENREF_43" \o "Butler, 2011 #109" 43].  
Silver Russell syndrome 
Phenotypic characteristics:
Silver-Russell syndrome (SRS) is characterized by intrauterine and post- natal growth retardation, manifested as proportionate short stature, with normal head circumference (hence relative macrocephaly), small triangular face (broad forehead and narrow chin), fifth finger clinodactyly and body asymmetry (that may result from diminished growth of affected side)  ADDIN EN.CITE <EndNote><Cite><Author>Eggermann</Author><Year>2010</Year><RecNum>115</RecNum><DisplayText>[44]</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eggermann, T.</author><author>Begemann, M.</author><author>Binder, G.</author><author>Spengler, S.</author></authors></contributors><auth-address>RWTH Aachen, Institute of Human Genetics, Aachen, Germany. teggermann@ukaachen.de</auth-address><titles><title>Silver-Russell syndrome: genetic basis and molecular genetic testing</title><secondary-title>Orphanet J Rare Dis</secondary-title><alt-title>Orphanet journal of rare diseases</alt-title></titles><periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></periodical><alt-periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></alt-periodical><pages>19</pages><volume>5</volume><edition>2010/06/25</edition><keywords><keyword>Algorithms</keyword><keyword>Chromosomes, Human, Pair 11/genetics/physiology</keyword><keyword>Chromosomes, Human, Pair 7/genetics/physiology</keyword><keyword>DNA Methylation/genetics/physiology</keyword><keyword>Genomic Imprinting/genetics/*physiology</keyword><keyword>Growth Disorders/genetics/*physiopathology</keyword><keyword>Humans</keyword><keyword>Silver-Russell Syndrome/genetics/*physiopathology</keyword><keyword>Uniparental Disomy/genetics/*physiopathology</keyword></keywords><dates><year>2010</year></dates><isbn>1750-1172 (Electronic)&#xD;1750-1172 (Linking)</isbn><accession-num>20573229</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20573229</url></related-urls></urls><custom2>2907323</custom2><electronic-resource-num>10.1186/1750-1172-5-19</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_44" \o "Eggermann, 2010 #115" 44].  
Genetic etiology:
SRS is a genetically heterogeneous condition. Nearly 10% of affected individuals carry a maternal uniparental disomy of chromosome 7 (UPD(7)mat), i.e. their two copies of chromosome 7 are inherited from their mothers, with no presence of the paternal copy. More than 38% show hypomethylation in the imprinting control region 1 (ICR1) in chromosome 11p15, and about 1% show small chromosomal aberrations. In about 7% of 11p15 hypomethylation carriers, demethylation of other imprinted loci can be detected. Clinically these patients do not differ from those with isolated 11p15 hypomethylation, whereas the UPD(7)mat patients generally show a milder phenotype  ADDIN EN.CITE <EndNote><Cite><Author>Eggermann</Author><Year>2010</Year><RecNum>115</RecNum><DisplayText>[44]</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eggermann, T.</author><author>Begemann, M.</author><author>Binder, G.</author><author>Spengler, S.</author></authors></contributors><auth-address>RWTH Aachen, Institute of Human Genetics, Aachen, Germany. teggermann@ukaachen.de</auth-address><titles><title>Silver-Russell syndrome: genetic basis and molecular genetic testing</title><secondary-title>Orphanet J Rare Dis</secondary-title><alt-title>Orphanet journal of rare diseases</alt-title></titles><periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></periodical><alt-periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></alt-periodical><pages>19</pages><volume>5</volume><edition>2010/06/25</edition><keywords><keyword>Algorithms</keyword><keyword>Chromosomes, Human, Pair 11/genetics/physiology</keyword><keyword>Chromosomes, Human, Pair 7/genetics/physiology</keyword><keyword>DNA Methylation/genetics/physiology</keyword><keyword>Genomic Imprinting/genetics/*physiology</keyword><keyword>Growth Disorders/genetics/*physiopathology</keyword><keyword>Humans</keyword><keyword>Silver-Russell Syndrome/genetics/*physiopathology</keyword><keyword>Uniparental Disomy/genetics/*physiopathology</keyword></keywords><dates><year>2010</year></dates><isbn>1750-1172 (Electronic)&#xD;1750-1172 (Linking)</isbn><accession-num>20573229</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20573229</url></related-urls></urls><custom2>2907323</custom2><electronic-resource-num>10.1186/1750-1172-5-19</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_44" \o "Eggermann, 2010 #115" 44].
Growth:
Children with SRS exhibit intrauterine growth retardation, accompanied by postnatal growth deficiency. Birth weight of  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/affected/" affected infants is typically two or more SD below the mean, and postnatal growth continues to be measured at two or more SD below the mean for length or height. Mean length of full-term babies with SRS at birth is 43.1 +/- 3.7 cm in both sexes. Growth velocity is normal in children with SRS. The pubertal growth spurt is reduced in the whole group. Mean adult height is 151.2 +/- 7.8 cm in males and 139.9 +/- 9.0 cm in females. Head circumference adjusted for age is in the lower normal range  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_45" \o "Wollmann, 1995 #116" 45]. Particularly, at birth, length, weight and head circumference are more restricted in patients with hypomethylation of the ICR1 on chromosome 11p15 than in cases with maternal UPD7. Later in life the figures become more similar  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_46" \o "Kotzot, 2008 #117" 46].

Prader-Willi syndrome
Phenotypic characteristics:
Prader-Willi syndrome (PWS) is characterized by decreased fetal movements, infantile lethargy, and severe neonatal and infantile central hypotonia with poor suck and feeding difficulties, which are associated with failure to thrive in early infancy and improve over time. Excessive eating evolves between ages 12 months and six years. The hyperphagia is followed by rapid weight gain, causing central obesity and gradual development of morbid obesity (unless eating is externally controlled). Non-insulin-dependent diabetes mellitus often occurs in obese individuals. Motor milestones and language development are delayed, with typical speech articulation defects. All individuals have some degree of cognitive impairment. Distinctive behavioral  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/phenotype/" phenotype, including temper tantrums, is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Characteristic facial features include narrow bifrontal diameter, almond-shaped palpebral fissures, down-turned mouth and strabismus. Other typical medical problems include sleep disturbance, hypopigmentation, small narrow hands and small feet  ADDIN EN.CITE <EndNote><Cite><Author>Gunay-Aygun</Author><Year>2001</Year><RecNum>119</RecNum><DisplayText>[47]</DisplayText><record><rec-number>119</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">119</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gunay-Aygun, M.</author><author>Schwartz, S.</author><author>Heeger, S.</author><author>O&apos;Riordan, M. A.</author><author>Cassidy, S. B.</author></authors></contributors><auth-address>Department of Pediatrics, Center for Genetics and Metabolism, Children&apos;s Hospital Medical Center, Akron, Ohio, USA.</auth-address><titles><title>The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria</title><secondary-title>Pediatrics</secondary-title><alt-title>Pediatrics</alt-title></titles><periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></periodical><alt-periodical><full-title>Pediatrics</full-title><abbr-1>Pediatrics</abbr-1></alt-periodical><pages>E92</pages><volume>108</volume><number>5</number><edition>2001/11/06</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gene Deletion</keyword><keyword>Humans</keyword><keyword>In Situ Hybridization, Fluorescence</keyword><keyword>Infant</keyword><keyword>Prader-Willi Syndrome/*diagnosis/genetics</keyword><keyword>Reproducibility of Results</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1098-4275 (Electronic)&#xD;0031-4005 (Linking)</isbn><accession-num>11694676</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/11694676</url></related-urls></urls><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_47" \o "Gunay-Aygun, 2001 #119" 47].
Genetic etiology:
PWS is caused by errors in genomic imprinting, with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have de novo deletion of the paternally derived 15q11-q13 region. Maternally disomy of chromosome 15 (the two copies of chromosome 15 are inherited from the mother, with  no evidence of the paternal copy) is found in about 25%, and the remaining affected individuals have either defects in the imprinting center controlling the activity of the imprinted genes, or other chromosome 15 rearrangement  ADDIN EN.CITE <EndNote><Cite><Author>Butler</Author><Year>2011</Year><RecNum>109</RecNum><DisplayText>[43]</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Butler, M. G.</author></authors></contributors><auth-address>Departments of Psychiatry &amp; Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA.</auth-address><titles><title>Prader-Willi Syndrome: Obesity due to Genomic Imprinting</title><secondary-title>Curr Genomics</secondary-title><alt-title>Current genomics</alt-title></titles><periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></periodical><alt-periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></alt-periodical><pages>204-15</pages><volume>12</volume><number>3</number><edition>2011/11/02</edition><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1875-5488 (Electronic)&#xD;1389-2029 (Linking)</isbn><accession-num>22043168</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22043168</url></related-urls></urls><custom2>3137005</custom2><electronic-resource-num>10.2174/138920211795677877</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_43" \o "Butler, 2011 #109" 43].
Growth:
Examination of spontaneous growth of individuals with PWS reveals that mean (SD) length of newborn babies with PWS is 50.2+/-2.8 cm (boys) and 48.9+/- 3.3 cm (girls). During the first year, the children's growth is nearly normal, but thereafter short stature is demonstrated in approximately 50% of PWS patients. Between 3 and 13 years of age, the 50th percentile for height in PWS is roughly identical with the 3rd percentile in healthy controls. After the age of 10 years, weight-for-height index in nearly all patients exceeds the normal range. The extent of pubertal growth is reduced for the group  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_48" \o "Wollmann, 1998 #120" 48], with lack of pubertal growth spurt  ADDIN EN.CITE <EndNote><Cite><Author>Butler</Author><Year>2011</Year><RecNum>109</RecNum><DisplayText>[43]</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Butler, M. G.</author></authors></contributors><auth-address>Departments of Psychiatry &amp; Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA.</auth-address><titles><title>Prader-Willi Syndrome: Obesity due to Genomic Imprinting</title><secondary-title>Curr Genomics</secondary-title><alt-title>Current genomics</alt-title></titles><periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></periodical><alt-periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></alt-periodical><pages>204-15</pages><volume>12</volume><number>3</number><edition>2011/11/02</edition><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1875-5488 (Electronic)&#xD;1389-2029 (Linking)</isbn><accession-num>22043168</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22043168</url></related-urls></urls><custom2>3137005</custom2><electronic-resource-num>10.2174/138920211795677877</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_43" \o "Butler, 2011 #109" 43]. Mean adult height is 161.6+/-8.1 cm (males) and 150.2+/-5.5 cm (females)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_48" \o "Wollmann, 1998 #120" 48]. Approximately 90% of individuals with PWS without growth hormone treatment will have short stature by adulthood  ADDIN EN.CITE <EndNote><Cite><Author>Butler</Author><Year>2011</Year><RecNum>109</RecNum><DisplayText>[43]</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Butler, M. G.</author></authors></contributors><auth-address>Departments of Psychiatry &amp; Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA.</auth-address><titles><title>Prader-Willi Syndrome: Obesity due to Genomic Imprinting</title><secondary-title>Curr Genomics</secondary-title><alt-title>Current genomics</alt-title></titles><periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></periodical><alt-periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></alt-periodical><pages>204-15</pages><volume>12</volume><number>3</number><edition>2011/11/02</edition><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1875-5488 (Electronic)&#xD;1389-2029 (Linking)</isbn><accession-num>22043168</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22043168</url></related-urls></urls><custom2>3137005</custom2><electronic-resource-num>10.2174/138920211795677877</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_43" \o "Butler, 2011 #109" 43].

Proposed mechanisms for abnormal growth in various genetic syndromes

Regarding the RAS/MAPK associated syndromes, some evidence has emerged suggesting interactions between specific genes along the RAS/MAPK pathway and growth hormone signaling. Presently the data is far from being based, and current hypothesis suggests that the main effect on growth is mediated by abnormal signaling through the RAS/MAPK pathway itself  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Zenker, 2009 #60" 6].
In Prader Willi syndrome, short stature is widely attributed to growth hormone deficiency  ADDIN EN.CITE <EndNote><Cite><Author>Butler</Author><Year>2011</Year><RecNum>109</RecNum><DisplayText>[43]</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Butler, M. G.</author></authors></contributors><auth-address>Departments of Psychiatry &amp; Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, Kansas, USA.</auth-address><titles><title>Prader-Willi Syndrome: Obesity due to Genomic Imprinting</title><secondary-title>Curr Genomics</secondary-title><alt-title>Current genomics</alt-title></titles><periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></periodical><alt-periodical><full-title>Curr Genomics</full-title><abbr-1>Current genomics</abbr-1></alt-periodical><pages>204-15</pages><volume>12</volume><number>3</number><edition>2011/11/02</edition><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1875-5488 (Electronic)&#xD;1389-2029 (Linking)</isbn><accession-num>22043168</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22043168</url></related-urls></urls><custom2>3137005</custom2><electronic-resource-num>10.2174/138920211795677877</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_43" \o "Butler, 2011 #109" 43].
The role of SHOX protein in growth has been extensively studied. Studies on human embryos between 26 and 52 days post-conception demonstrated a role for SHOX in the development of limbs and other bone and mesoderm-derived structures  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_49" \o "Clement-Jones, 2000 #121" 49]. SHOX expression was most prominent in the mid-portion of limbs, especially the elbow and knee. It was also expressed in the distal ulna/radius and wrist  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_49" \o "Clement-Jones, 2000 #121" 49]. This expression pattern was felt to explain the short stature, bowing and shortening of the forearms and lower legs, Madelung deformity, and shortening of the fourth metacarpals seen in LWD and Turner syndrome  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_49" \o "Clement-Jones, 2000 #121" 49]. SHOX protein was identified in human growth plate hypertrophic chondrocytes, a finding that further supports the substantial role of SHOX in bone development  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_50" \o "Marchini, 2004 #122" 50,  HYPERLINK \l "_ENREF_51" \o "Munns, 2004 #124" 51]. The evolving database suggests that SHOX acts as a nuclear  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/transcription-factor/" transcription factor that inhibits cellular growth and apoptosis, possibly through the up-regulation of p53  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_50" \o "Marchini, 2004 #122" 50]. Mutated SHOX protein was demonstrated to have both abnormal nuclear  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/translocation/" translocation and transcription properties  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_52" \o "Sabherwal, 2004 #123" 52]. These results lead to the suggestion that in the absence of wild-type SHOX, chondrocytes may undergo atypical proliferation and differentiation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_50" \o "Marchini, 2004 #122" 50]. This could explain the short stature associated with LWD. It has been shown that single missense mutations in SHOX, present in individuals with LWD or ISS, alter the biological function of SHOX with loss of  HYPERLINK "http://www.ncbi.nlm.nih.gov/books/n/gene/glossary/def-item/dna/" DNA binding, dimerization, and/or nuclear localization  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_53" \o "Schneider, 2005 #125" 53]. 
In SRS, the most probable explanation for the phenotype in UPD(7)mat carriers is the disturbed expression of imprinted genes on chromosome 7. UPD(7)mat is generally associated with growth retardation, whereas UPD(7)pat is not. It has been therefore hypothesized, that a diminished expression of paternally expressed gene(s) or an over-expression of maternally expressed factor(s) on chromosome 7 causes SRS, and hence, short stature  ADDIN EN.CITE <EndNote><Cite><Author>Eggermann</Author><Year>2010</Year><RecNum>115</RecNum><DisplayText>[44]</DisplayText><record><rec-number>115</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">115</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eggermann, T.</author><author>Begemann, M.</author><author>Binder, G.</author><author>Spengler, S.</author></authors></contributors><auth-address>RWTH Aachen, Institute of Human Genetics, Aachen, Germany. teggermann@ukaachen.de</auth-address><titles><title>Silver-Russell syndrome: genetic basis and molecular genetic testing</title><secondary-title>Orphanet J Rare Dis</secondary-title><alt-title>Orphanet journal of rare diseases</alt-title></titles><periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></periodical><alt-periodical><full-title>Orphanet J Rare Dis</full-title><abbr-1>Orphanet journal of rare diseases</abbr-1></alt-periodical><pages>19</pages><volume>5</volume><edition>2010/06/25</edition><keywords><keyword>Algorithms</keyword><keyword>Chromosomes, Human, Pair 11/genetics/physiology</keyword><keyword>Chromosomes, Human, Pair 7/genetics/physiology</keyword><keyword>DNA Methylation/genetics/physiology</keyword><keyword>Genomic Imprinting/genetics/*physiology</keyword><keyword>Growth Disorders/genetics/*physiopathology</keyword><keyword>Humans</keyword><keyword>Silver-Russell Syndrome/genetics/*physiopathology</keyword><keyword>Uniparental Disomy/genetics/*physiopathology</keyword></keywords><dates><year>2010</year></dates><isbn>1750-1172 (Electronic)&#xD;1750-1172 (Linking)</isbn><accession-num>20573229</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20573229</url></related-urls></urls><custom2>2907323</custom2><electronic-resource-num>10.1186/1750-1172-5-19</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_44" \o "Eggermann, 2010 #115" 44]. 
The concept of fetal programming suggests that there are critical periods in fetal development, during which insults or stimulants can lead to long lasting effects on structure and function. At the same fashion fetal growth restriction may be a response to maternal disease, environmental cues, or a metabolic or genetic disorder. It has been suggested that changes in methylation patterns in genes, that show methylation alterations related to IUGR, might be present also in other syndromes associated with pre-natal growth restriction, because these changes have been seen in Silver-Russel syndrome phenotype  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_54" \o "Hall, 2010 #126" 54]. Such changes were proposed to reflect a universal mammalian survival mechanism involving epigenetic modifications  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_54" \o "Hall, 2010 #126" 54]. The theory behind developmental origins of adult health and disease suggests that there are mammalian epigenetic fetal survival mechanisms that down-regulate fetal growth, both in order for the fetus to survive until birth and to prepare it for a restricted extra-uterine environment, and that these mechanisms have long lasting effects on the adult health of the individual  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_54" \o "Hall, 2010 #126" 54].  
Others believe that, in evolutionary terms, fetal growth, which depends on uterine and placental function, is too labile a phase to affect final height. Hochberg and Albertsson-Wikland suggest that there is an evolutionary adaptive strategy of plasticity in the timing of the transition from infancy into childhood, intended to match environmental cues and energy supply. These authors propose that humans have evolved to withstand energy crises by decreasing their body size, and that evolutionary short-term adaptations to energy crises use epigenetic mechanisms which modify the transition into childhood, culminating in short stature  ADDIN EN.CITE <EndNote><Cite><Author>Hochberg</Author><Year>2008</Year><RecNum>127</RecNum><DisplayText>[55]</DisplayText><record><rec-number>127</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hochberg, Z.</author><author>Albertsson-Wikland, K.</author></authors></contributors><auth-address>Meyer Children&apos;s Hospital, POB 9602, Haifa 31096, Israel. z_hochberg@rambam.health.gov.il</auth-address><titles><title>Evo-devo of infantile and childhood growth</title><secondary-title>Pediatr Res</secondary-title><alt-title>Pediatric research</alt-title></titles><periodical><full-title>Pediatr Res</full-title><abbr-1>Pediatric research</abbr-1></periodical><alt-periodical><full-title>Pediatr Res</full-title><abbr-1>Pediatric research</abbr-1></alt-periodical><pages>2-7</pages><volume>64</volume><number>1</number><edition>2008/07/25</edition><keywords><keyword>Adaptation, Physiological/genetics</keyword><keyword>*Body Size/genetics</keyword><keyword>*Child Development</keyword><keyword>Child, Preschool</keyword><keyword>Endocrine System/metabolism</keyword><keyword>Energy Metabolism/genetics</keyword><keyword>*Epigenesis, Genetic</keyword><keyword>*Evolution, Molecular</keyword><keyword>Growth Disorders/genetics/physiopathology</keyword><keyword>Growth and Development/genetics</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Obesity/genetics/physiopathology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0031-3998 (Print)&#xD;0031-3998 (Linking)</isbn><accession-num>18652011</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t&#xD;Review</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18652011</url></related-urls></urls><electronic-resource-num>10.1203/PDR.0b013e318177590f</electronic-resource-num><language>eng</language></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_55" \o "Hochberg, 2008 #127" 55]. Based on this theory, energy crises might result from genetic abnormalities causing the same cellular net effect, leading to short stature.

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Figure 1. RAS-MAPK signaling and disorders of the neuro-cardio-facial-cutaneous spectrum  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Zenker, 2009 #60" 6]. Arrows point to the clinical entities related to the respective genes. Arrow width symbolizes the proportion of patients each gene accounts for. Dotted arrows indicate relationships reported only in single cases. 











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P.</author></authors></contributors><auth-address>Department of Child Health, Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands. helma.vangameren@tno.nl</auth-address><titles><title>Healthy growth in children with Down syndrome</title><secondary-title>PLoS One</secondary-title><alt-title>PloS one</alt-title></titles><periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></periodical><alt-periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></alt-periodical><pages>e31079</pages><volume>7</volume><number>2</number><edition>2012/03/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Body Height/physiology</keyword><keyword>Cephalometry</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Down Syndrome/*physiopathology</keyword><keyword>Female</keyword><keyword>*Growth and Development</keyword><keyword>*Health</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Male</keyword><keyword>Netherlands</keyword><keyword>Reference Standards</keyword><keyword>Young Adult</keyword></keywords><dates><year>2012</year></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>22363551</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22363551</url></related-urls></urls><custom2>3281925</custom2><electronic-resource-num>10.1371/journal.pone.0031079</electronic-resource-num><language>eng</language></record></Cite></EndNote>sD���y������K�	_ENREF_3�D<EndNote><Cite><Author>Van Gameren-Oosterom</Author><Year>2012</Year><RecNum>29</RecNum><DisplayText>[3]</DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Van Gameren-Oosterom, H. B.</author><author>Van Dommelen, P.</author><author>Oudesluys-Murphy, A. M.</author><author>Buitendijk, S. E.</author><author>Van Buuren, S.</author><author>Van Wouwe, J. 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_ENREF_26�D<EndNote><Cite><Author>Deardorff</Author><Year>2007</Year><RecNum>90</RecNum><DisplayText>[27]</DisplayText><record><rec-number>90</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">90</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deardorff, M. A.</author><author>Kaur, M.</author><author>Yaeger, D.</author><author>Rampuria, A.</author><author>Korolev, S.</author><author>Pie, J.</author><author>Gil-Rodriguez, C.</author><author>Arnedo, M.</author><author>Loeys, B.</author><author>Kline, A. D.</author><author>Wilson, M.</author><author>Lillquist, K.</author><author>Siu, V.</author><author>Ramos, F. J.</author><author>Musio, A.</author><author>Jackson, L. S.</author><author>Dorsett, D.</author><author>Krantz, I. D.</author></authors></contributors><auth-address>Division of Human and Molecular Genetics, The Children&apos;s Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.</auth-address><titles><title>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation</title><secondary-title>Am J Hum Genet</secondary-title><alt-title>American journal of human genetics</alt-title></titles><periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></periodical><alt-periodical><full-title>Am J Hum Genet</full-title><abbr-1>American journal of human genetics</abbr-1></alt-periodical><pages>485-94</pages><volume>80</volume><number>3</number><edition>2007/02/03</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Cell Cycle Proteins/*genetics</keyword><keyword>Child</keyword><keyword>Chondroitin Sulfate Proteoglycans/*genetics</keyword><keyword>Chromosomal Proteins, Non-Histone/*genetics</keyword><keyword>Crystallography, X-Ray</keyword><keyword>DNA Mutational Analysis</keyword><keyword>De Lange Syndrome/diagnosis/*genetics</keyword><keyword>Female</keyword><keyword>*Genetic Variation</keyword><keyword>Humans</keyword><keyword>Intellectual Disability/diagnosis/*genetics</keyword><keyword>Male</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Mutation/*genetics</keyword><keyword>Phenotype</keyword><keyword>Protein Conformation</keyword><keyword>Sequence Homology, Amino Acid</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0002-9297 (Print)&#xD;0002-9297 (Linking)</isbn><accession-num>17273969</accession-num><work-type>Research Support, N.I.H., Extramural&#xD;Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17273969</url></related-urls></urls><custom2>1821101</custom2><electronic-resource-num>10.1086/511888</electronic-resource-num><language>eng</language></record></Cite></EndNote>uD���y������K�
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_ENREF_52�D<EndNote><Cite><Author>Marchini</Author><Year>2004</Year><RecNum>122</RecNum><DisplayText>[50]</DisplayText><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="5eaws0rs9w99v7ef0a9xdevipdertv52pa2x">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchini, A.</author><author>Marttila, T.</author><author>Winter, A.</author><author>Caldeira, S.</author><author>Malanchi, I.</author><author>Blaschke, R. J.</author><author>Hacker, B.</author><author>Rao, E.</author><author>Karperien, M.</author><author>Wit, J. M.</author><author>Richter, W.</author><author>Tommasino, M.</author><author>Rappold, G. A.</author></authors></contributors><auth-address>Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.</auth-address><titles><title>The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>37103-14</pages><volume>279</volume><number>35</number><edition>2004/05/18</edition><keywords><keyword>Antimetabolites, Antineoplastic/pharmacology</keyword><keyword>*Apoptosis</keyword><keyword>Blotting, Western</keyword><keyword>Body Height</keyword><keyword>Bromodeoxyuridine/pharmacology</keyword><keyword>Cell Cycle</keyword><keyword>Cell Cycle Proteins/metabolism</keyword><keyword>Cell Division</keyword><keyword>Cell Line, Tumor</keyword><keyword>Cell Separation</keyword><keyword>Cells, Cultured</keyword><keyword>Chondrocytes/*metabolism</keyword><keyword>Cyclin-Dependent Kinase Inhibitor p21</keyword><keyword>Cyclin-Dependent Kinase Inhibitor p27</keyword><keyword>Cyclins/metabolism</keyword><keyword>Fibroblasts/metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>Gene Deletion</keyword><keyword>Growth Plate/*metabolism</keyword><keyword>Homeodomain Proteins/chemistry/*genetics/*physiology</keyword><keyword>Humans</keyword><keyword>Immunohistochemistry</keyword><keyword>In Situ Nick-End Labeling</keyword><keyword>Mouth/metabolism</keyword><keyword>*Mutation</keyword><keyword>Protein Structure, Tertiary</keyword><keyword>Retinoblastoma Protein/metabolism</keyword><keyword>Retroviridae/genetics</keyword><keyword>Time Factors</keyword><keyword>Transcription Factors/*genetics/*physiology</keyword><keyword>Tumor Suppressor Protein p53/metabolism</keyword><keyword>Tumor Suppressor Proteins/metabolism</keyword></keywords><dates><year>2004</year><pub-dates><date>Aug 27</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>15145945</accession-num><work-type>Research Support, Non-U.S. Gov&apos;t</work-type><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15145945</url></related-urls></urls><electronic-resource-num>10.1074/jbc.M307006200</electronic-resource-num><language>eng</language></record></Cite></EndNote>uD���y������K�
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