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A rare genetic osteolysis syndrome resulting from protein-truncating variants in exon 34 of the NOTCH2 gene. These variants disrupt only the PEST domain, escape nonsense-mediated decay, and are postulated to function through a gain-of-function mechanism. This condition is characterized by acroosteolysis of distal phalanges and generalized osteoporosis, associated with additional ossification anomalies, craniofacial dysmorphism, dental anomalies and a wide range of other characteristics. Hearing loss, renal cysts, and cardiovascular anomalies are variably present.
Features include always present findings: Narrow mouth, Hypertelorism, Thick eyebrow, and Conductive hearing impairment and others; and very common findings: Foot acroosteolysis. 58 total HPO annotations.
Organ System | Phenotype Count | Example Features |
|---|---|---|
Bones and joints | 11 | Kyphoscoliosis, Joint hypermobility, Crowded carpal bones |
NOTCH2 encodes notch receptor 2 (2,471 aa). Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Highest expression in Cells Cultured fibroblasts (76.5 TPM) and Artery Aorta (56.8 TPM).
Acroosteolysis dominant type is caused by mutations in the NOTCH2 gene on chromosome 1.
The NOTCH2 protein participates in FRINGE-modified NOTCH2 extracellular fragment (NECD2) and FRINGE-modified NOTCH2 Extracellular Fragment (NECD2) pathways.
NOTCH2 is classified as a druggable target (Cell Surface, Clinically Actionable, and Druggable Genome categories) with score 14.9.
Genetic testing for NOTCH2 is available. Testing is considered confirmatory for diagnosis.
Phenotype severity distribution: 8 always present features, 1 very common feature, 6 common features.
Estimated prevalence: <1 in 1,000,000 (VERY_RARE).
No clinical trials have been registered for acroosteolysis dominant type.
20 publications have been identified in PubMed for acroosteolysis dominant type. Research spans Case Report / Case Series (70%), Basic Science / Preclinical (20%), and Review / Meta-Analysis (5%).
Research Type | Count | % of Total |
|---|---|---|
Patient case studies | 14 | 70% |
Data assembled from 7 of 12 sources · Last updated Sep 19, 2026, 1:53 PM UTC
Online Mendelian Inheritance in Man
European rare disease database
Genetic and Rare Diseases Info Center
Common questions about acroosteolysis dominant type
Brain and nerves
3 |
Hydrocephalus, Intellectual disability, Global developmental delay |
Growth and development | 2 | Short stature, Failure to thrive |
Head and neck | 2 | Coarse facial features, High palate |
Kidneys and urinary system | 2 | Polycystic kidney dysplasia, Renal cyst |
Arms and legs | 2 | Foot acroosteolysis, Osteolytic defects of the phalanges of the hand |
Ears | 1 | Conductive hearing impairment |
Heart and blood vessels | 1 | Ventricular septal defect |
Digestive system | 1 | Intestinal malrotation |
Skin | 1 | Short nail |
4 |
20% |
Research summaries | 1 | 5% |
Disease patterns and progression | 1 | 5% |
Hasan M (2026). [PMID: 41694951](https://pubmed.ncbi.nlm.nih.gov/41694951/). *Cureus*. [Case Report / Case Series]
Bylstra Y (2026). [PMID: 41520097](https://pubmed.ncbi.nlm.nih.gov/41520097/). *European journal of human genetics : EJHG*. [Epidemiology / Natural History]
Xuan W (2026). [PMID: 41928326](https://pubmed.ncbi.nlm.nih.gov/41928326/). *Journal of medical case reports*. [Case Report / Case Series]
Ito Y (2026). [PMID: 42100904](https://pubmed.ncbi.nlm.nih.gov/42100904/). *Clin Dysmorphol*. [Case Report / Case Series]
Lanzafame R (2026). [PMID: 42123373](https://pubmed.ncbi.nlm.nih.gov/42123373/). *Int J Mol Sci*. [Case Report / Case Series]
Ren H (2025). [PMID: 39745791](https://pubmed.ncbi.nlm.nih.gov/39745791/). *Journal of the American Society of Nephrology : JASN*. [Basic Science / Preclinical]
Basaran AE (2025). [PMID: 41007038](https://pubmed.ncbi.nlm.nih.gov/41007038/). *Children (Basel, Switzerland)*. [Case Report / Case Series]
Bartholomew RA (2025). [PMID: 41058026](https://pubmed.ncbi.nlm.nih.gov/41058026/). *Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology*. [Case Report / Case Series]
Franco AS (2025). [PMID: 40235644](https://pubmed.ncbi.nlm.nih.gov/40235644/). *Bone reports*. [Case Report / Case Series]
Wang Y (2025). [PMID: 40104444](https://pubmed.ncbi.nlm.nih.gov/40104444/). *Research (Washington, D.C.)*. [Basic Science / Preclinical]