Clinical Guidance

No correlation has been established between the severity of phenotype and the underlying SHOX pathogenic variant [, , , ]. Based on a limited number of studies, the frequency of LWS is greater than SHOX-deficient short stature caused by a SHOX enhancer deletion , 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 . Thus, this issue remains unresolved.

Source: GeneReviews — "SHOX Deficiency Disorders"

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.

Source: GeneReviews — "SHOX Deficiency Disorders"

Diagnostic Criteria

The phenotypic spectrum of SHOX deficiency disorders, caused by haploinsufficiency of the short stature homeobox-containing gene (SHOX), ranges from nonspecific short stature with absence of mesomelia and Madelung deformity (called SHOX-deficient short stature in this GeneReview) 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 following clinical and radiographic findings.

Clinical Findings of LWD

Short stature is defined as height below the third centile 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 th...

Source: GeneReviews — "SHOX Deficiency Disorders"

Differential Diagnosis

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

• Turner syndrome in females (See .)

• Children of both sexes with short stature of unknown cause (often called idiopathic short stature [ISS]). ISS is defined as height below the third centile in an individual for whom no skeletal, hormonal, chromosomal, or genetic etiology . With the recent use of methods to detect SHOX deletions/duplications and SHOX enhancer deletions, SHOX-deficient short stature appears to comprise 10% to 20% of children with apparent ISS [, , , , ]. (Using less sensitive molecular genetic testing methods, the prevalence of SHOX-deficient short stature in children who had been identified as having ISS was estimated at 2%-10% [, , , , , , ].)

Source: GeneReviews — "SHOX Deficiency Disorders"

Management Guidelines

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 :

• Growth parameters. Height, arm span, and sitting height. Calculate extremities-to-trunk ratio or sitting height-to-height ratio .

• 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

Short Stature

For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 g/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 . This effect caused a similar gain in final height as well . No adverse radiologic effects were noted in those who were treated .

Source: GeneReviews — "SHOX Deficiency Disorders"

Clinical Guidance

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 .

Source: GeneReviews — "SHOX Deficiency Disorders"

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.

Source: GeneReviews — "SHOX Deficiency Disorders"

Surveillance Guidelines

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.

Source: GeneReviews — "SHOX Deficiency Disorders"