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SHOX Deficiency Disorders

, MD and , PhD.

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Initial Posting: ; Last Update: August 20, 2015.


Clinical characteristics.

The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to nonspecific short stature at the mild end of the spectrum. In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined. In LWD the classic clinical triad is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shorted in relation to the proximal portion, can be evident first in school-aged children and increases with age in frequency and severity. Madelung deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist) typically develops in mid-to-late childhood and is more common and severe in females. The phenotype of short stature caused by SHOX deficiency (in the absence of mesomelia and Madelung deformity) is highly variable, even within the same family.


The diagnosis of SHOX deficiency is established in a proband with either a SHOX single nucleotide variant or a deletion that can encompass the SHOX coding region and/or the enhancer region regulating SHOX expression.


Treatment of manifestations: For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. For painful bilateral Madelung deformity (which is uncommon): wrist splints and supports during periods of increased discomfort and the use of ergonomic devices, such as ergonomic computer key boards. Different operative procedures have been attempted to decrease pain and restore wrist function.

Surveillance: For children with SHOX deficiency: biannual measurement of growth.

Agents/circumstances to avoid: If Madelung deformity is associated with discomfort, physical activities such as lifting, gripping, writing, typing, and sports that strain the wrist should be limited and ergonomic aids sought.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment are warranted for sibs at risk for SHOX deficiency in order to identify as early as possible those who would benefit from recombinant human growth hormone (rhGH) treatment.

Genetic counseling.

SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. Each child of an individual with a SHOX deficiency disorder has a 50% chance of inheriting the SHOX pathogenic variant. If both parents have SHOX deficiency, the offspring have a 50% chance of having a SHOX deficiency disorder, a 25% chance of having Langer type of mesomelic dwarfism, and a 25% chance of having neither condition. If the SHOX pathogenic variant has been identified in one or both parents, prenatal testing for pregnancies at increased risk is possible; however, the phenotype of the SHOX deficiency disorder cannot be accurately predicted on the basis of prenatal molecular genetic testing results.

GeneReview Scope

SHOX Deficiency Disorders: Included Phenotypes
  • Leri-Weill dyschondrosteosis 1
  • Short stature caused by SHOX deficiency

For other genetic causes of this phenotype, see Differential Diagnosis.


The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from nonspecific short stature at the mild end of the spectrum to Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum.

Suggestive Findings

SHOX-related Leri-Weill dyschondrosteosis (LWD) should be suspected in individuals with the classic clinical findings of the triad of short stature, mesomelia, and Madelung wrist deformity and characteristic radiographic findings.

Clinical Findings

Short stature is defined as height below the third percentile of the reference population.

Mesomelia (disproportionate shortening of the middle portion of the limbs) is present in 60%-100% of females and 45%-82% of males with LWD older than age six years [Kosho et al 1999, Schiller et al 2000, Grigelioniene et al 2001, Ross et al 2001, Munns et al 2003b].

This shortening of the forearm and lower leg can be assessed by two ratios:

  • Extremities to trunk ratio. A low extremities to trunk ratio (sum of arm span and calculated leg length divided by the sitting height) less than 1.95 + 0.5 x height (metric) is indicative of shortening of arms and legs; it serves as a sensitive auxologic test to detect SHOX deficiency [Binder et al 2003].
  • Sitting height to height ratio. A high sitting to height ratio is indicative of shortening of the legs and can also be used as the first auxologic test when screening for short children with SHOX deficiency [Malaquias et al 2013, Wolters et al 2013].

Madelung wrist deformity, caused by an abnormal radial, ulna, and carpal alignment, is characterized by spontaneous dorsal subluxation of the distal ulna resulting in a lateral "dinner fork" appearance of the wrist first described by Madelung [1878].

Radiographic Findings

The radiographic criteria for Madelung deformity [Dannerberg et al 1939, Langer 1965, Fagg 1988] include the following main abnormalities:

  • Radius
    • Triangulation of the distal epiphysis
    • Early fusion of the ulnar half of the distal epiphysis
    • Localized lucency at the distal ulnar border
    • Decreased length
    • Dorsal and ulnar curve
  • Carpal bones
    • Pyramidalization of the carpal row becoming wedge-shaped with the oslunatum at its tip
  • Ulna
    • Decreased length
    • Dorsal subluxation
    • Triangular deformity of the epiphysis

Short stature caused by SHOX deficiency should be suspected in children with a first-degree relative with clinical LWD or SHOX deficiency disorder and one of the following [Binder et al 2000, Ezquieta et al 2002, Ogata et al 2002, Rappold et al 2002, Binder et al 2003, Binder 2011]:

  • Disproportionate short stature (young school age)
  • Madelung deformity (older school age)
  • Short stature and specific minor abnormalities (see Clinical Characteristics, Clinical Description)

Establishing the Diagnosis

The diagnosis of SHOX deficiency is established in a proband with either a SHOX deletion or a SHOX single nucleotide variant (see Table 1). The deletion can encompass the coding region of the gene and/or the enhancer region regulating SHOX expression.

Deletions can encompass all or part of SHOX or only enhancer sequences, leaving SHOX intact [Schneider et al 2005b, Benito-Sanz et al 2006, Huber et al 2006, Chen et al 2009, Rosilio et al 2012].

Partial and complete duplications of SHOX have also been described [Benito-Sanz et al 2012, Sandoval et al 2014, van Duyvenvoorde et al 2014, Wit & Oostdijk 2015] but their clinical relevance is less clear.

SHOX is located on the pseudoautosomal region of the X chromosome at Xp22.3 and the pseudoautosomal region of the Y chromosome at Yp11.3; thus, in usual circumstances SHOX is present in two identical copies:

  • In females, one copy is present on each X chromosome
  • In males, one copy is present on the X chromosome and one copy – sometimes called SHOX(Y) – is present on the Y chromosome

Genetic testing approaches can include single-gene testing, genomic testing, and chromosome analysis.

Single-gene testing

  • Deletion/duplication analysis. Overall, more than 80% of individuals with SHOX deficiency have a deletion that may vary in size between 10 kb and 2.5 Mb or more.
    • Deletions and duplications of SHOX including its enhancer regions can be detected with good accuracy by multiplex ligation-dependent probe amplification (MLPA). In this instance only data from the SHOX region is analyzed. Single probe deletions should always be confirmed by alternative methods.
    • Deletions can also be detected using whole-genome SNP array analysis, which can detect CNVs encompassing SHOX and its enhancers. Ideally, determining heterozygosity for a SNP(s) involves analysis of DNA from the proband and both parents.
  • Sequence analysis. If no SHOX deletion is identified, sequence analysis should be performed to identify single nucleotide variants in SHOX.

Genomic testing can be used if single-gene testing has not confirmed a diagnosis in an individual with features of SHOX deficiency. Such testing may include whole-exome sequencing (WES) or whole-genome sequencing (WGS).

For issues to consider in interpretation of genomic test results, click here.

Cytogenetic testing. If either a contiguous gene syndrome encompassing signs of a SHOX deficiency disorder (in addition to other distinctive features) or an X;Y chromosomal translocation is suspected, a G-banded karyotype should be carried out [Ballabio et al 1989, Shears et al 1998, Shears et al 2002]. Rarely, individuals with LWD may have one of the following:

Table 1.

Summary of Molecular Genetic Testing Used in SHOX Deficiency Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method 3, 4
SHOXSequence analysis 5~10%-20%
Gene-targeted deletion/duplication analysis 6~80%-90% 7

See Molecular Genetics for information on allelic variants detected in this gene.


Currently, about 10% of individuals with LWD do not have a demonstrable SHOX pathogenic variant and may either represent a false-negative result beyond the limits of current technology or represent phenocopies (true negatives).


Numbers vary between laboratories using different methodologies. Numbers also differ in patients from different ethnic origins.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects deletions or duplications that can be intragenic or in enhancer elements upstream or downstream of SHOX. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Most of the pathogenic variants detected are deletions.

Test characteristics. See Clinical Utility Gene Card [Albuisson et al 2012] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

Leri-Weill Dyschondrosteosis (LWD)

Short stature. Natural growth in SHOX deficiency is not well studied. Mean birth length is only mildly reduced, at 0.6-0.9 SD below the mean [Munns et al 2003a, Binder et al 2004]. In contrast, infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [Ross et al 2001, Binder et al 2003, Munns et al 2003b]. During childhood, there is probably no relevant additional loss of height. The pubertal growth spurt, however, seems to be blunted resulting in an additional height deficit. In a review of 129 individuals with SHOX deficiency, Munns et al [2003b] reported a progressive decline in the height standard deviation score from birth (-1.05), through childhood (female -2.23, male -2.10) and into final adult height (female -2.84, male -2.36).

Mesomelia. Mesomelic disproportion of the skeleton with shortening of the extremities can be evident first in school-aged children and increase with age in frequency and severity [Ross et al 2001].

Madelung deformity. Like mesomelia, Madelung deformity evolves with time and is generally more common and more severe in females. During infancy and early childhood, children with LWD may have subtle radiologic signs of Madelung deformity (i.e., lucency of the distal radius), but they are usually asymptomatic and the physical examination is normal.

Madelung deformity typically develops in mid-to-late childhood. The first common sign is a subtle reduction in pronation and supination of the forearm. The complete deformity with distal subluxation of the ulna (dinner fork sign) evolves during puberty and is associated with further restriction of forearm supination and pronation [Vickers & Nielsen 1992, Munns et al 2001].

Rarely, Madelung deformity causes joint pain in adolescence [Schmidt-Rohlfing et al 2001].

Other features of LWD [Rao et al 2001, Ross et al 2001, Munns et al 2003b, Rappold et al 2007, Rosilio et al 2012]:

  • Hypertrophy of calf muscles
  • Short fourth metacarpals
  • Increased carrying angle of the elbow
  • High-arched palate
  • Scoliosis
  • High body mass index (not caused by excess of fat mass)

No other visceral involvement occurs. Intellect is normal.

Short Stature Caused by SHOX Deficiency

The phenotype is highly variable, even within the same family.

In the absence of Madelung deformity and mesomelia, the diagnosis of LWD cannot be made. In these instances, the diagnosis is short stature caused by SHOX deficiency.

In adults with SHOX deficiency, the proportion of LWD versus short stature without features of LWD is not well defined.


In LWD, Madelung deformity results from a zone of dyschondrosteosis (dysplasia) at the medial aspect of the growth plate (physis) of the distal radius. In the zone of dyschondrosteosis, normal chondrocyte columns are replaced with disorganized non-columnar nests of chondrocytes in varying stages of maturation [Munns et al 2001] that cause premature fusion of the physis and thus localized early cessation of longitudinal bone growth. The differential growth rate of the medial distal radius and the lateral distal radius pulls the radial epiphysis out of line [Vickers & Nielsen 1992].

Genotype-Phenotype Correlations

There is no established correlation between the severity of phenotype and the underlying SHOX pathogenic variant [Clement-Jones et al 2000, Schiller et al 2000, Grigelioniene et al 2001, Ross et al 2001].

Based on a limited number of studies, the frequency of LWS is three to ten times greater than isolated short stature in individuals with a SHOX enhancer deletion [Chen et al 2009, Benito-Sanz et al 2012, Bunyan et al 2013], suggesting that enhancer deletions cause a more severe phenotype. However, in contrast, in the French population deletions of the downstream enhancer region of SHOX appear to be associated with a milder phenotype [Rosilio et al 2012].


The penetrance of SHOX deficiency is high, but its clinical expression is highly variable, becoming more pronounced with age and being more severe in females.

The female-to-male ratio in studied cohorts with SHOX deficiency is increased. The cause is unclear.


Estimates of the prevalence of SHOX deficiency are dependent on the inclusion criteria used for the selection of persons tested, the size of the cohort tested, and the genetic tests available for detecting pathogenic variants of SHOX and its enhancer regions.

LWD. Estimates of the prevalence of SHOX deficiency in LWD range from 70% to 90% [Binder et al 2004, Jorge & Arnhold 2007, Rappold et al 2007, Rosilio et al 2012].

Children with idiopathic short stature and no signs of LWD. Estimates of the presence of SHOX deficiency in this group of children ranges from 2% to 15% depending on the test methods used [Ezquieta et al 2002, Rappold et al 2002, Binder et al 2003, Stuppia et al 2003, Schneider et al 2005b, Huber et al 2006, Rappold et al 2007, Hirschfeldova et al 2012, Rosilio et al 2012, Sandoval et al 2014]. Taking into account only the most recent papers that use MLPA and Sanger sequencing to search for pathogenic variants, the frequency of SHOX deficiency in children with idiopathic short stature and no signs of LWD ranges from 6% to 15%. Given the results of studies of SHOX pathogenic variants in children with apparent idiopathic short stature and given that not all individuals with a SHOX pathogenic variant have short stature, it has been estimated that the prevalence of SHOX deficiency is at least 1:1,000.

Differential Diagnosis

The differential diagnosis of isolated short stature caused by SHOX deficiency includes the following:

The differential diagnosis of LWD caused by SHOX deficiency includes the following:

  • Turner syndrome (see Genetically Related Disorders)
  • LWD caused by pathogenic variants at an unidentified alternate locus or gene(s) outside the SHOX locus
  • Trauma to, infection of, or tumors in the distal radial growth plate


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SHOX deficiency, physical examination with attention to the following is indicated [Rappold et al 2007, Binder 2011]:

  • Growth parameters. Height, arm span, and sitting height. Calculate extremities to trunk ratio or sitting height to height ratio (see Diagnosis).
  • Assessment of pubertal stage in preadolescents to determine if use of recombinant human growth hormone (rhGH) is appropriate
  • Madelung deformity. Prominence of distal ulna, limitation of forearm pronation and supination, and wrist pain
  • Scoliosis
  • Body mass index. The body mass index is frequently above the mean; mainly because of shortening of the legs.

Treatment of Manifestations

Short stature

  • For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. Hand/wrist radiographs for bone age determination should be taken at the initial visit and annually during rhGH therapy to assess maturation tempo.
  • Treatment with high-dose rhGH augments the growth of children with SHOX deficiency to the same extent as in Turner syndrome according to a two-year randomized controlled trial [Blum et al 2007]. This effect caused a similar gain in final height as well [Blum et al 2013]. No adverse radiologic effects were noted in those who were treated.

Painful bilateral Madelung deformity (uncommon)

  • Conservative management consists of wrist splints and supports during periods of increased discomfort and the use of ergonomic devices, such as ergonomic computer key boards. These measures may reduce wrist discomfort, but do not alter the natural history of the deformity [Fagg 1988, Schmidt-Rohlfing et al 2001].
  • Different operative procedures have been attempted to decrease pain, and restore wrist function [Anton et al 1938]; although Anton et al did not recommend operating until skeletal maturity because of concern that surgery at an early age may result in further deformity, Vickers & Nielsen [1992] and Schmidt-Rohlfing et al [2001] reported encouraging results from prophylactic physiolysis of the ulnar (lateral) aspect of the distal radius and excision of the Vickers ligament during mid-to-late childhood. Their rationale for early intervention is to alter the natural history of the deformity by excising the area of dyschondrosteosis in the distal radius, thus restoring growth in the distal radius [Vickers & Nielsen 1992]. They reported decreased pain, increased function, and a reduction in wrist deformity following surgery over a period of 15 months to 12 years of follow up. They also speculate that MRI may allow for the early detection and subsequent removal of the Vickers ligament, an abnormal fibro-elastic ligament that runs from the lunate to the ulna aspect of the distal radius that may play a central role in the development of Madelung deformity [Vickers & Nielsen 1992]. Similar results have been reported by Carter & Ezaki [2000] when a dome osteotomy of the radial metaphysis is combined with release of the Vickers ligament [Carter & Ezaki 2000].


The growth of a child with SHOX deficiency should be monitored every six months.

Agents/Circumstances to Avoid

If Madelung deformity is associated with discomfort, physical activities such as lifting, gripping, writing, typing, and sports that strain the wrist should be limited and ergonomic aids sought [Fagg 1988].

Evaluation of Relatives at Risk

It is appropriate to evaluate the siblings of a patient with SHOX deficiency in order to identify as early as possible those who would also benefit from recombinant human growth hormone (rhGH) treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on Xp and Yp follow the rules of autosomal inheritance; thus, a SHOX pathogenic variant responsible for SHOX deficiency can be located on either the X or Y chromosome of an affected male, or on either of the X chromosomes of an affected female.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with SHOX deficiency have an affected parent.
  • A proband with SHOX deficiency may have the disorder as the result of a de novo pathogenic variant. The exact proportion of cases caused by a de novo pathogenic variant is unknown.
  • In males obligatory crossover during meiosis I results in transfer of genes located within pseudoautosomal region 1 from the Y chromosome to the X chromosome and vice versa. Because of the high recombination frequency in pseudoautosomal region 1on Xp and Yp, males produce a mixture of sperm in which some harbor a Y-linked SHOX deletion and some an X-linked SHOX deletion. Because segregation of these sperm is identical to autosomal dominant inheritance: (1) in some families, such recombination results in the LWD phenotype (e.g., a father bearing a Y-linked SHOX deletion has a daughter with an X-linked SHOX deletion); and (2) father-to-son transmission can be observed [Flanagan et al 2002, Sabherwal et al 2004a, Kant et al 2011].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination, radiographs of the wrists, and molecular genetic testing.
  • The family history of some individuals diagnosed with SHOX deficiency may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing have been performed on the parents of the proband.

Note: If the parent is the individual in whom the SHOX pathogenic variant first occurred, s/he may have a somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • If the SHOX pathogenic variant cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported to date.

Offspring of a proband

  • Each child of an individual with SHOX deficiency has a 50% chance of inheriting the SHOX pathogenic variant.
  • If both parents have SHOX deficiency, the offspring have a 50% chance of having SHOX deficiency, a 25% chance of having a fetus or infant with a Langer type of mesomelic dwarfism (see Genetically Related Disorders), and a 25% chance of having neither condition.
  • Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with SHOX deficiency may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are usually distinct from those of the parents [Ross et al 2003].

    If both parents have a dominantly inherited bone growth disorder, the offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having normal stature and bone growth, and a 25% chance of having double heterozygosity for both disorders.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with SHOX deficiency has the SHOX pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the SHOX pathogenic variant has been identified in one or both parents, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing. However, the phenotypic spectrum of SHOX deficiency disorders is broad and phenotype cannot be accurately predicted on the basis of prenatal molecular genetic testing results.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Bundesverband Kleinwüchsige Menschen (BKMF)
    Leinestrasse 2
    28199 Bremen
    Phone: 49-421-336169-0
    Fax: 49-421-336169-18
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SHOX Difficiency Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for SHOX Difficiency Disorders (View All in OMIM)


Molecular Genetic Pathogenesis

The short stature homeobox-containing gene (SHOX) is occasionally written using alternative nomenclature: PHOG [Ellison et al 1997] and SHOXY. These gene aliases have sequence homology with SHOX. SHOXY is SHOX located at Yp11.3. Because the abbreviation for the short stature homeobox-containing gene, SHOX, does not make any reference to the chromosome on which it is located, it is confusing to differentiate between SHOX and SHOXY, as they are the same gene located on the X and on the Y chromosome. Pathogenic variants within the pseudoautosomal region occur frequently; the frequency with which mutation of SHOX occurs on the X or Y chromosome is unclear, but rather irrelevant as this gene at the tip of the pseudoautosomal region has an exchange rate of 50% in male meiosis [Kant et al 2011].

SHOX escapes X-chromosome inactivation.

Because there is no mouse ortholog for SHOX, it has not been possible to explore the biologic properties of this gene using mouse as a model [Clement-Jones et al 2000]. Nevertheless, effects of human SHOX expression expressing the human SHOXa cDNA under the control of a murine Col2a1 promoter and enhancer (Tg(Col2a1-SHOX) have been analyzed in transgenic mice [Beiser et al 2014]. In addition, chicken has turned out to be a valuable animal model for SHOX during limb development [Tiecke et al 2006, Sabherwal et al 2007, Durand et al 2010].

In situ hybridization studies on human embryos between 26 and 52 days post-conception demonstrated a role for SHOX in limb and other bone or mesoderm-derived structures [Clement-Jones et al 2000]. SHOX was most strongly expressed in the mid-portion of limbs, especially the elbow and knee. It was also expressed in the distal ulna/radius and wrist [Clement-Jones et al 2000]. This expression pattern provides an explanation for the short stature, bowing, and shortening of the forearms and lower legs, the Madelung deformity, and the shortening of the fourth metacarpals seen in LWD and Turner syndrome [Clement-Jones et al 2000]. Recently, SHOX protein was identified in human growth plate hypertrophic chondrocytes,further supporting a role for SHOX in bone development [Marchini et al 2004, Munns et al 2004].

SHOX was also expressed in the first and second pharyngeal arches, suggesting that it may play a role in the development of the palatine maxillary sleeves, mandible, auricular ossicles, and the external auditory meatus [Clement-Jones et al 2000]. As such, haploinsufficiency of SHOX may cause the high-arched palate, micrognathia, and sensorineural deafness of Turner syndrome [Clement-Jones et al 2000]. Of equal interest, SHOX was not expressed in developing heart, kidney, or vascular tissue, suggesting that SHOX-related haploinsufficiency is unlikely to play a role in the development of abnormalities of these organs seen in Turner syndrome [Clement-Jones et al 2000]. This finding may explain why individuals with SHOX-related haploinsufficiency disorders do not have the extraskeletal manifestations of Turner syndrome. In contrast, Rao et al [1997] found expression of SHOXa in skeletal muscle, pancreas, heart, and bone marrow fibroblasts and SHOXb in fetal kidney, skeletal muscle, and bone marrow fibroblasts. See Normal gene product.

The phenotype of Langer mesomelic dysplasia, with severe deformity of the limbs and mild hypoplasia of the mandible, suggests that SHOX is most biologically active in these regions and less so in the unaffected skeletal structures. One may have also expected to see abnormalities of metacarpals, vertebra, and palate, as these are abnormal in SHOX-related haploinsufficiency associated with LWD and TS. SHOX is a homeobox gene and acts as a transcription regulator, with many downstream targets that modify growth and stature [Rao et al 1997, Rao et al 2001].

The work of Gudrun Rappold and colleagues regarding the functional properties of SHOX [Rao et al 2001, Blaschke et al 2003, Marchini et al 2004, Sabherwalet al 2004a, Sabherwal et al 2004b] suggests that SHOX acts as a nuclear transcription factor that inhibits cellular growth and apoptosis, possibly through the up-regulation of p53 [Marchini et al 2004]. Mutated SHOX protein was demonstrated to have both abnormal nuclear translocation and transcription properties [Sabherwal et al 2004b]. These results led to the suggestion that in the absence of wild-type SHOX, chondrocytes may undergo atypical proliferation and differentiation [Marchini et al 2004, Marchini et al 2007]. This could explain the growth plate histology described above and the short stature associated with LWD. Schneider et al [2005a] have shown that single missense pathogenic variants in SHOX, which were present in individuals with LWD or ISS, alter the biologic function of SHOX with loss of DNA binding, dimerization, and/or nuclear localization [Schneider et al 2005a]. They postulate that these mechanisms could result in the LWD/ISS phenotype.

More recent work has elucidated direct and indirect targets of the SHOX transcription factor and helped to elucidate the developmental pathways involved in SHOX action. The targets BNP, FGFR3, and Ctgf are directly regulated by SHOX, whereas the regulation of Agc1 is indirect [Marchini et al 2007, Aza-Carmona et al 2011, Decker et al 2011, Beiser et al 2014].

Gene structure. SHOX encodes two major transcripts, SHOXa (NM_000451.3) and SHOXb (NM_006883.2), each containing five coding exons, and differing only in their 3'UTR and a small region of the coding sequence [Rao et al 1997]. Meanwhile, further transcript variants have been described, suggesting that alternative splicing contributes to the regulation of SHOX expression [Durand et al 2011]. For a summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 170 unique exonic allelic variants of SHOX have been described. An up-to-date list of these can be found on the Human Short Stature Gene Allelic Variant Database Web Site. (For more information, see Table A.)

Normal gene product

Abnormal gene product. The homeodomain of SHOX mediates several key functions including nuclear localization, DNA binding, and protein-protein interaction [Schneider et al 2005a]. Mutation within the homeodomain interferes with these processes and results in the skeletal defects. Mutation outside the homeodomain and deletions may lead to a reduced level of SHOX protein, hereby affecting growth and skeletal development.


Literature Cited

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Chapter Notes

Author History

Gerhard Binder, MD (2015-present)
Ian Glass, MBChB, MD, FRCP, FACMG; University of Washington (2005-2015)
Craig Munns, MBBS, PhD, FRACP; The Children’s Hospital at Westmead (2005-2015)
Gudrun A Rappold, PhD (2015-present)

Revision History

  • 20 August 2015 (me) Comprehensive update posted live
  • 1 February 2008 (cd) Revision: FISH testing specific to SHOX deletions no longer listed separately in the GeneTests Laboratory Directory; duplication/deletion analysis available
  • 4 October 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically
  • 22 January 2007 (cd) Revision: sequence analysis no longer clinically available
  • 12 December 2005 (me) Review posted to live Web site
  • 25 October 2004 (cm) Original submission
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