A comprehensive overview of Cardiospondylocarpofacial Syndrome based on published medical research. All information is drawn from peer-reviewed journals and case studies.
Cardiospondylocarpofacial syndrome (CSCFS; OMIM #157800) is caused by heterozygous pathogenic variants in the MAP3K7 gene, located on chromosome 6q15. The gene encodes TGF-β-activated kinase 1 (TAK1), a serine-threonine protein kinase that is widely expressed and participates in multiple molecular and cellular processes.
TAK1 forms a complex with specific binding proteins and modulates downstream effectors including c-Jun amino-terminal kinases (JNKs), extracellular-signal regulated kinases (ERKs), p38 MAP kinase, and nuclear factor-κB — affecting a wide range of cellular processes including cell growth and differentiation, immune function, stress responses, and apoptosis.
The nearly ubiquitous expression of TAK1 and the early lethality of knockout mice speak to the critical importance of this protein in embryonic development. In CSCFS, MAP3K7 variants have been shown to decrease TAK1 autophosphorylation and disrupt downstream TAK1-dependent signaling pathways — a key distinction from the related condition Frontometaphyseal Dysplasia Type 2 (FMD2), where variants cause elevated phosphorylation.
CSCFS follows an autosomal dominant inheritance pattern. All known variants are heterozygous and de novo in the majority of reported cases. To date, all small in-frame deletions and splice variants have been associated exclusively with CSCFS, whereas missense variants can cause either CSCFS or FMD2 depending on their specific location and effect on kinase activity.
Key Gene Facts
Related Condition
Frontometaphyseal Dysplasia 2 (FMD2) is caused by different variants in the same MAP3K7 gene, but causes elevated TAK1 phosphorylation. The two conditions share some features but can be clinically distinguished.
CSCFS can present differently in each individual. Not every person will have all features. Severity varies widely across reported cases.
Recognition of characteristic facial features, skeletal abnormalities, and cardiac findings. Many patients are initially misdiagnosed with Noonan syndrome or other RASopathies due to overlapping features.
Prior negative genetic testing commonly includes karyotype, chromosomal microarray, PTPN11 sequencing, fragile X, and subtelomeric FISH. CSCFS is frequently a diagnosis reached after exclusion of more common syndromes.
Whole exome sequencing of the patient and both parents (trio-WES) is currently the most effective method for identifying MAP3K7 variants. WES has identified all genetically confirmed CSCFS cases in the literature.
Identified variants are confirmed by Sanger sequencing. De novo variants are confirmed by verifying absence of the variant in both biological parents.
Variants are classified using ACMG/AMP guidelines. All confirmed CSCFS variants are located in the kinase domain of MAP3K7. De novo status (PS2), rarity in controls (PM2), and protein length/function changes (PM4) support pathogenicity.
Consider CSCFS in a child presenting with two or more of the following:
Fewer than 30 genetically confirmed CSCFS cases exist in medical literature worldwide. Each case contributes critical knowledge about this ultra-rare condition.
Patient
6 patients across 2 families + 2 unrelated individuals
Genetic Variant
In-frame 3-bp deletions; missense variants W241R and G110C in MAP3K7
Outcome
Survivors — father and adult relatives included; one infant death from diaphragmatic hernia complications
Key Findings
Le Goff C, Rogers C, Le Goff W, et al. Heterozygous mutations in MAP3K7, encoding TGF-β-activated kinase 1, cause cardiospondylocarpofacial syndrome. Am J Hum Genet. 2016; 99:407–413.
View publicationAbuBakr F, Jeffries L, Ji W, McGrath JM, Lakhani SA. A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype. Cold Spring Harb Mol Case Stud. 2020; 6(3):a005207.
View publicationMorlino S, Castori M, Dordoni C, et al. A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder. Eur J Hum Genet. 2018; 26:582–586.
View publicationNyuzuki H, Ozawa J, Nagasaki K, et al. A severe case of cardiospondylocarpofacial syndrome with a novel MAP3K7 variant. Hum Genome Var. 2024; 11:8.
View publicationDas BB, Criscuolo JJ. Neonatal dilated cardiomyopathy and cardiospondylocarpofacial syndrome linked to a novel MAP3K7 gene mutation. Ann Pediatr Cardiol. 2025; 18(1):68–71.
View publicationYang Q, Zhang Q, Yi S, et al. Genetic diagnosis and clinical characteristics analysis of cardiospondylocarpofacial syndrome in a Chinese family. Front Pediatr. 2025; 13:1651803.
View publicationShepherd WB, Colaiacovo S, Campbell C, Saleh M. A novel MAP3K7 mutation in a child with cardiospondylocarpofacial syndrome and orofacial clefting. Clin Genet. 2023; 103:254–255.
View publicationImportant note: The information on this page is intended for educational purposes to help families, caregivers, and medical professionals understand CSCFS. It is not a substitute for professional medical advice. Always consult a qualified geneticist or specialist for diagnosis and treatment decisions.