SHOX-Related Skeletal Features
- TURNER SYNDROME results from complete or partial absence of one X chromosome (classically 45,X, with mosaic and structural variants) in females, causing SHORT STATURE, gonadal dysgenesis with OVARIAN FAILURE, and characteristic somatic features; many of the skeletal features (and the short stature) are attributable to HAPLOINSUFFICIENCY of the SHOX (short-stature homeobox) gene - the same gene whose mutations cause Leri-Weill dyschondrosteosis and contribute to idiopathic short stature.
- The CLASSIC SHOX-related SKELETAL features are: disproportionate SHORT STATURE, CUBITUS VALGUS (increased carrying angle at the elbow), GENU VALGUM, SHORT FOURTH (and fifth) METACARPALS (a positive metacarpal sign), MADELUNG DEFORMITY of the wrist, a high-arched palate, a short webbed neck and a shield (broad) chest.
- There is an increased risk of SPINAL DEFORMITY - SCOLIOSIS and KYPHOSIS - which should be screened for and monitored through growth. Quantify it: in a 306-patient review, 37 (12%) had a radiographically relevant curve, of which 73% were MILD, 11% moderate and 16% severe - so severe deformity affected about 2% of the whole cohort, and 4 patients came to spinal fusion.
- DO NOT BLAME GROWTH HORMONE FOR THE CURVE. The intuitive teaching that GH accelerates scoliosis was tested in that cohort (62% GH-treated) and GH was NOT a risk factor for having a curve, for its severity at diagnosis, or for progression (P greater than 0.05 for all). With only 37 events this argues against a large effect rather than proving none - but monitor the spine because curves occur, not on the assumption that GH drives them, and do not withhold GH on that basis. No validated predictor of curve progression in Turner syndrome exists.
- Bone health is important: REDUCED bone mineral density (osteoporosis) is common, related in part to OESTROGEN DEFICIENCY from ovarian failure, with an increased FRACTURE risk - so bone health and timely oestrogen replacement matter.
- The orthopaedic picture INTERFACES with endocrine THERAPY: GROWTH-HORMONE therapy is used to improve final adult height, and OESTROGEN replacement (for the gonadal failure) is important for pubertal development and for BONE density - the orthopaedic surgeon manages the skeletal features in this context.
- MANAGEMENT is largely SURVEILLANCE and supportive within a multidisciplinary team: monitor STATURE/growth, SPINE (scoliosis/kyphosis) and limb ALIGNMENT, optimise BONE HEALTH (oestrogen, vitamin D/calcium, weight-bearing activity), and treat significant deformities (e.g. Madelung deformity, symptomatic genu valgum) on their merits, alongside the systemic (cardiac, renal, endocrine) care of the syndrome.
- “Turner syndrome = 45,X (and variants) in females; SHORT STATURE + ovarian failure. Many SKELETAL features from SHOX haploinsufficiency.
- “Classic skeletal signs: CUBITUS VALGUS, GENU VALGUM, SHORT 4th/5th METACARPALS (metacarpal sign), MADELUNG deformity, high-arched palate, short webbed neck, shield chest.
- “Spinal deformity in 12% (37/306) - 73% mild, 16% severe; 4 came to fusion. REDUCED bone density (oestrogen-related fracture risk). Growth-hormone (stature) + oestrogen (puberty/bone) therapy.
- “GH IS NOT THE CULPRIT: in that cohort GH was not a risk factor for a curve, its severity, or its progression (P greater than 0.05 for all). Monitor the spine because curves happen - don't withhold GH.
Short stature + cubitus valgus + genu valgum + short 4th/5th metacarpals + Madelung deformity + high-arched palate + short webbed neck - largely from SHOX haploinsufficiency.
Increased scoliosis/kyphosis and reduced bone density (osteoporosis/fracture risk, oestrogen-related). Therapy interfaces: growth hormone (stature) + oestrogen (puberty/bone).
Skeletal Features & Management
Turner syndrome (45,X and variants) in females causes short stature, ovarian failure and characteristic somatic features, with many of the skeletal features attributable to SHOX haploinsufficiency. The classic signs are cubitus valgus, genu valgum, short fourth/fifth metacarpals (metacarpal sign), Madelung deformity, high-arched palate, short webbed neck and shield chest. There is increased scoliosis/kyphosis and reduced bone density (osteoporosis/fracture risk, partly from oestrogen deficiency). Management interfaces with growth-hormone therapy (for height) and oestrogen replacement (for puberty and bone), and the orthopaedic role is surveillance of stature/spine/alignment, bone-health optimisation, and treatment of significant deformities (Madelung, symptomatic genu valgum) on their merits.
The orthopaedic features of Turner syndrome are mostly the recognisable SHOX-related signs - short stature, cubitus valgus, genu valgum, short fourth and fifth metacarpals and Madelung deformity - and recognising this signature can even prompt the diagnosis. But the orthopaedic surgeon should look beyond the obvious limb signs: scoliosis and kyphosis are more common and should be screened for and monitored through growth, and bone mineral density is often reduced, with an increased fracture risk related in part to the oestrogen deficiency of ovarian failure, so bone health and timely oestrogen replacement are important. Management is largely surveillance and supportive within a multidisciplinary team, with growth-hormone therapy used for stature and oestrogen for puberty and bone, and significant deformities treated on their merits. Turner syndrome is also a multisystem disorder (cardiac - including aortic - renal and endocrine), so any orthopaedic intervention is undertaken with awareness of these comorbidities and in coordination with the wider team.
The Metacarpal Sign (Short Fourth Metacarpal)
- Brachymetacarpia. The fourth metacarpal (and sometimes the fifth) is abnormally short - a dysplastic feature of the SHOX skeletal phenotype. Clinically, when the patient makes a fist, the affected knuckle is depressed (a dimple replaces the normal knuckle prominence over the short metacarpal).
- The positive metacarpal (Archibald) sign. On a PA hand radiograph, draw a tangent line touching the distal heads of the fourth and fifth metacarpals and extend it proximally: normally it passes just distal to (misses) the head of the third metacarpal, but with a short fourth metacarpal the line intersects or passes through the third metacarpal head - a positive metacarpal sign.
- Significance and mimics. It is a useful pointer to Turner syndrome but is not specific: the same short fourth metacarpal is seen in pseudohypoparathyroidism / pseudopseudohypoparathyroidism (Albright hereditary osteodystrophy), in other SHOX disorders, and as an isolated familial/idiopathic trait - so it supports, rather than makes, the diagnosis.
Q: What is the metacarpal sign in Turner syndrome and how is it elicited?
A: It reflects a short fourth (and sometimes fifth) metacarpal (brachymetacarpia), a SHOX skeletal feature. On a PA hand radiograph a tangent line along the distal heads of the fourth and fifth metacarpals normally passes distal to the third metacarpal head; if the fourth is short it intersects the third metacarpal head - a positive metacarpal (Archibald) sign, seen clinically as a depressed knuckle on making a fist. It points to Turner but is not specific (also pseudohypoparathyroidism / Albright hereditary osteodystrophy and other SHOX disorders).
Growth-Hormone Therapy and the Orthopaedic / Perioperative Interface
- Growth hormone and the spine - the intuitive claim is not supported. It is often taught that by accelerating growth velocity, growth hormone unmasks or worsens a curve. The largest cohort to test this (306 patients, of whom 190 (62%) received GH) found that GH therapy was NOT a risk factor for the diagnosis of a major spinal curve, for a more severe curve at diagnosis, or for curve progression (P greater than 0.05 for all). Among the 37 patients with a curve, 24 (65%) had received GH and 13 (35%) had not - proportions close to the cohort as a whole. Read this as the best available evidence rather than proof of safety: it is a retrospective univariate analysis with only 37 curve events, so a modest effect could have been missed. The practical conclusion is unchanged - monitor the spine through growth - but monitor it because scoliosis occurs in this population, not because GH is presumed to drive it, and do not withhold or interrupt GH on that reasoning alone.
- Cardiac/aortic clearance before surgery. Turner syndrome carries a high rate of bicuspid aortic valve and coarctation and a predisposition to aortic root dilatation and dissection. Before any elective orthopaedic surgery and general anaesthetic, cardiac assessment (echocardiography, cardiology input) is essential, and blood-pressure and aortic surveillance continue perioperatively.
- Renal and bone considerations. Renal anomalies (for example a horseshoe kidney or collecting-system duplication) affect fluid/drug handling and positioning. The reduced bone mineral density means poorer implant purchase and a higher fracture risk, so fixation is planned accordingly and oestrogen, vitamin D and calcium are optimised.
Q: What must the orthopaedic surgeon check before operating on a girl with Turner syndrome, and how does growth-hormone therapy affect the spine?
A: Obtain cardiac clearance (echocardiography/cardiology) - Turner carries bicuspid aortic valve, coarctation and a risk of aortic root dilatation/dissection - and account for renal anomalies and the reduced bone density (poorer fixation; optimise oestrogen/vitamin D/calcium). On growth hormone, resist the intuitive answer: in the largest cohort (306 patients, 62% GH-treated) GH was not a risk factor for having a spinal curve, for its severity at diagnosis, or for progression (P greater than 0.05 for all). Monitor the spine through growth because 12% have a curve, not because GH is assumed to cause it - and do not withhold GH on that reasoning.
How Much Spinal Deformity, and How Much of It Matters
"Increased risk of scoliosis and kyphosis" is right but unquantified, and the numbers change how you counsel a family. In the largest single-institution review, 306 patients followed from 2007 to 2021:
- 37 of 306 (12%) had a radiographically relevant spinal deformity. For context that is several times the roughly 2 to 3 per cent quoted for adolescent idiopathic scoliosis in the general population, so the increased risk is real - but it also means almost nine in ten girls with Turner syndrome do not develop a curve.
- Most curves are mild. Of the 37, 27 (73%) were mild, 4 (11%) moderate and 6 (16%) severe. So severe deformity affected 6 of the whole cohort of 306 - about 2%.
- Surgery is uncommon. Of the 6 with severe curves, 4 underwent spinal fusion and 1 was braced; the sixth was braced before dying of a cardiovascular cause - a reminder, in the middle of a spinal discussion, that the cardiac disease is what kills in this syndrome.
- What to say to a family. Screen the spine through growth, expect that a curve found will most likely be mild, and reserve alarm for the small minority. Note the limitations: a single tertiary paediatric centre, retrospective chart review, so ascertainment depends on who was imaged and referral bias may inflate the rate relative to an unselected Turner population. The authors themselves call for further study of what predicts progression - no validated risk factor for curve progression in Turner syndrome has been identified.
Mnemonics & Memory Aids
TURNER
Hook:TURNER: Turner (SHOX), Ulnar/elbow cubitus valgus, Reduced bone density, Neck short/webbed, Extremity (short metacarpals/Madelung), Rule the spine in.
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“A short-statured girl has cubitus valgus, short fourth metacarpals and a Madelung deformity. What syndrome and mechanism do you consider, and what are the orthopaedic priorities?”
What it is
- 45,X (and mosaic/structural variants) in females
- Short stature, ovarian failure, characteristic somatic features
- Many skeletal features from SHOX haploinsufficiency
Classic skeletal signs
- Cubitus valgus, genu valgum
- Short fourth/fifth metacarpals (metacarpal sign); Madelung deformity
- High-arched palate, short webbed neck, shield chest
Spine & bone
- Spinal deformity in 12% (37 of 306): 73% mild, 11% moderate, 16% severe; 4 came to fusion
- Growth hormone NOT a risk factor for curve presence, severity or progression (P greater than 0.05 for all)
- No validated predictor of curve progression exists - screen through growth regardless
- Reduced bone mineral density (oestrogen-related fracture risk)
- Optimise oestrogen, vitamin D/calcium, weight-bearing activity
Management
- Growth-hormone therapy (stature); oestrogen replacement (puberty/bone)
- Surveillance of stature/spine/alignment; treat significant deformity (Madelung, genu valgum)
- Multidisciplinary care (cardiac/aortic, renal, endocrine comorbidities)
Evidence & Key Studies
SHOX gene deletions and the skeletal features shared with Turner syndrome
- SCOPE - READ THIS FIRST: the 900 children studied all had a NORMAL KARYOTYPE and so did NOT have Turner syndrome. The association between SHOX and the Turner phenotype is the paper's premise, not its finding. Its own result concerns SHOX mutations in idiopathic short stature.
- 900 patients with height below the third percentile (or minus 2 SD) and no obvious Leri-Weill skeletal features were analysed - 750 for intragenic mutations by SSCP and sequencing, 150 for whole-gene deletions by FISH. This was the largest such series at the time.
- SHOX mutations were found in 2.4% of children with short stature: 9 of 750 intragenic mutations (of which at least 3 were judged functional) and 3 of 150 complete gene deletions. The mutation spectrum is biased, the vast majority being COMPLETE GENE DELETIONS. The authors note this prevalence is similar to that of growth-hormone deficiency or of Turner syndrome itself.
- The link to the Turner skeletal signature comes from FAMILY STUDIES: older relatives carrying the same mutation showed mild Turner-like features - high-arched palate, short neck, ABNORMAL AURICULAR DEVELOPMENT, cubitus valgus, genu valgum, short fourth metacarpals and Madelung deformity. This is the observation that supports attributing those features to SHOX haploinsufficiency.
- Limitations: a genetic prevalence study, not a skeletal one - no radiographic scoring, no measure of how often each feature occurs, and the family-member phenotypes are descriptive.
Scoliosis and kyphosis prevalence in Turner syndrome: a retrospective review at a paediatric tertiary care medical centre
- The largest single-institution review of spinal deformity in Turner syndrome known to its authors: 306 patients, retrospective chart review 2007-2021.
- 37 of 306 (12%) had a radiographically relevant spinal deformity - 27 of 37 (73%) mild, 4 (11%) moderate and 6 (16%) severe. Of the 6 severe curves, 4 had spinal fusion and 1 was braced; the sixth was braced before a cardiovascular-related death.
- KEY NEGATIVE FINDING: growth hormone was used by 190 of 306 (62%). On univariate analysis GH therapy was NOT a risk factor for the diagnosis of a major spinal curve, for a more severe curve at diagnosis, or for curve progression (P greater than 0.05 for all) - contradicting the common teaching that GH accelerates curves in Turner syndrome.
- Among those with a curve, 24 of 37 (65%) had received GH versus 13 (35%) who had not, closely mirroring the 62%/38% split of the whole cohort.
- Limitations: retrospective, single tertiary paediatric centre, univariate analysis only, and just 37 curve events - so this is evidence against a large GH effect rather than proof of none, and referral bias may inflate the 12% relative to an unselected Turner population. The authors state that further study is needed to determine risk factors for curve progression, so none is currently validated.
The spinal figures - 37 of 306 (12%) with a curve, the 73/11/16 per cent mild-moderate-severe split, the 4 fusions, and the finding that growth hormone was not a risk factor for curve presence, severity or progression - come from Marx (DOI), a single-centre retrospective review. The Turner-like skeletal features in SHOX-mutation carriers (high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, Madelung deformity) and the 2.4% SHOX-mutation rate in short stature come from Rappold (DOI) - noting that its 900 patients had NORMAL karyotypes and did not have Turner syndrome, so it supports the SHOX mechanism rather than measuring anything in Turner patients. The 45,X karyotype and ovarian failure, the reduced bone mineral density and oestrogen-related fracture risk, the metacarpal (Archibald) sign, and the cardiac, aortic and renal comorbidities are standard, well-established teaching.
What is not established: no validated risk factor for spinal-curve progression in Turner syndrome has been identified - the authors of the only sizeable series call for further study. There is no Turner-specific fracture-rate figure quoted here, no threshold bone-density value that triggers intervention, no evidence base for implant selection or fixation technique in the reduced bone density, and no trial of any orthopaedic intervention in this population. The 12% curve prevalence comes from one tertiary centre and may not transfer to an unselected Turner population.