Langer mesomelic dysplasia

Summary

Langer mesomelic dysplasia (MONDO:0009588) is a disease caused by SHOX (GenCC Definitive), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include trastuzumab and tucatinib.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SHOX (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 20
• Phenotypes (HPO): 13
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0001191	Abnormal carpal morphology	Very frequent (80-99%)
HP:0002983	Micromelia	Very frequent (80-99%)
HP:0003067	Madelung deformity	Very frequent (80-99%)
HP:0003510	Severe short stature	Very frequent (80-99%)
HP:0005026	Mesomelic/rhizomelic limb shortening	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0006492	Aplasia/Hypoplasia of the fibula	Very frequent (80-99%)
HP:0008873	Disproportionate short-limb short stature	Very frequent (80-99%)
HP:0009465	Ulnar deviation of finger	Very frequent (80-99%)
HP:0040071	Abnormal morphology of ulna	Very frequent (80-99%)
HP:0100864	Short femoral neck	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Langer mesomelic dysplasia
Mondo ID	MONDO:0009588
MeSH	C537267
OMIM	249700
Orphanet	2632
NCIT	C126876
SNOMED CT	38494008
UMLS	C0432230
MedGen	96585
GARD	0003553
Is cancer (heuristic)	no

Also known as: Langer mesomelic dysplasia · langer mesomelic dysplasia, pseudoautosomal recessive · Langer syndrome · Langer type mesomelic dysplasia · LMD · mesomelic dwarfism of the hypoplastic ulna, fibula and mandible type · mesomelic dwarfism, Langer type

Data availability: 20 ClinVar variants · 5 GenCC gene-disease records · 7 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › mesomelic dysplasia › Langer mesomelic dysplasia

Related subtypes (5): mesomelic dysplasia, Kantaputra type, mesomelic dwarfism, Nievergelt type, mesomelic dwarfism, Reinhardt-Pfeiffer type, upper limb mesomelic dysplasia, mesomelic dysplasia, Savarirayan type

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

20 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 6 pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29994	NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)	SHOX	Pathogenic	criteria provided, single submitter
4535998	NC_000023.10:g.(595562_601555)(612320?)del	SHOX	Pathogenic	criteria provided, single submitter
9874	NG_009385.2:g.(?5001)(40068_?)del	SHOX	Pathogenic	no assertion criteria provided
9879	NM_000451.4(SHOX):c.502C>T (p.Arg168Trp)	SHOX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9880	NM_000451.4(SHOX):c.728dup (p.Pro244fs)	SHOX	Pathogenic	criteria provided, single submitter
9881	NM_000451.4(SHOX):c.352_353dup (p.Arg119fs)	SHOX	Pathogenic	criteria provided, single submitter
9884	NC_000023.11:g.(651585_658784)_(659412_1759412)del	SHOX	Pathogenic	no assertion criteria provided
3062248	NM_000451.4(SHOX):c.419del (p.His140fs)	LOC107652445	Likely pathogenic	criteria provided, single submitter
287763	NM_000451.4(SHOX):c.577G>A (p.Ala193Thr)	SHOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805452	NM_000451.4(SHOX):c.728del (p.Pro243fs)	SHOX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034222	NM_000451.4(SHOX):c.389A>C (p.Asn130Thr)	LOC107652445	Uncertain significance	criteria provided, single submitter
3598417	NM_000451.4(SHOX):c.374C>G (p.Thr125Arg)	LOC107652445	Uncertain significance	criteria provided, single submitter
1034223	NM_000451.4(SHOX):c.38A>G (p.Asp13Gly)	SHOX	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
2498325	NM_000451.4(SHOX):c.547G>C (p.Val183Leu)	SHOX	Uncertain significance	criteria provided, single submitter
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
191362	NM_006883.2(SHOX):c.-512C>A	SHOX	Benign	criteria provided, single submitter
36776	NM_000451.4(SHOX):c.63C>T (p.Gly21=)	SHOX	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
448375	NM_000451.4(SHOX):c.634-14G>T	SHOX	Benign/Likely 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	Definitive	X-linked	Langer mesomelic dysplasia	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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05305365	PHASE2	ACTIVE_NOT_RECRUITING	Study Assessing QBS72S For Treating Brain Metastases
NCT06016387	PHASE2	RECRUITING	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 Mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRASTUZUMAB	4	1
TUCATINIB	4	1