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spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

spondylo-megaepiphyseal-metaphyseal dysplasia

MONDO:0013228

Also known as:SMMD

Overview

GeneticsAutosomal recessive · NKX3-2 (chr 4)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Pseudoepiphyses of hand bones, Delayed vertebral ossification, Coxa vara, and Disproportionate short-trunk short stature and others; and common findings: Motor delay, Hydrocephalus, Long hallux, and Proximal placement of thumb and others. 33 total HPO annotations.

Organ System	Phenotype Count	Example Features
Bones and joints	7	Pseudoepiphyses of hand bones, Delayed vertebral ossification, Kyphoscoliosis

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

NKX3-2 encodes NK3 homeobox 2 (333 aa). Transcriptional repressor that acts as a negative regulator of chondrocyte maturation. Highest expression in Colon Sigmoid (33.0 TPM) and Colon Transverse (14.2 TPM).

Spondylo-megaepiphyseal-metaphyseal dysplasia is associated with mutations in the NKX3-2 gene on chromosome 4.

The NKX3-2 protein participates in RUNX2 gene expression from distal (P1) promoter is inhibited by NKX3-2, MSX2 and RUNX2-P1, and stimulated by DLX5,(DLX6), NKX3-2:RUNX2 gene, and Regulation of RUNX2 expression and activity pathways.

NKX3-2 is classified as a druggable target with score 4.7.

Diagnosis

Genetic testing for NKX3-2 is available. Testing is considered confirmatory for diagnosis.

Prognosis

Phenotype severity distribution: 9 always present features, 14 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Data assembled from 5 of 12 sources · Last updated Sep 20, 2026, 12:32 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:613330

Orphanet

European rare disease database

Orphanet:228387

GARD

Genetic and Rare Diseases Info Center

GARD:17154

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

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spondylo-megaepiphyseal-metaphyseal dysplasia

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Prognosis

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

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