Cantú syndrome

Cantú syndrome
Other namesHypertrychotic osteochondrodysplasia[1]
This photo shows a person with Cantú syndrome, who has coarse facial features that are characteristic of this syndrome.
SymptomsHypertrichosis, osteochondrodysplasia, cardiomegaly, others[2]
CausesMutation in ABCC9 gene[3]
Diagnostic methodEchocardiogram, X-ray[4]
TreatmentScoliosis is managed via bracing[5]

Cantú syndrome is a rare genetic disorder characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly, among other symptoms.[6][5] Fewer than 50 cases have been described in the literature; they are associated with mutations in the ABCC9 (SUR2) and KCNJ8 (Kir6.1) genes, which encode subunits of ATP-sensitive potassium channels (KATP channels).[7][3][5]

Signs and symptoms

Heart/patent ductus arteriosus.

The main features of this condition are hypertrichosis, osteochondrodysplasia, and cardiomegaly. There is also a characteristic facies. Other features include patent ductus arteriosus, congenital hypertrophy of the left ventricle, and pericardial effusions.[2]

Neurodevelopmental outcome appears normal, but obsessive traits and anxiety have been reported.[8] It may also be associated with recurrent infections with low immunoglobulin levels and gastric bleeding, and additional possible associations include lymphoedema and heterochromia iridis.[9][10]

Most people with Cantú syndrome eventually develop high-output cardiac hypertrophy or cardiomegaly and congestive heart failure due to long-term low systemic vascular resistance and consequent cardiac remodeling.[11][12]

Cause

Cantú syndrome is inherited via an autosomal dominant manner.

Cantú syndrome is caused by gain-of-function mutations in genes encoding subunits of ATP-sensitive potassium channels (KATP channels), including ABCC9 (encoding the sulfonylurea receptor 2 or SUR2) and KCNJ8 (encoding Kir6.1).[7][3] It is apparently inherited in an autosomal dominant fashion.[13] Both the ABCC9 and KCNJ8 genes are located on the short arm of chromosome 12 (12p12).[14][15] In one study, mutations in ABCC9 were responsible for 25 of 31 cases of Cantú syndrome.[16][17][18]Physiologically, SUR2 is significant in vascular relaxation, among other effects.[19] An increase in O2 tension after birth, plus decreasing PGE2 (a common prostaglandin[20]) causes inhibition of voltage-gated potassium channels and contraction of smooth muscle (in ductus).[16]

The effects of KATP potassium channel openers like minoxidil, diazoxide, and pinacidil have been found to mimic the symptoms of Cantú syndrome.[21][7][22] Examples of these KATP potassium channel opener effects include hypertrichosis, pericardial effusions, pulmonary hypertension, edema, and coarsening of facial features, among others.[7] Relatedly, there has been concern that excessive doses of minoxidil and other KATP potassium channel openers might cause a "drug-induced Cantú syndrome".[7]

Diagnosis

Medical personnel perform echocardiogram

This condition can be diagnosed by genetic testing.[23] Furthermore, an echocardiogram and X-ray may help in the diagnosis.[4]

Differential diagnosis

The differential diagnosis of this condition consists of the following:[5]

Treatment

The treatment/management for Cantú syndrome is based on surgical option for patent ductus arteriosus in early life and management of scoliosis via bracing. Furthermore, regular echocardiograms are needed for the individual who has exhibited this condition.[5] KATP potassium channel blockers like glibenclamide (glyburide) might be useful in the treatment of Cantú syndrome.[7]

History

This condition was described in 1982 by José María Cantú and colleagues.[24][25]

See also

References

  1. ↑ "OMIM Entry - # 239850 - CANTU SYNDROME". omim.org. Archived from the original on 2019-03-30. Retrieved 2017-04-01.
  2. 1 2 "Cantu syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2019-03-29. Retrieved 2017-03-31.
  3. 1 2 3 Reference, Genetics Home. "ABCC9 gene". Genetics Home Reference. Archived from the original on 29 March 2019. Retrieved 23 March 2017.
  4. 1 2 Kirk, Edwin P.; Scurr, Ingrid; van Haaften, Gijs; van Haelst, Mieke M.; Nichols, Colin G.; Williams, Maggie; Smithson, Sarah F.; Grange, Dorothy K. (2017-04-01). "Clinical utility gene card for: Cantú syndrome". European Journal of Human Genetics. 25 (4): 512. doi:10.1038/ejhg.2016.185. ISSN 1018-4813. PMC 5386410. PMID 28051078.
  5. 1 2 3 4 5 Grange, Dorothy K.; Nichols, Colin G.; Singh, Gautam K. (1993-01-01). "Cantú Syndrome and Related Disorders". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID 25275207. Archived from the original on 2020-08-13. Retrieved 2017-08-30.Initial posting 2014
  6. ↑ Engels H, Bosse K, Ehrbrecht A, et al. (August 2002). "Further case of Cantú syndrome: exclusion of cryptic subtelomeric chromosome aberrations". Am. J. Med. Genet. 111 (2): 205–9. doi:10.1002/ajmg.10560. PMID 12210352.
  7. 1 2 3 4 5 6 McClenaghan C, Nichols CG (September 2022). "Kir6.1 and SUR2B in Cantú syndrome". American Journal of Physiology. Cell Physiology. 323 (3) C920–C935. doi:10.1152/ajpcell.00154.2022. PMC 9467476. PMID 35876283. As mentioned earlier, the hair-growth-promoting properties of minoxidil were clear from initial development. [...] Of concern, if excessive doses are used, even topically, there is the potential for minoxidil to have systemic effects—precipitating a possible "drug-induced Cantú syndrome." Indeed [pulmonary hypertension (PH)], edema, coarsening of facial features, and even reopening of the ductus arteriosus are associated with the Kir6.1/SUR2B active [potassium channel openers (KCOs)] minoxidil and diazoxide (156–158). Multiple KCOs induce and prolong anagen, the rapidly dividing stage of hair, in cultured follicles to promote growth, which can be reversed by the KATP inhibitor tolbutamide (86–88, 159). It is possible that CS-associated mutations have the same hair growth cycle effects, though this requires clarification. Thinking more broadly about the electrical consequences, KATP activation versus voltage-gated calcium channel (VGCC) activation would be expected to have opposing electrophysiological effects, and interestingly Timothy syndrome, caused by gain-of-function mutations in the VGCC, CaV1.2 is associated with baldness at birth (160), potentially the reverse mechanistic phenomenon.
  8. ↑ Grange, Dorothy K.; Roessler, Helen I.; McClenaghan, Conor; Duran, Karen; Shields, Kathleen; Remedi, Maria S.; Knoers, Nine V. A. M.; Lee, Jin-Moo; Kirk, Edwin P.; Scurr, Ingrid; Smithson, Sarah F.; Singh, Gautam K.; van Haelst, Mieke M.; Nichols, Colin G.; van Haaften, Gijs (2019). "Cantú syndrome: Findings from 74 patients in the International Cantú Syndrome Registry". American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 181 (4): 658–681. doi:10.1002/ajmg.c.31753. ISSN 1552-4876. PMC 7654223. PMID 31828977.
  9. ↑ García-Cruz, Diana; Mampel, Alejandra; Echeverria, Maria I.; Vargas, Ana L.; Castañeda-Cisneros, Gema; Davalos-Rodriguez, Nory; Patiño-Garcia, Brenda; Garcia-Cruz, Maria O.; Castañeda, Victor; Cardona, Ernesto G.; Marin-Solis, Bertha; Cantu, Jose M.; Nuñez-Reveles, Nelly; Moran-Moguel, Cristina; Thavanati, Pavarthi K. R. (2011-01-20). "Cantu syndrome and lymphoedema". Clinical Dysmorphology. 20 (1): 32–37. doi:10.1097/MCD.0b013e32833d015c. ISSN 0962-8827. PMID 20890180.
  10. ↑ Scurr, Ingrid; Wilson, Louise; Lees, Melissa; Robertson, Stephen; Kirk, Edwin; Turner, Anne; Morton, John; Kidd, Alexa; Shashi, Vandana; Stanley, Christy; Berry, Margaret; Irvine, Alan D.; Goudie, David; Turner, Claire; Brewer, Carole (2011). "Cantú syndrome: Report of nine new cases and expansion of the clinical phenotype". American Journal of Medical Genetics Part A. 155 (3): 508–518. doi:10.1002/ajmg.a.33885. ISSN 1552-4833. PMID 21344641. Archived from the original on 2024-11-21. Retrieved 2025-04-23.
  11. ↑ Nichols CG (June 2025). "Bayliss-Starling Prize Lecture: KATP channel pathophysiology - a whole-body odyssey". J Physiol. 603 (11): 3293–3305. doi:10.1113/JP287415. PMC 12720494. PMID 40449010. The increased cardiac contractility and massive cardiac enlargement seen in CS (typically hearts are almost double normal size) (Singh et al., 2022) is not trivially predicted for any GOF in sarcolemmal KATP channels. Renin-angiotensin signalling (RAS) is elevated in CS mice, and cardiac enlargement can be reversed by RAS blockade (McClenaghan, Huang, Matkovich et al., 2020) or by dominant-negative suppression of smooth muscle KATP (McClenaghan, Huang, Yan et al., 2020), indicating that cardiac remodelling is a secondary consequence of the vascular GOF. While the cardiac enlargement helps to compensate for the abnormal vasodilatation and increased blood volume, it may ultimately be detrimental. It is thus is accompanied by expression of genes associated with pathological hypertrophy (McClenaghan, Huang, Matkovich et al., 2020), and such changes may underlie the gradual development of heart failure that is seen in older CS patients (Singh et al., 2022).
  12. ↑ Singh GK, McClenaghan C, Aggarwal M, Gu H, Remedi MS, Grange DK, Nichols CG (December 2022). "A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome". J Am Heart Assoc. 11 (24) e027363. doi:10.1161/JAHA.122.027363. PMC 9798820. PMID 36515236.
  13. ↑ Reference, Genetics Home. "Cantú syndrome". Genetics Home Reference. Archived from the original on 2019-03-29. Retrieved 2017-03-23.
  14. ↑ Cooper, Paige E.; Reutter, Heiko; Woelfle, Joachim; Engels, Hartmut; Grange, Dorothy K.; van Haaften, Gijs; van Bon, Bregje W.; Hoischen, Alexander; Nichols, Colin G. (2014). "Cantú Syndrome Resulting from Activating Mutation in the 8 Gene". Human Mutation. 35 (7): 809–813. doi:10.1002/humu.22555. ISSN 1098-1004. PMC 4277879. PMID 24700710.
  15. ↑ GeneCards Human Gene Database. "KCNJ8 Gene - GeneCards | KCNJ8 Protein | KCNJ8 Antibody". www.genecards.org. Archived from the original on 2022-11-23. Retrieved 2025-04-23.
  16. 1 2 Nichols, Colin G.; Singh, Gautam K.; Grange, Dorothy K. (2013-03-29). "KATP channels and cardiovascular disease: Suddenly a syndrome". Circulation Research. 112 (7): 1059–1072. doi:10.1161/CIRCRESAHA.112.300514. ISSN 0009-7330. PMC 3660033. PMID 23538276.
  17. ↑ van Bon BW, Gilissen C, Grange DK, Hennekam RC, Kayserili H, Engels H, Reutter H, Ostergaard JR, Morava E, Tsiakas K, Isidor B, Le Merrer M, Eser M, Wieskamp N, de Vries P, Steehouwer M, Veltman JA, Robertson SP, Brunner HG, de Vries BB, Hoischen A (June 2012). "Cantú syndrome is caused by mutations in ABCC9". Am J Hum Genet. 90 (6): 1094–1101. doi:10.1016/j.ajhg.2012.04.014. PMC 3370286. PMID 22608503.
  18. ↑ Harakalova M, van Harssel JJ, Terhal PA, van Lieshout S, Duran K, Renkens I, Amor DJ, Wilson LC, Kirk EP, Turner CL, Shears D, Garcia-Minaur S, Lees MM, Ross A, Venselaar H, Vriend G, Takanari H, Rook MB, van der Heyden MA, Asselbergs FW, Breur HM, Swinkels ME, Scurr IJ, Smithson SF, Knoers NV, van der Smagt JJ, Nijman IJ, Kloosterman WP, van Haelst MM, van Haaften G, Cuppen E (May 2012). "Dominant missense mutations in ABCC9 cause Cantú syndrome". Nat Genet. 44 (7): 793–796. doi:10.1038/ng.2324. PMID 22610116.
  19. ↑ McClenaghan, Conor; Huang, Yan; Yan, Zihan; Harter, Theresa M.; Halabi, Carmen M.; Chalk, Rod; Kovacs, Attila; Haaften, Gijs van; Remedi, Maria S.; Nichols, Colin G. (2020-03-02). "Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity". The Journal of Clinical Investigation. 130 (3): 1116–1121. doi:10.1172/JCI130571. ISSN 0021-9738. PMC 7269588. PMID 31821173.
  20. ↑ Pubchem. "Prostaglandin E2 | C20H32O5 - PubChem". pubchem.ncbi.nlm.nih.gov. Archived from the original on 2019-03-30. Retrieved 2017-04-01.
  21. ↑ Ong MM, Li Y, Lipner SR (October 2025). "Oral Minoxidil for Alopecia Treatment: Risks, Benefits, and Recommendations". American Journal of Clinical Dermatology. 27 (1): 101–119. doi:10.1007/s40257-025-00990-4. PMID 41118052. Minoxidil sulphate's effect on smooth muscle relaxation is related to its ability to open cell surface adenosine triphosphate (ATP)-sensitive potassium (KATP) channels and induce an efflux of potassium, resulting in hyperpolarisation of cell membranes, as demonstrated in in vitro smooth muscle and follicular models (Meisheri et al., 1988). Clinically, the observation that chemically unrelated KATP channel openers such as diazoxide and pinacidil cause hypertrichosis in humans provides indirect in vivo support for this mechanism (Koblenzer and Baker, 1968). Furthermore, minoxidil sulphate, as well as other KATP channel openers such as pinacidil, cromakalin and nicorandil, increase uptake of thymidine and cysteine by mouse vibrissae follicles (Salido et al., 2013). Cantu syndrome is an autosomal dominant disorder characterised by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. It is caused by mutations in ABCC9, which encodes a regulatory subunit of SUR2, a KATP channel opener expressed not only in smooth muscle but also in HFs (Ohko et al., 2020). This leads to constitutive activation of the KATP channel, thus providing a potential mechanistic link to minoxidil's ability to induce hair growth.
  22. ↑ Ohko K, Nakajima K, Nakajima H, Hiraki Y, Kubota K, Fukao T, Miyatake S, Matsumoto N, Sano S (March 2020). "Skin and hair abnormalities of Cantu syndrome: A congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil". The Journal of Dermatology. 47 (3): 306–310. doi:10.1111/1346-8138.15216. PMID 31907964.
  23. ↑ "Hypertrichotic osteochondrodysplasia - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 2018-05-27. Retrieved 2017-04-01.
  24. ↑ Cantú JM, García-Cruz D, Sánchez-Corona J, Hernández A, Nazará Z (1982). "A distinct osteochondrodysplasia with hypertrichosis- Individualization of a probable autosomal recessive entity". Hum Genet. 60 (1): 36–41. doi:10.1007/BF00281261. PMID 7076246.
  25. ↑ Penchaszadeh VB, Rojas-Martinez A, Llerena A (March 2014). "A tribute to José María ("Chema") Cantú". Genet Mol Biol. 37 (1 Suppl): 310–314. doi:10.1590/s1415-47572014000200018. PMC 3983575. PMID 24764766.

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