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 shortened 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 (called SHOX-deficient short stature in this GeneReview) is highly variable, even within the same family.

Diagnosis/testing.

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

Management.

Treatment of manifestations: For prepubertal children with SHOX-deficient 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 individuals with LWD and 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 keyboards. Different operative procedures have been attempted to decrease pain and restore wrist function.

Surveillance: For children with a SHOX deficiency disorder: 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-deficient short stature 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. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (Yp) follow the rules of autosomal inheritance; thus, a SHOX pathogenic variant responsible for SHOX deficiency can be located on either the X or the Y chromosome of an affected male, or on either of the X chromosomes of an affected female.

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.

Suggestive Findings

SHOX-related Leri-Weill dyschondrosteosis (LWD) should be suspected in individuals with the following clinical and radiographic findings.

Radiographic Findings of LWD

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 os lunatum at its tip
• Ulna
  • Decreased length
  • Dorsal subluxation
  • Triangular deformity of the epiphysis

SHOX-deficient short stature 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.)

The following two testing algorithms have been proposed:

• A scoring system based on various clinical signs including body disproportion, arm span:height ratio <96.5%, sitting height:height ratio >55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [Rappold et al 2007]. Items scored and the scoring weight were derived by multivariate analysis in 1,608 individuals with short stature including 68 with molecularly confirmed SHOX deficiency (i.e., presence of pathogenic variants / deletions in the coding region; note that enhancers had not yet been identified). See Rappold et al [2007], Figure 1 and Table 7 (full text).
  While the values for body disproportions in children and adults are useful, they may not apply to very young children [Jorge & Arnhold 2007].
• A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [Binder 2011]. See Figure 1.

Figure 1.

This schema provides an algorithmic approach to SHOX pathogenic variant screening in a child with short stature. Minor abnormalities (*) in SHOX deficiency are shortening of the fourth and fifth metacarpals, high-arched palate, increased carrying angle (more...)

Note: The absence of the above signs does not exclude the diagnosis of SHOX deficiency, especially in very young children.

Establishing the Diagnosis

The diagnosis of SHOX deficiency is established in a proband who has either of the following on molecular genetic testing (see Table 1) [Marchini et al 2016]:

• A heterozygous SHOX deletion (80%-90% of affected individuals)
  • 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 the short arm of each X chromosome (Xp).
    • In males, one copy is present on the short arm of the X chromosome (Xp) and one copy – sometimes called SHOX(Y) – is present on the short arm of the Y chromosome (Yp).
  • 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].
• A SHOX heterozygous pathogenic (or likely pathogenic) variant (10%-20% of affected individuals)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous SHOX variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include gene-targeted testing and comprehensive genomic testing depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SHOX deficiency is broad, individuals with the distinctive findings of Leri-Weill dyschondrosteosis (LWD) described in Suggestive Findings are likely to be diagnosed using a combination of chromosomal microarray analysis (CMA) and gene-targeted testing (see Option 1), whereas individuals with SHOX-deficient short stature in which the phenotype may be indistinguishable from many other inherited disorders with short stature –particularly in early childhood – are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The phenotypic spectrum of SHOX deficiency disorders ranges from Leri-Weill dyschondrosteosis (LWD) at the severe end of the spectrum to SHOX-deficient short stature (without mesomelia or Madelung deformity) at the mild end. In adults with SHOX deficiency, the proportion of LWD versus SHOX-deficient short stature 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 shortened 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 SHOX-deficient short stature is highly variable, even within the same family.

Genotype-Phenotype Correlations

No correlation has been established 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 greater than SHOX-deficient short stature caused by 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. In the French population, however, deletions of the downstream enhancer region of SHOX appear to be associated with a milder phenotype [Rosilio et al 2012]. Thus, this issue remains unresolved.

Penetrance

While the penetrance of SHOX deficiency is high, its clinical expression is highly variable, becomes more pronounced with age, and is more severe in females.

For reasons unknown, the female-to-male ratio in studied cohorts with SHOX deficiency is increased.

Prevalence

Estimates of the prevalence of SHOX deficiency depend 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 short stature of unknown cause (often called idiopathic short stature) and no signs of LWD. Taking into account the most recent reports that use MLPA and Sanger sequencing to detect SHOX deletions/duplications and SHOX enhancer deletions, the frequency of SHOX-deficient short stature in children with short stature of unknown cause and no signs of LWD ranges from 6% to 22% (for a review see Marchini et al [2016]).

Given the results of studies of SHOX pathogenic variants in children with short stature of unknown cause 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SHOX deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended [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. Frequently above the mean; mainly because of shortening of the legs
• Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Surveillance

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

In case of growth failure or short stature, treatment with recombinant human growth hormone is an option to increase growth rate and adult height; consultation with a pediatric endocrinologist is recommended.

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 clarify the genetic status of the sibs of an affected individual 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 ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, homologous genes located on the short arm of the X chromosome (Xp) and the short arm of the Y chromosome (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.
• 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.
• In males an 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 1 on 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, in some families such recombination results in [Flanagan et al 2002, Sabherwal et al 2004a, Kant et al 2011]:
  • The LWD phenotype (e.g., a father bearing a Y-linked SHOX deletion has a daughter with an X-linked SHOX deletion); and
  • Father-to-son transmission.
• 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, the parent may have 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 and/or is known to have the SHOX pathogenic variant identified in the proband, the risk to the sibs is 50%; intrafamilial clinical expression can be highly variable.
• If the SHOX pathogenic variant cannot be detected in the DNA of either parent, the recurrence 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.
• If the parents have not been tested for the SHOX pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SHOX deficiency because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [Ramachandrappa et al 2018].

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 inheriting one pathogenic variant and having SHOX deficiency, a 25% chance of inheriting two pathogenic variants and having 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. The risk to other family members depends on the status of the proband's parents: if a parent has the SHOX pathogenic variant, the parent's 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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SHOX pathogenic variant has been identified in one or both parents, prenatal and preimplantation genetic testing are possible. However, the phenotypic spectrum of SHOX deficiency disorders is broad and the phenotype cannot be accurately predicted on the basis of prenatal molecular genetic testing results.

Molecular Pathogenesis

The short stature homeobox-containing gene (SHOX) is located within the pseudoautosomal region of the X (Xp22.3) and Y (Yp11.3) chromosomes. Although SHOX on the Y chromosome has been referred to as SHOXY, the official gene name, SHOX, does not refer to the chromosome on which it is located. Of note, SHOX escapes X-chromosome inactivation. The frequency with which pathogenic variants in SHOX occur on the X or Y chromosome is not known but is irrelevant, as this gene, located at the tip of the pseudoautosomal region, has an exchange rate of 50% in male meiosis [Kant et al 2011].

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 variants. More than 1,200 unique DNA variants and more than 180 pathogenic variants in SHOX have been described. An up-to-date list of these can be found on the Human Short Stature Gene Allelic Variant Database website (grenada.lumc.nl/LSDB_list/lsdbs/SHOX). (For more information, see Table A.)

The majority of SHOX pathogenic variants are large deletions encompassing the entire gene as well as adjacent genes.

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, Bunyan et al 2016, Benito-Sanz et al 2017, Hirschfeldova & Solc 2017, Upners et al 2017].

Normal gene product

• SHOXa, a 292-amino-acid protein [Rao et al 1997], is expressed in skeletal muscle, placenta, heart, bone marrow fibroblasts, and growth plate chondrocytes [Marchini et al 2004, Munns et al 2004].
• SHOXb, a 225-amino-acid protein [Rao et al 1997], is isolated to fetal kidney, placenta, and bone marrow fibroblasts [Rao et al 1997].

Because there is no SHOX mouse ortholog, use of a mouse knockout model has not been possible [Clement-Jones et al 2000]. However, expression of human SHOXa cDNA under the control of a murine Col2a1 promoter and enhancer has been analyzed in transgenic mice [Beiser et al 2014]. Chicken SHOX models have also been a valuable model for limb development [Tiecke et al 2006, Sabherwal et al 2007, Durand et al 2010].

In human embryos SHOX is most strongly expressed in the mid-portion of limbs (especially the elbow and knee) and also 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]. SHOX protein was also 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 is 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].

SHOX acts as a nuclear transcription factor that inhibits cellular growth and apoptosis, possibly through the upregulation of p53 [Rao et al 2001, Blaschke et al 2003, Marchini et al 2004, Sabherwal et al 2004a, Sabherwal et al 2004b]. In the absence of normal SHOX, chondrocytes may undergo atypical proliferation and differentiation [Marchini et al 2004, Marchini et al 2007, Marchini et al 2016].

Direct and indirect targets of the SHOX transcription factor have been described. 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].

An influence of SHOX as a regulator on FGFR3 signaling, CNP/Npr2 signaling and Bmp4 signaling and RUNX activity have been described (for a review see Marchini et al [2016]).

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

Schneider et al [2005a] have shown that single missense pathogenic variants in SHOX, which were present in individuals with LWD or children with short stature of unknown cause (often called idiopathic short stature), alter the biologic function of SHOX with loss of DNA binding, dimerization, and/or nuclear localization [Schneider et al 2005a].

Recently, the first genetic modifier of SHOX deficiency, CYP26C1 (which is associated with a more severe phenotype), was described [Montalbano et al 2016]. Subsequently, pathogenic variants in CYP26C1 in the absence of pathogenic variants in SHOX have been associated with short stature [Montalbano et al 2018].

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

• 28 June 2018 (bp) Comprehensive update posted live
• 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 live
• 25 October 2004 (cm) Original submission

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