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SHOX-Related Haploinsufficiency Disorders

Includes: Leri-Weill Dyschondrosteosis, Dyschondrosteosis, SHOX-Related Short Stature


Author Information
Staff Specialist, Genetic and Metabolic Bone Disorders
Institute of Endocrinology and Diabetes
The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Division of Genetics and Developmental Medicine
Department of Pediatrics
Children's Hospital and Regional Medical Center
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: February 1, 2008.


Clinical characteristics.

Short stature homeobox (SHOX)-related haploinsufficiency disorders range from Leri-Weill dyschondrosteosis (LWD) at the more severe end of the spectrum to SHOX-related short stature at the mild end of spectrum. The classic clinical triad in LWD is short stature, mesomelia, and Madelung deformity. Mesomelia, in which the middle portion of a limb is shorted in relation to the proximal portion, is the most frequent clinical finding. Madelung deformity includes abnormal alignment of the radius, ulna, and carpal bones at the wrist; it typically develops in mid-to-late childhood and is more common and severe in females. Individuals with SHOX-related short stature have disproportionate short stature and/or wrist abnormalities consistent with those described in Madelung deformity.


The SHOX genes located on the pseudo-autosomal regions of the X and Y chromosomes are the only genes known to be associated with SHOX-related haploinsufficiency. Molecular genetic testing detects SHOX deletions/mutations in 100% of individuals with SHOX-related haploinsufficiency and in approximately 70% of individuals with features of LWD.


Management of short stature in LWD caused by SHOX-related haploinsufficiency includes treatment with recombinant human growth hormone (rhGH) to improve final adult height; concurrent use of rhGH and gonadotropin-releasing hormone agonist (GnRHa) may prevent the blunted pubertal growth spurt caused by the presence of estrogen. Wrist splints and supports and ergonomic devices may reduce wrist discomfort associated with Madelung deformity; physiolysis of the ulnar aspect of the distal radius and excision of the Vickers ligament during mid-to-late childhood may decrease pain and restore wrist function. Surveillance includes biannual height evaluations and annual wrist radiographs. Molecular genetic testing of at-risk family members ensures early treatment with rhGH therapy to improve growth.

Genetic counseling.

SHOX-related haploinsufficiency disorders are inherited in a pseudo-autosomal dominant manner. Each child of an individual with a SHOX-related haploinsufficiency disorder has a 50% chance of inheriting the mutation. If both parents have a SHOX-related haploinsufficiency disorder, the offspring have a 50% chance of having a SHOX-related haploinsuficiency disorder, a 25% chance of having Langer type of mesomelic dwarfism, and a 25% chance of having neither condition. Prenatal testing is possible; however, requests for prenatal testing for these disorders is not common.


Clinical Diagnosis

Short stature homeobox (SHOX) haploinsufficiency disorders range from Leri-Weill dyschondrosteosis (LWD) at the more severe end of the spectrum to SHOX-related short stature at the mild end of spectrum.

Leri-Weill Dyschondrosteosis (LWD)

The classic clinical triad includes short stature, mesomelia, and Madelung deformity.

Mesomelia, the most frequent clinical finding in individuals with LWD, is present in 60% to 100% of females and 45% to 82% of males [Kosho et al 1999, Schiller et al 2000, Grigelioniene et al 2001, Ross et al 2001, Munns et al 2003b]. In this condition, the middle portion of a limb is shortened in relation to the proximal portion. This shortening is reflected as:

  • Short arm span (i.e., an arm span <-1.88 standard deviation (SD) below the age-matched mean) [Gerver & de Bruin 1996]
  • Reduced lower limb measurements (i.e., upper-segment to lower-segment ratio >+1.88 SD) [McKusick 1972]

Madelung deformity includes a variety of wrist deformities sharing abnormal radial, ulna, and carpal alignment [Herdman et al 1966]. The three possible outcomes of radial head dyschondrosteosis outlined below depend on the resolution of the abnormal mechanical forces at the wrist [Vickers & Nielsen 1992]. The most common is classic Madelung deformity. Within the one kindred, all three wrist phenotypes can be seen.

  • Classic Madelung deformity. Dorsal subluxation of the distal ulna resulting in a "dinner fork" deformity of the wrist
  • Reverse Madelung deformity. Volar subluxation of the distal ulna
  • Chevron carpus. Maintenance of the alignment of the wrist, resulting in impingement of the lunate bone on the distal radius, the most painful variant

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

  • Radius
    • Decreased length
    • Dorsal and ulnar curve
    • Triangulation and unequal growth of the distal epiphysis
    • Early fusion of the ulnar half of the distal epiphysis
    • Localized lucency at the distal ulnar border
    • Osteophyte formation at the inferior ulnar border caused by attachment of the Vickers ligament, which runs from the proximal pole of the lunate to the distal radial metaphysis
    • Ulnar and volar angulation of the distal articular surface
  • Ulna
    • Decreased length
    • Dorsal subluxation
    • Deformity and enlargement of the head
  • Carpal bones
    • Wedge-shaped, apex proximal, to conform to the deformed radius and ulna

SHOX-Related Short Stature

The majority of children ascertained thus far with short stature caused by SHOX-related haploinsufficiency have disproportionate short stature and/or wrist abnormalities consistent with the spectrum of findings in Madelung deformity [Binder et al 2000, Ezquieta et al 2002, Ogata et al 2002, Rappold et al 2002, Binder et al 2003]. Further detailed phenotypic analysis of children and adults with SHOX-related short stature is needed before this entity can be correctly defined.


Cytogenetic testing. Usually the submicroscopic deletions of SHOX that cause the SHOX-related haploinsufficiency disorders are not detectable by G-banded karyotyping. Rarely individuals with LWD may have either:

Molecular Genetic Testing

Gene. The SHOX (short stature homeobox-containing) gene located on the pseudo-autosomal region of the X-chromosome at Xp22.3 and the pseudo-autosomal region of the Y-chromosome at Yp11.3 is the only gene known to be associated with SHOX-related haploinsufficiency. SHOX is present in two identical copies in all individuals:

  • 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

Note: In all molecular genetic work to date, no attempt has been made to differentiate between SHOX and SHOX(Y).

Clinical uses

Clinical testing

Deletion/duplication analysis. Overall, approximately two thirds of individuals with SHOX-related haploinsufficiency have large-scale SHOX deletions that vary in size between 90 kb and 2.5 Mb or more [Schneider et al 2005b].

  • The majority of deletions share a proximal breakpoint located between SHOX and the locus DXYS233 with consistent loss of DXYS163.
  • The distal breakpoint is more variable. Fine mapping suggests the presence of a common (proximal) 'hot spot' 5-kb sequence in which the breakpoints occur.
  • The markers immediately 5' to SHOX, CAII and DXYS201, appear to be deleted in all large-scale SHOX deletions [Schneider et al 2005b].

Deletions can be detected using:

  • Fluorescence in situ hybridization (FISH). The vast majority of SHOX deletions are detectable by FISH with one of the several available cosmid probes (e.g., 34F5, which contains SHOX exons III to VIb).
  • Heterozygosity testing. Use of SNPs can detect virtually all deletions associated with SHOX-related haploinsufficiency because a hot spot of recombination around this locus results in a high degree of heterozygosity [May et al 2002]. Because SNP analysis detects deletions as null alleles, SNP analysis may identify deletions that cannot be detected using FISH [Flanagan et al 2002; Fujimura, unpublished observation]. Complete absence of heterozygosity for a sequential series of SNPs spanning SHOX is strong evidence for (but not absolute proof) of a SHOX deletion.

    Ideally, determining hemizygosity for a SNP(s) involves analysis of DNA from the proband and both parents; however, in practice, both parents are often not available for testing. Therefore a panel of informative SNPs is used to test the presence/absence of a deletion. At a minimum, the immediate 5' markers, CAII and DXYS201, should be used; ideally, several intragenic SNPs would be used [Schneider et al 2005b].
  • Copy number analysis. MLPA and other methods that detect changes in copy number for SHOX can also be used.

Mutation scanning/sequence analysis. Overall, approximately one third of mutations causing SHOX-related haploinsufficiency are point mutations. These can be detected with sequence analysis or mutation scanning [Niesler et al 2002, Morizio et al 2003].

Table 1.

Summary of Molecular Genetic Testing Used in SHOX-Related Haploinsufficiency Disorders

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency & Distribution
Mutation Classification in SHOX-Related Haploinsufficiency LWD Only 3
SHOXDeletion/duplication analysis 4Deletions ~70% ~40%
Mutation scanning / sequence analysis 5 Sequence variants~30% ~30%

See Table A. Genes and Databases for chromosome locus and protein name.


See Molecular Genetics for information on allelic variants.


Currently, 30% of LWD cases do not have a demonstrable SHOX mutation and may either represent a false negative result beyond the limits of current technology or represent phenocopies (true negatives).


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Loss of one copy of an informative heterozygous SNP(s) indicates a null SHOX allele, most likely caused by a deletion; if not detected by FISH, this hemizygous loss of sequence may be presumed to be smaller than those detectable by FISH.

Testing Strategy


Depending on laboratory availability, either FISH analysis or SNP analysis is an appropriate initial test.


If no deletion is identified, sequence analysis or mutation scanning of SHOX to identify point mutations may be undertaken.


If either a contiguous gene syndrome that encompasses signs of SHOX-related haploinsufficiency 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].

Clinical Characteristics

Clinical Description

Leri-Weill Dyschondrosteosis (LWD)

Short stature. In an analysis of 26 individuals with LWD and documented SHOX-related haploinsufficiency and review of 129 individuals with SHOX-related haploinsufficiency identified in the literature, Munns et al [2003b] reported a progressive decline in the height standard deviation score (SDS) from birth (-1.05), through childhood (female -2.23, male -2.10) and into final adult height (female -2.84, male -2.36). In a longitudinal analysis of seven females with SHOX-related haploinsufficiency, Fukami et al [2004] found a similar height reduction of 0.6 SDS between childhood and final adult height. The loss in height SD may reflect a blunted pubertal growth spurt caused by the presence of estrogen that has accelerated maturation of the epiphyseal cartilage [Munns et al 2003b, Fukami et al 2004]. Nonetheless, before a definitive statement on the growth pattern associated with LWD can be made, more comprehensive longitudinal studies are required.

Mesomelia. Ross et al [2001] reported a significant reduction in radial length z-score in persons with LWD and a SHOX mutation. Munns et al [2003b] demonstrated that arm span SD, like height SD, decreases between childhood (-3.6±0.79) and final adult height (-4.5±1.06), which may reflect the escalated maturation effect of estrogen. Stature disproportion was reported by Binder et al [2003], who reported the utility of limiting SHOX molecular genetic testing to children with an extremities-trunk ratio less than 1.95+1/2 height (m) [Binder et al 2003].

Madelung deformity. Madelung deformity is generally more common and more severe in females.

During infancy and early childhood, children with LWD may have subtle radiological signs of Madelung deformity, but they are usually asymptomatic and physical examination is normal apart from subtle reductions in pronation and supination. Madelung deformity typically develops in mid-to-late childhood and may progress during the pubertal growth spurt [Vickers & Nielsen 1992, Munns et al 2001]. In contrast, one analysis of wrist radiographs of 39 individuals with LWD and SHOX-related haploinsufficiency found that the severity of Madelung deformity was not significantly different between females who were Tanner stage 5 (adult) and Tanner stage 1 (prepubertal) [Ross et al 2001]. Further investigation is needed to determine the severity of the deformity at varying ages.

During later childhood, Madelung deformity may be progressive with restriction of forearm supination and pronation and wrist pain following repetitive wrist movements or exercise [Vickers & Nielsen 1992, Munns et al 2001].The carpal joint pain has been described as an ache or cramp, exacerbated by lifting, gripping, writing, typing, and sports [Fagg 1988]. Wrist pain may remit spontaneously in early adulthood, but often increases in the later years as a result of mechanical derangement of the wrist [Fagg 1988] and the onset of osteoarthritis.

Other. Other features of LWD include [Rao et al 2001, Ross et al 2001, Munns et al 2003b]:

  • Muscle hypertrophy/muscular habitus
  • Short 4th metacarpal
  • Increased carrying angle at the elbow
  • High-arched palate
  • Scoliosis
  • Exostoses

No other visceral involvement occurs.

Intellect is normal.

Pathophysiology. 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]. Whether the resulting Madelung deformity is classic, reverse, or chevron carpus depends on the resolution of the abnormal mechanical forces at the wrist.

Genotype-Phenotype Correlations

No correlation between the severity of phenotype and the underlying SHOX mutation has been found [Clement-Jones et al 2000, Schiller et al 2000, Grigelioniene et al 2001, Ross et al 2001, Munns et al 2003b].

The same nonsense mutation, 674C>T, has been observed in SHOX-related short stature and LWD.

No phenotypic differences have been noted between individuals with a deletion in SHOX and those with point mutations [Ross et al 2001, Munns et al 2003b].

No sequence or expression differences are present between the X and Y homologs of SHOX. No apparent differences occur in the LWD phenotype between males who have the SHOX mutation on their X-chromosome versus those who have the SHOX mutation on their Y-chromosome.


Penetrance of the LWD phenotype appears to be incomplete within families segregating SHOX-related haploinsufficiency [Munns et al 2003b]. This may result in the diagnosis of SHOX-related short stature in some family members but not others [Rappold et al 2002]. Because abnormalities of growth may precede the development of Madelung deformity, the diagnosis of LWD may not be made until late in the second decade.

As reviewed in Munns et al [2003b], both bilateral Madelung deformity and short stature are more common and severe in females than males, which has led to an excess of females in clinical studies of SHOX-related haploinsufficiency [Binder et al 2003, Munns et al 2003b, Stuppia et al 2003, Fukami et al 2004]. The female:male ratio from these reports is 90:32 (2.8:1). Although, it has been suggested that the parent of origin and the sex chromosome (i.e., the X- or Y-chromosome) harboring the SHOX mutation may account for this sex-specific variation in phenotype and the skewed sex ratio in LWD, conclusive evidence is lacking thus far [Rosenfeld 2001, Ross et al 2001]. Other explanations for these observations include a different hormonal milieu between males and females and modifiers/sex-modulated expression of the phenotype.


No evidence of anticipation in LWD exists.


Because of the variation in phenotype, the prevalence of SHOX-related haploinsufficiency disorders is unknown.

Schneider et al [2005b] found SHOX deletions in 2% of more than 1500 individuals with idiopathic short stature (ISS) defined as a height below the third centile or below -2 SD in the absence of a chronic disease known to influence growth [Schneider et al 2005b]. No data were provided on family history of short stature or stature proportions.

Given the results of studies of SHOX mutations in children with apparent idiopathic short stature and given that not all individuals with a SHOX mutation have short stature, it has been estimated that the prevalence of SHOX-related haploinsufficiency is at least 1:4000 [Binder et al 2003].

Differential Diagnosis

The differential diagnosis of SHOX-related short stature includes the following:

The differential diagnosis of Madelung deformity includes the following [Munns et al 2001]:

  • Turner syndrome (see Genetically Related Disorders)
  • Leri-Weill dyschondrosteosis caused by mutations at an unidentified alternate locus or gene(s). Cormier-Daire et al [2001], Flanagan et al [2002], and Binder et al [2004] excluded a SHOX coding mutation in 20% to 40% of individuals meeting clinical diagnostic criteria for LWD. An alternative explanation to a second (close) LWD locus in Xpter for at least some of these cases is that of a positional effect from deletion of putative regulatory elements some 300 kb centromeric to SHOX. This hypothesis is supported by co-segregation of LWD and monoallelic expression of the SHOXb transcript in bone marrow fibroblasts with co-inheritance of a hemizygous deletion at the 3' marker DXYS233, 300 kb centromeric to SHOX [Flanagan et al 2002, Benito-Sanz et al 2005].
  • Hereditary multiple exostoses (HME) is characterized by multiple exostoses, benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones. Exostoses can be associated with a reduction in skeletal growth, bony deformity, restricted motion of joints, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. Mutations of EXT1 or EXT2 are causative. Inheritance is autosomal dominant.
  • Multiple epiphysial dysplasia (MED). Dominant MED presents early in childhood, usually with pain in the hips and/or knees following exercise. The limbs are relatively short in comparison to the trunk. Adult height is either in the lower range of normal or only mildly shortened. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints. Milder forms presenting in early adulthood also occur. Mutations in five genes have been shown to cause dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. Data suggest that mutations in other, as yet unidentified, genes are also causative.
  • Dysostosis multiplex of the mucopolysaccaridoses (mucopolysaccharidosis type 1, MPS I) is a progressive multisystem disorder with features ranging over a continuum from mild to severe. Starting in early childhood, progressive skeletal dysplasia (dysostosis multiplex) involving all bones is seen in all individuals with severe MPS I. By three years of age, linear growth ceases. Individuals with intermediate MPS I have progressive somatic involvement, including dysostosis multiplex, starting at approximately age three to eight years. Individuals with mild MPS I are often diagnosed after 15 years of age and generally have normal intellect, normal stature, and a normal lifespan. Deficiency of lysosomal enzyme α-L-iduronidase resulting from mutation in IDUA, is causative. Inheritance is autosomal recessive.
  • Sickle cell disease is characterized by variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction. Consequences of hemolysis include chronic anemia, jaundice, predisposition to aplastic crisis, cholelithiasis, and delayed growth and sexual maturation. Vascular occlusion and tissue ischemia can result in acute and chronic injury to virtually every organ of the body, most significantly the spleen, brain, lungs, and kidneys. The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in HBB and defined by the presence of hemoglobin S (Hb S). Inheritance is autosomal recessive.
  • Trauma to, infection of, or tumors in the distal radial growth plate.


Evaluations Following Initial Diagnosis

Physical examination with attention to the following is indicated:

  • Growth parameters. Height, arm span, leg length, and sitting height
  • Madelung deformity. Prominence of distal ulna, limitation of wrist pronation and supination, and wrist pain
  • Scoliosis. Physical examination and x-rays if indicated
  • Pubertal status

If treatment for short stature with recombinant human growth hormone (rhGH) is considered, thyroid function tests and formal evaluation of the growth hormone axis may be considered.

Treatment of Manifestations

Short stature

  • Treatment with recombinant human growth hormone (rhGH) augments the growth of individuals with LWD and may improve final adult height [Munns et al 2003a]. Although no reports are available, it seems reasonable that individuals with SHOX-related short stature would also benefit from rhGH. Munns et al [2003b] reported no deterioration in bilateral Madelung deformity or stature disproportion with rhGH therapy.
  • The concurrent use of rhGH and gonadotropin-releasing hormone agonist (GnRHa) to delay pubertal onset in females with LWD may be of benefit when onset of puberty is early or Madelung deformity is present [Ogata et al 2001].

Bilateral Madelung deformity

  • 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, improve cosmesis, and restore wrist function [Anton & Reitz 1938]; although Anton and Reitz 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 following are appropriate:

  • Biannual to annual height evaluation to allow for the timely instigation of rhGH therapy
  • Annual wrist radiographs from age six years to evaluate for Madelung deformity and to monitor the tempo of its progression

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

Because the identification of the SHOX mutation in the sib of a proband may be beneficial in allowing for the early instigation of rhGH therapy if growth is poor, molecular genetic testing of at-risk family members (parents, then sibs) should be offered if the causative mutation has been identified in the proband.

Identification of the SHOX mutation in the sib of a proband may lead to the prophylactic excision of the Vickers ligament if this therapy proves effective in preventing or slowing the progression of Madelung deformity.

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

Therapies Under Investigation

Larger clinical trials of rhGH for short stature are underway.

Early surgical intervention for bilateral Madelung deformity once a Vickers ligament is found on MRI is under investigation.

Search for access to information on clinical studies for a wide range of diseases and conditions.

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-related haploinsufficiency disorders are inherited in a pseudo-autosomal dominant manner. In pseudo-autosomal dominant inheritance, homologous genes located on Xp and Yp follow the rules of autosomal inheritance; thus, a SHOX mutation responsible for SHOX-related haploinsufficiency 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

Note: Although most individuals diagnosed with SHOX-related haploinsufficiency have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. If the parent is the individual in whom the mutation first occurred, s/he may have a somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

Offspring of a proband

  • Each child of an individual with a SHOX-related haploinsufficiency disorder has a 50% chance of inheriting the mutation.
  • If both parents have a SHOX-related haploinsufficiency disorder, the offspring have a 50% chance of having a SHOX-related haploinsufficiency disorder, a 25% chance of having a fetus or infant with a Langer type of mesomelic dwarfism, and a 25% chance of having neither condition.
  • Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with a SHOX-related haploinsufficiency disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk is before pregnancy.

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 disease-causing mutation has been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like SHOX-related haploinsufficiency disorders) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.


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-Related Haploinsufficiency Disorders: Genes and Databases

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

Table B.

OMIM Entries for SHOX-Related Haploinsufficiency Disorders (View All in OMIM)


Molecular Genetic Pathogenesis

The short stature homeobox-containing gene (SHOX) is occasionally written using alternative nomenclature: SS, GCFX, 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, one located on the X and one on the Y chromosome. The frequency with which SHOX mutations occur on the X or Y chromosome is unclear.

SHOX escapes X-chromosome inactivation.

Because there is no mouse ortholog for SHOX, it has not been possible to explore the biological properties of this gene using an animal model [Clement-Jones et al 2000]. 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 was felt to explain 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, which further supports 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 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 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 extra-skeletal 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.

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. Being a homeobox gene, SHOX is likely to act 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, Sabherwal et 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 lead to the suggestion that in the absence of wild-type SHOX, chondrocytes may undergo atypical proliferation and differentiation [Marchini et al 2004]. This could explain the growth plate histology described above and the short stature associated with LWD. More recent work by Schneider et al [2005a] has shown that single missense mutations in SHOX, which were present in individuals with LWD or ISS, alter the biological 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.

Further studies are needed to understand the developmental pathways involved in SHOX action and explain the phenotypic heterogeneity associated with mutations in this gene.

Gene structure. The short stature homeobox-containing gene (SHOX) has two isoforms, SHOXa and SHOXb, each containing five exons, and differing only in their 3'UTR and a very small region of the coding sequence. SHOXa is 1,870 bp and SHOXb is 1,349 bp [Rao et al 1997]. These isoforms are identical for SHOX located on the X and Y chromosome. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Fifty-nine 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 at (For more information, see Table A.)

Normal gene product

Abnormal gene product. The earliest detection of SHOX expression in human embryo limbs has been from 32 days' post-conception [Clement-Jones et al 2000]. Similar results were obtained by Ellison et al [1997] using an artificial yeast construct. They demonstrated an additional 5' untranslated exon. Being a homeobox gene, SHOX is likely to act as a transcription regulator, with many downstream targets that modify growth and stature [Rao et al 1997, Clement-Jones et al 2000, Rao et al 2001]. SHOX protein has since been identified in the human growth plate from 12 weeks' gestation until growth plate fusion in late childhood [Munns et al 2004].


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Chapter Notes

Revision History

  • 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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