SHOX-related short stature

Summary

SHOX-related short stature (MONDO:0010367) is a disease with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include clofarabine, somapacitan, and somatrogon.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 34
• Phenotypes (HPO): 16
• Clinical trials: 6

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0001773	Short foot	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002857	Genu valgum	Very frequent (80-99%)
HP:0002967	Cubitus valgus	Very frequent (80-99%)
HP:0002982	Tibial bowing	Very frequent (80-99%)
HP:0009821	Forearm undergrowth	Very frequent (80-99%)
HP:0003067	Madelung deformity	Very frequent (80-99%)
HP:0009816	Lower limb undergrowth	Very frequent (80-99%)
HP:0003712	Skeletal muscle hypertrophy	Very frequent (80-99%)
HP:0005856	Ulnar radial head dislocation	Very frequent (80-99%)
HP:0005974	Episodic ketoacidosis	Very frequent (80-99%)
HP:0001513	Obesity	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	SHOX-related short stature
Mondo ID	MONDO:0010367
MeSH	C564479
OMIM	300582
Orphanet	314795
DOID	DOID:0112120
SNOMED CT	763868006
UMLS	C1845118
MedGen	375584
GARD	0017434
Is cancer (heuristic)	no

Also known as: ISS · short stature, idiopathic familial · short stature, idiopathic, X-linked

Data availability: 34 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › SHOX-related short stature

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 5 pathogenic, 5 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 benign, 2 likely pathogenic, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
191363	NM_006883.2(SHOX):c.-645_-644insGTT	SHOX	Pathogenic	no assertion criteria provided
265858	NM_000451.4(SHOX):c.528G>C (p.Glu176Asp)	SHOX	Pathogenic	no assertion criteria provided
374328	NM_000451.4(SHOX):c.544+1G>A	SHOX	Pathogenic	no assertion criteria provided
66087	NC_000024.9:g.730550_778092del	SHOX	Pathogenic	no assertion criteria provided
933226	NM_000451.4(SHOX):c.-19G>A	SHOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
983025	NM_000451.4(SHOX):c.349C>T (p.Gln117Ter)	SHOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9872	NM_000451.4(SHOX):c.583C>T (p.Arg195Ter)	SHOX	Pathogenic	criteria provided, multiple submitters, no conflicts
635523	NM_000451.4(SHOX):c.479G>A (p.Arg160His)	SHOX	Likely pathogenic	no assertion criteria provided
973779	NM_000451.4(SHOX):c.49A>T (p.Lys17Ter)	SHOX	Likely pathogenic	no assertion criteria provided
287437	NM_000451.4(SHOX):c.440G>A (p.Arg147His)	LOC107652445	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805449	NM_000451.4(SHOX):c.399G>C (p.Glu133Asp)	LOC107652445	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
287763	NM_000451.4(SHOX):c.577G>A (p.Ala193Thr)	SHOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803710	NM_006883.2(SHOX):c.676T>C (p.Ter226Arg)	SHOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
93095	NM_000451.4(SHOX):c.86A>C (p.Lys29Thr)	SHOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598417	NM_000451.4(SHOX):c.374C>G (p.Thr125Arg)	LOC107652445	Uncertain significance	criteria provided, single submitter
4526497	NM_000451.4(SHOX):c.446A>G (p.Glu149Gly)	LOC107652445	Uncertain significance	criteria provided, single submitter
1686192	NM_000451.4(SHOX):c.673CACCCGCACCTG[3] (p.225HPHL[3])	SHOX	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709316	NM_000451.4(SHOX):c.277+2dup	SHOX	Uncertain significance	criteria provided, single submitter
265856	NM_006883.2(SHOX):c.-372G>A	SHOX	Uncertain significance	no assertion criteria provided
265857	NM_000451.4(SHOX):c.528= (p.Glu176=)	SHOX	Uncertain significance	no assertion criteria provided
265859	NM_000451.4(SHOX):c.*41C>A	SHOX	Uncertain significance	criteria provided, single submitter
265860	NM_000451.4(SHOX):c.*284_*285dup	SHOX	Uncertain significance	no assertion criteria provided
3892433	NM_000451.4(SHOX):c.611C>T (p.Ala204Val)	SHOX	Uncertain significance	criteria provided, single submitter
3892434	NM_000451.4(SHOX):c.83G>T (p.Gly28Val)	SHOX	Uncertain significance	criteria provided, single submitter
397603	NM_000451.4(SHOX):c.803A>G (p.Lys268Arg)	SHOX	Uncertain significance	no assertion criteria provided
496584	NM_000451.4(SHOX):c.236A>T (p.Lys79Met)	SHOX	Uncertain significance	criteria provided, single submitter
992440	NM_000451.4(SHOX):c.-65C>A	SHOX	Uncertain significance	criteria provided, multiple submitters, no conflicts
992441	NM_000451.4(SHOX):c.544+10G>A	SHOX	Uncertain significance	no assertion criteria provided
36775	NM_000451.4(SHOX):c.400C>A (p.Arg134=)	LOC107652445	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
191361	NM_006883.2(SHOX):c.-507G>C	SHOX	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SHOX	Supportive	Autosomal dominant	SHOX-related short stature	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHOX	Orphanet:240	Léri-Weill dyschondrosteosis
SHOX	Orphanet:2632	Langer mesomelic dysplasia
SHOX	Orphanet:314795	SHOX-related short stature

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHOX	HGNC:10853	ENSG00000185960	O15266	Short stature homeobox protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHOX	Short stature homeobox protein	Transcription factor that controls fundamental aspects of growth.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHOX	Transcription factor	no		HTH_motif, HD, OAR_dom

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
subcutaneous adipose tissue	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHOX	31	tissue_specific	yes	calcaneal tendon, subcutaneous adipose tissue, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHOX	1,001

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SHOX	O15266	63.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal system development	1	125.8×	0.024	SHOX
positive regulation of transcription by RNA polymerase II	1	14.9×	0.086	SHOX
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SHOX

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SHOX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SHOX

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SHOX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
PHASE2	2
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT07226089	PHASE3	RECRUITING	Comparison of Weekly Somatrogon to Daily Genotropin in Children Born Small for Gestational Age or With Idiopathic Short Stature.
NCT02727803	PHASE2	RECRUITING	Personalized NK Cell Therapy in CBT
NCT05497804	PHASE2	ACTIVE_NOT_RECRUITING	Combination Treatment Therapy Approaches for the Treatment of High-Risk Multiple Myeloma, REACH Trial
NCT03267888	PHASE1/PHASE2	COMPLETED	Pembrolizumab and Radiation Therapy in Patients With Relapsed or Refractory Multiple Myeloma
NCT01619761	PHASE1	UNKNOWN	NK Cells in Cord Blood Transplantation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLOFARABINE	4	1
SOMAPACITAN	4	1
SOMATROGON	4	1
SOMATROPIN	4	1
CHEMBL4216935	0	1