Cantú syndrome

Recommended panel testing at Breda Genetics for this condition:

Cantú syndrome, Berardinelli-Seip syndrome and their differential diagnosis [incl. mucopolysacchcaridosis I, II, IVA, mucolipidosis III, and alpha-mannosidosis and Beckwith-Wiedemann syndrome] (ABCC9, KCNJ8, AGPAT2, BSCL2, CDKN1C, IDUA, IDS, GALNS, GNPTAB, GNPTG, MAN2B1).

If negative, the following panels may be considered:

Cardiomyopathy, dilated (ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CSRP3, CRYAB, DES, DMD, DSG2, EYA4, FKTN, GATAD1, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, NEXN, PLN, PRDM16, PSEN1, PSEN2, RBM20, SCN5A, SDHA, SGCD, TAZ, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

Cardiomyopathy, hypertrophic (ACTC1, ACTN2, CALR3, CAV3, CSRP3, FLNC, GLA, JPH2, LAMP2, LDB3, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEXN, PLN, PRKAG2, PTPN11, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

Summary

Cantú syndrome is a very rare congenital syndrome so far described in just less than 30 cases worldwide. The main features of Cantú  syndrome are hypertrichosis with scalp hair extended onto the forehead and general increase in body hair, osteochondrodysplasia, cardiomegaly and dysmorphisms like macrocephaly, coarse face, thick eyebrows, epicantal folds, prominent supraorbital ridges, broad nasal bridge, anteverted nares, long and large philtrum, full lips, and macroglossia. Newborns present with neonatal macrosomia (enlarged body size) and generalized edema, whether in childhood the patients usually have a muscular appearance with little subcutaneous fat.

Acromegaloid facial appearance and hypertrichosis with acromegaloid facial features are disorders which can be considered included within the spectrum of Cantú syndrome.

Cardiomegaly is found in the majority of patients with occasional pericardial effusions. Other cardiac manifestations include patent ductus arteriosus, ventricular hypertrophy, and pulmonary hypertension, in almost all cases.

Psychomotor manifestations include delayed motor development due to hypotonia. Most patients show speech delay and a minority may have learning difficulties or intellectual disability.

Osteochondrodysplastic features include thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones.

Molecular diagnosis

Cantú  syndrome is caused by heterozygous mutation in the ABCC9 or much more infrequently by mutation in the KCNJ8 gene. So far only missense mutations have been described (de novo in almost all cases). Of note, a distal deletion of chromosome 1p36 has been detected in a patient with traits typical of Cantú syndrome plus other characteristics. Therefore, it has been suggested that patients with Cantú  syndrome with unusual or more severe features may be analyzed for subtelomeric deletions.

Differential diagnosis

Genetic disorders included in the differential diagnosis of Cantu syndrome are: lysosomal storage diseases (many individuals with Cantú syndrome are initially thought to have a lysosomal storage disorder due to the presence of coarse facial features and hirsutism), Beckwith-Wiedemann syndrome, Berardinelli-Seip congenital lipodystrophy, and hypertrophic cardiomyopathy or dilated cardiomyopathy.

Recommended panel testing at Breda Genetics for this condition:

Cantú syndrome, Berardinelli-Seip syndrome and their differential diagnosis [incl. mucopolysacchcaridosis I, II, IVA, mucolipidosis III, and alpha-mannosidosis and Beckwith-Wiedemann syndrome] (ABCC9, KCNJ8, AGPAT2, BSCL2, CDKN1C, IDUA, IDS, GALNS, GNPTAB, GNPTG, MAN2B1)

If negative, the following panels may be considered:

Cardiomyopathy, dilated (ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CSRP3, CRYAB, DES, DMD, DSG2, EYA4, FKTN, GATAD1, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, NEXN, PLN, PRDM16, PSEN1, PSEN2, RBM20, SCN5A, SDHA, SGCD, TAZ, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

Cardiomyopathy, hypertrophic (ACTC1, ACTN2, CALR3, CAV3, CSRP3, FLNC, GLA, JPH2, LAMP2, LDB3, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEXN, PLN, PRKAG2, PTPN11, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL)

References:

Cantú Syndrome and Related Disorders. Grange DK, Nichols CG, Singh GK. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2014 Oct 2. PMID: 25275207

A patient with monosomy 1p36, atypical features and phenotypic similarities with Cantu syndrome. Tan TY, Bankier A, Slater HR, Northrop EL, Zacharin M, Savarirayan R. Am J Med Genet A. 2005 Dec 15;139(3):216-20. PMID: 16278903

Clinical utility gene card for: Cantú syndrome. Kirk EP, Scurr I, van Haaften G, van Haelst MM, Nichols CG, Williams M, Smithson SF, Grange DK. Eur J Hum Genet. 2017 Apr;25(4). PMID: 28051078

Dominant missense mutations in ABCC9 cause Cantú syndrome. 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. Nat Genet. 2012 May 18;44(7):793-6. PMID: 22610116

Cantú syndrome is caused by mutations in ABCC9. 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. Am J Hum Genet. 2012 Jun 8;90(6):1094-101. PMID: 22608503

Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities – support for the role of K(ATP) channels in this condition. Brownstein CA, Towne MC, Luquette LJ, Harris DJ, Marinakis NS, Meinecke P, Kutsche K, Campeau PM, Yu TW, Margulies DM, Agrawal PB, Beggs AH. Eur J Med Genet. 2013 Dec;56(12):678-82. PMID: 24176758

Cantú syndrome resulting from activating mutation in the KCNJ8 gene. Cooper PE, Reutter H, Woelfle J, Engels H, Grange DK, van Haaften G, van Bon BW, Hoischen A, Nichols CG. Hum Mutat. 2014 Jul;35(7):809-13. PMID: 24700710