SHOX-related haploinsufficiency

SHOX-related haploinsufficiency forms a clinical spectrum, ranging from a mild, non-specific short stature to a more severe presentation of Leri-Weill dyschondrosteosis (LWD). The clinical presentation is influenced by a number of factors.

The phenotype of SHOX-related haploinsufficiency often becomes more distinguished over time, and is variable. Females tend to be more severely affected than males, though it is unclear why. The main presentations are:

• isolated short stature (without other features);
• short stature with subtle growth differences of the limbs and radiological findings; and
• LWD, featuring the classic triad of short stature, mesomelia and Madelung wrist deformity (dinner fork appearance of the wrist). Intellect is usually not affected.

Loss of both SHOX alleles (meaning no SHOX protein is produced) causes Langer mesomelic dysplasia: severe hypoplasia, or aplasia, of the ulna and fibula, with thickening and curving of the radius and tibia. Hypoplasia of the mandible may also occur.

The short stature homeobox (SHOX) gene is located on the sex chromosomes (X and Y) in the pseudoautosomal region 1 (PAR1), a region that escapes x-inactivation . The X and Y chromosomes commonly have unique genes, but in the pseudoautosomal region they are homologous. Thus, both males and females will have two copies of the SHOX gene, one on each of their sex chromosomes.

The SHOX gene contributes to skeletal development, particularly that of the arms and legs. Dosage of the SHOX protein is imperative to function. Loss-of-function genetic variants in one of the SHOX genes results in haploinsufficiency of the overall protein product, leading to growth failure.

Interestingly, loss of the SHOX gene explains the short stature phenotype in Turner syndrome (in which part or all of the X chromosome is missing). The majority of SHOX pathogenic variants (around 80%–90%) are deletions or duplications, with the remaining 10%–20% typically comprising missense variants.

For information about testing, see Presentation: Clinical suspicion of SHOX deficiency.

Because of the chance of crossover and recombination between homologous SHOX alleles, rules of autosomal dominant inheritance are followed. There is a one-in-two chance that a child will inherit an altered SHOX gene from an affected parent, regardless of whether the SHOX variant originated from an X or Y parent allele. Thus, a father with LWD caused by a Y-linked SHOX deletion can pass it on to his daughter as an X-linked SHOX deletion.

Langer mesomelic dysplasia is inherited in a pseudo autosomal recessive inheritance pattern, whereby both copies of the SHOX gene are dysfunctional or deleted.

A personalised assessment of chance of recurrence would be advised through a referral to the clinical genetics team. If a familial pathogenic variant is known, options for pregnancy include pre-implantation genomic testing and prenatal testing. The clinical presentation could not be predicted based on molecular testing results, however.

Management of children with SHOX-related haploinsufficiency should be delivered via a multidisciplinary team that includes an endocrinologist, orthopaedic surgeon and occupational therapist. Growth hormone is licensed for the treatment of SHOX deficiency in the UK.

For clinicians

• GeneReviews: SHOX deficiency
• NHS England: Genomic Medicine Service Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Management Consortium: Skeletal dysplasia best practice guidance

References:

• Binder G. ‘Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy’. Hormone Research in Paediatrics 2011: volume 75, issue 2, pages 81–89. DOI: 10.1159/000324105

For patients

• Child Growth Foundation: SHOX deficiency