RESEARCH LETTER
A Patient With Cantu´ Syndrome Associated With Fatal Bronchopulmonary Dysplasia and Pulmonary Hypertension Jae Young Park,1 Soo Hyun Koo,1 Yu Jin Jung,1 Yun-Jung Lim,2 and Mi Lim Chung1* 1
Department of Pediatrics, Haeundae Paik Hospital, College of Medicine, Inje University, Pusan, Korea
2
Department of Radiology, Haeundae Paik Hospital, College of Medicine, Inje University, Pusan, Korea
Manuscript Received: 6 March 2014; Manuscript Accepted: 7 March 2014
TO THE EDITOR: We describe a patient with Cantu´ syndrome confirmed by mutation analysis with associated cardiopulmonary complications. A female infant was born by vaginal delivery at 35 and 6/7 weeks of gestation, after a pregnancy complicated by polyhydramnios beginning at 32 weeks. She was the first child of nonconsanguineous Korean parents. Her birth weight was 3,240 g, length was 50 cm, and head circumference was 35 cm, all of which were >90th centile. Hypertrichosis was evident at birth. She had a coarse face with fullness of upper eyelids, a wide nasal bridge, and thick vermillion of the upper and lower lips (Fig. 1a). The initial chest radiograph showed relatively small lung volumes with mild cardiomegaly. On day 3, an echocardiogram showed a large patent ductus arteriosus (PDA) measuring 7 mm. It did not respond to medical treatment and was surgically ligated on the patient’s seventh day of life. Repeat echocardiogram noted persistent pulmonary hypertension. Routine laboratory investigations were normal, including thyroid function tests. Her plasma and urine amino acid profile, lysosomal enzyme analysis and peripheral blood karyotype were normal. Ultrasonography of the head and abdomen and ophthalmological examination results were normal. A follow-up chest radiograph showed persistent cardiomegaly and worsening bronchopulmonary dysplasia (BPD) (Fig. 1b). However, despite gentle ventilatory support with steroid therapy, her BPD progressed, and a tracheostomy was performed at 82 days of age. Supplemental nitrous oxide gas was administered. A follow-up echocardiogram showed progressive pulmonary hypertension with tricuspid and mitral regurgitation and interventricular septal wall thickening (10 mm), but relatively good ventricular function (left ventricular ejection fraction, 75%). At 4 months of age, cranial magnetic resonance imaging showed atrophic changes of the brain. The baby’s general condition continued to worsen and she developed recurrent and refractory pneumothoraces and sepsis. She eventually died of cor pulmonale, sepsis, and pneumothorax at 248 days of age. Genetic testing for Cantu´ syndrome was recommended by a clinical laboratory geneticist in the Netherlands who was consulted, and a heterozygous c.4385C>G (p.Ala1462Gly) mutation in ABCC9 was found postmortem. The alanine at position 1,462 is conserved from human to zebrafish and its substitution into glycine is predicted to have a deleterious effect on SUR2 protein function.
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Park JY, Koo SH, Jung YJ, Lim Y-J, Chung ML. 2014. A patient with Cantu´ syndrome associated with fatal bronchopulmonary dysplasia and pulmonary hypertension. Am J Med Genet Part A 164A:2118–2120.
After determination of the mutation, retrospective review of the infant’s phenotype, cardiac manifestations, and radiologic findings were all consistent with Cantu´ syndrome. We then conducted mutation analysis and biologic parentage analysis. Neither parent had the pathogenic mutation in the ABCC9. Biologic parentage analysis confirmed that they are truly biologic parents of the patient. We conclude that, the mutation of the patient likely has been arisen de novo in the proband and was the cause of the Cantu´ syndrome. The authors declare that these studies are not considered to be research at their institution. Cantu´ syndrome is a rare disorder comprising congenital hypertrichosis, distinctive facial features, osteochondrodysplasia, and cardiomegaly and was first described by Cantu´ et al. [1982]. Only approximately 40 patients with Cantu´ syndrome have been reported [Nevin et al., 1996; Garcı´a-Cruz et al., 1997; Rosser et al., 1998; Robertson et al., 1999; Concolino et al., 2000; Lazalde et al., 2000; Engels et al., 2002; Tan et al., 2005; Grange et al., 2006; Garcı´a-Cruz et al., 2011; Kurban et al., 2011; Scurr et al., 2011; Harakalova et al., 2012; van Bon et al., 2012]. Hypertrichosis and dysmorphic facies are observed in most patients with Cantu´ syndrome and are usually evident at birth. Conflict of interest: none. Correspondence to: Dr. Mi Lim Chung, Department of Pediatrics, Haeundae Paik Hospital, College of Medicine, Inje University, 1435, Jwa-dong, Haeundae-gu, Pusan 612-030, Korea. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 8 April 2014 DOI 10.1002/ajmg.a.36563
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FIG. 1. a: Facial photograph of the patient showing thick scalp hair with forehead hypertrichosis and a coarse facial appearance with fullness of upper eyelids, a wide nasal bridge, and thick vermillion of the upper and lower lips. b: Chest radiograph showing persistent cardiomegaly and bronchopulmonary dysplasia. c: Radiograph of the baby at 6 months of age showing broad ribs and a slightly narrow thorax. White arrows indicate delayed ossification of the humeral and femoral epiphyses compared with normal infants of the same age. The black line indicates the narrow interpedicular distance in the caudal lumbar spine.
Affected infants have thick scalp hair extending onto the forehead and heavy, generalized body hair. A coarse facial appearance is also typical, with a wide or depressed nasal bridge, epicanthal folds, and a wide mouth with thick vermillion of the lips. In addition, macrosomia and macrocephaly are also frequently observed. Grange et al. [2006] reviewed the cardiac manifestations of Cantu´ syndrome and suggested that cardiomegaly seems to be caused by increased cardiac muscle mass, not by a true cardiomyopathy. Most reported patients have shown normal ventricular function. A PDA is the only significant reported structural heart defect, and surgical ligation is needed in some cases. Pulmonary hypertension has also been observed in patients with Cantu´ syndrome, as in the patient described here. However, the cause of pulmonary hypertension in Cantu´ syndrome is unknown, and its long-term outcome cannot be predicted. Scurr et al. [2011] reported a patient with pulmonary hypertension who appeared to respond to steroid therapy and gradually improved; they suggested the possibility of inflammation as an underlying pathology of Cantu´ syndrome. However, no reported patient has been as severely affected as the patient reported here, and this patient’s pulmonary hypertension was not responsive to repeated steroid therapy. We could not determine the underlying pathphysiology of the patient’s pulmonary hypertension because we did not perform cardiac catheterization. Now that the genetic cause of Cantu´ syndrome is known, some of the manifestations may be explained as a consequence of ABCC9 dysfunction, although this does not explain all of the manifestations. Furthermore, the clinical course of the present patient was significantly different from that of the previously reported patients. It is not possible for us to determine if the cardiopulmonary complications are a direct consequence of the Cantu´ syndrome and ABCC9 dysfunction or if they are coincidental. Additional reports are necessary to affirm or refute this association. The known radiological features of osteochondroplasia in Cantu´ syndrome are a narrow thorax, wide ribs, coxa valga, osteopenia,
enlarged medullary canals with an “Erlenmeyer-flask” appearance, and metaphyseal widening of long bones [Rosser et al., 1998; Concolino et al., 2000]. Other described skeletal abnormalities include flattened or ovoid vertebral bodies, thickened calvaria, growth arrest in the metaphyses, and small terminal phalange of the thumbs and halluces [Engels et al., 2002; Czeschik et al., 2013]. The patient reported here had no features of osteochondrodysplasia of Cantu´ syndrome at birth; however, at 2–3 months of age, some characteristic findings were observed on radiologic examination, including wide ribs, delayed ossification of the humeral and femoral epiphyses, and narrow interpedicular distance of the caudal lumbar spine (Fig. 1c). Heterozygous missense mutations of ABCC9 cause Cantu´ syndrome [Harakalova et al., 2012]. The SUR2 protein encoded by ABCC9 is part of an ATP-sensitive potassium channel complex (ATP-sensitive meaning that KATP channels open and close in response to the intracellular ADP/ATP ratio) that functions primarily in the heart, skeletal muscle, and smooth muscle. The ABCC9 mutations may disturb the structure, thereby leading to dysfunction of the KATP channels. By electrophysiological measurements, ABCC9 mutations were found to reduce the ATP-mediated potassium channel inhibition, resulting in channel opening and eventually leading to the various clinical features of Cantu´ syndrome [Harakalova et al., 2012]. Cantu´ syndrome is a channelopathy and further understanding of the underlying pathologic mechanism may lead to effective therapeutic options [Bregje et al., 2012].
REFERENCES Bregje WM, 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. 2012. Cantu
2120 syndrome is caused by mutations in ABCC9. Am J Med Genet 90: 1094–1101. Cantu´ JM, Garcı´a-Cruz D, Sa´nchez-Corona J, Herna´ndez A, Nazara´ Z. 1982. A distinct osteochondrodysplasia with hypertrichosis— Individualization of a probable autosomal recessive entity. Hum Genet 60:36–41. Concolino D, Formicola S, Camera G, Strisciuglio P. 2000. Congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia (Cantu´ syndrome): A new case with unusual radiological findings. Am J Med Genet 92:191–194.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 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. 2012. Dominant missense mutations in ABCC9 cause Cantu´ syndrome. Nat Genet 44:793–796. Kurban M, Kim CA, Kiuru M, Fantauzzo K, Cabral R, Abbas O, Levy B, Christiano AM. 2011. Copy number variations on chromosome 4q 26-27 are associated with Cantu´ syndrome. Dermatology 223:316–320. Lazalde B, Sanchez-Urbina R, Nuno-Arana I, Bitar WE, Ramirez-Duenas M. 2000. Autosomal dominant inheritance in Cantu´ syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly). Am J Med Genet 94:412–427.
Czeschik JC, Voigt C, Goecke TO, Ludecke HJ, Wagner N, Kuechler A, Wieczorek D. 2013. Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. Am J Med Genet Part A 161A:295–300.
Nevin NC, Mullholland HC, Thomas PS. 1996. Congenital hypertrichosis, cardiomegaly and mild osteochondrodysplasia. Am J Med Genet 66:33– 38.
Engels H, Bosse K, Ehrbrecht A, Zahn S, Hoischen A, Propping P, Bindl L, Reutter H. 2002. Further case of Cantu´ syndrome: Exclusion of cryptic subtelomeric chromosome aberrations. Am J Med Genet 111:205–209.
Robertson SP, Kirk E, Bernier F, Brereton J, Turner A, Bankier A. 1999. Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Cantu´ syndrome. Am J Med Genet 85:395–402.
Garcı´a-Cruz D, Sa´nchez-Corona J, Nazara´ Z, Garcı´a-Cruz MO, Figuera LE, Castanˇeda V, Cantu´ JM. 1997. Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Further delineation of a new genetic syndrome. Am J Med Genet 69:138–151.
Rosser EM, Kaarianen H, Hurst JA, Baraiser M, Hall CM, Clayton P, Leonard JV. 1998. Three patients with the osteochondrodysplasia and hypertrichosis syndrome—Cantu´ syndrome. Clin Dysmorphol 7:1–7.
Garcı´a-Cruz D, Mampel A, Echeverria MI, Vargas AL, Castanˇeda-Cisneros G, Cavalos-Rodriguez N, Patino-Garcia B, Sa´nchez-Corona J, Nazara´ Z, Garcı´a-Cruz MO, Castanˇeda V, Cardona EG, Marin-Solis B, Cantu´ JM, Nunez-Reveles N, Moran-Moguel C, Thavanati PK, Ramirez-Garcia S, Sanchez-Corona J. 2011. Cantu´ syndrome and lymphoedema. Clin Dysmorphol 20:32–37. Grange DK, Lorch SM, Cole PL, Singh GK. 2006. Cantu´ syndrome in a woman and her two daughters: Further confirmation of autosomal dominant inheritance and review of the cardiac manifestations. Am J Med Genet Part A 140A:1673–1680. 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
Scurr I, Wilson L, Lees M, Robertson S, Kirk E, Turner A, Morton J, Kidd A, Shashi V, Stanley C, Berry M, Irvine AD, Goudie D, Turner C, Brewer C, Smithson S. 2011. Cantu´ syndrome: Report of nine new cases and expansion of the clinical phenotype. Am J Med Genet Part A 155A: 508–518. Tan TY, Bankier A, Slater HR, Northrop EL, Zacharin M, Savarirayan R. 2005. A patient with monosomy 1p36, atypical features and phenotypic similarities with Cantu´ syndrome. Am J Med Genet Part A 139A:216– 220. 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. 2012. Cantu´ syndrome is caused by mutations in ABCC9. Am J Hum Genet 90:1094–1101.
A Patient With Cantu´ Syndrome Associated With Fatal Bronchopulmonary Dysplasia and Pulmonary Hypertension Jae Young Park,1 Soo Hyun Koo,1 Yu Jin Jung,1 Yun-Jung Lim,2 and Mi Lim Chung1* 1
Department of Pediatrics, Haeundae Paik Hospital, College of Medicine, Inje University, Pusan, Korea
2
Department of Radiology, Haeundae Paik Hospital, College of Medicine, Inje University, Pusan, Korea
Manuscript Received: 6 March 2014; Manuscript Accepted: 7 March 2014
TO THE EDITOR: We describe a patient with Cantu´ syndrome confirmed by mutation analysis with associated cardiopulmonary complications. A female infant was born by vaginal delivery at 35 and 6/7 weeks of gestation, after a pregnancy complicated by polyhydramnios beginning at 32 weeks. She was the first child of nonconsanguineous Korean parents. Her birth weight was 3,240 g, length was 50 cm, and head circumference was 35 cm, all of which were >90th centile. Hypertrichosis was evident at birth. She had a coarse face with fullness of upper eyelids, a wide nasal bridge, and thick vermillion of the upper and lower lips (Fig. 1a). The initial chest radiograph showed relatively small lung volumes with mild cardiomegaly. On day 3, an echocardiogram showed a large patent ductus arteriosus (PDA) measuring 7 mm. It did not respond to medical treatment and was surgically ligated on the patient’s seventh day of life. Repeat echocardiogram noted persistent pulmonary hypertension. Routine laboratory investigations were normal, including thyroid function tests. Her plasma and urine amino acid profile, lysosomal enzyme analysis and peripheral blood karyotype were normal. Ultrasonography of the head and abdomen and ophthalmological examination results were normal. A follow-up chest radiograph showed persistent cardiomegaly and worsening bronchopulmonary dysplasia (BPD) (Fig. 1b). However, despite gentle ventilatory support with steroid therapy, her BPD progressed, and a tracheostomy was performed at 82 days of age. Supplemental nitrous oxide gas was administered. A follow-up echocardiogram showed progressive pulmonary hypertension with tricuspid and mitral regurgitation and interventricular septal wall thickening (10 mm), but relatively good ventricular function (left ventricular ejection fraction, 75%). At 4 months of age, cranial magnetic resonance imaging showed atrophic changes of the brain. The baby’s general condition continued to worsen and she developed recurrent and refractory pneumothoraces and sepsis. She eventually died of cor pulmonale, sepsis, and pneumothorax at 248 days of age. Genetic testing for Cantu´ syndrome was recommended by a clinical laboratory geneticist in the Netherlands who was consulted, and a heterozygous c.4385C>G (p.Ala1462Gly) mutation in ABCC9 was found postmortem. The alanine at position 1,462 is conserved from human to zebrafish and its substitution into glycine is predicted to have a deleterious effect on SUR2 protein function.
Ó 2014 Wiley Periodicals, Inc.
How to Cite this Article: Park JY, Koo SH, Jung YJ, Lim Y-J, Chung ML. 2014. A patient with Cantu´ syndrome associated with fatal bronchopulmonary dysplasia and pulmonary hypertension. Am J Med Genet Part A 164A:2118–2120.
After determination of the mutation, retrospective review of the infant’s phenotype, cardiac manifestations, and radiologic findings were all consistent with Cantu´ syndrome. We then conducted mutation analysis and biologic parentage analysis. Neither parent had the pathogenic mutation in the ABCC9. Biologic parentage analysis confirmed that they are truly biologic parents of the patient. We conclude that, the mutation of the patient likely has been arisen de novo in the proband and was the cause of the Cantu´ syndrome. The authors declare that these studies are not considered to be research at their institution. Cantu´ syndrome is a rare disorder comprising congenital hypertrichosis, distinctive facial features, osteochondrodysplasia, and cardiomegaly and was first described by Cantu´ et al. [1982]. Only approximately 40 patients with Cantu´ syndrome have been reported [Nevin et al., 1996; Garcı´a-Cruz et al., 1997; Rosser et al., 1998; Robertson et al., 1999; Concolino et al., 2000; Lazalde et al., 2000; Engels et al., 2002; Tan et al., 2005; Grange et al., 2006; Garcı´a-Cruz et al., 2011; Kurban et al., 2011; Scurr et al., 2011; Harakalova et al., 2012; van Bon et al., 2012]. Hypertrichosis and dysmorphic facies are observed in most patients with Cantu´ syndrome and are usually evident at birth. Conflict of interest: none. Correspondence to: Dr. Mi Lim Chung, Department of Pediatrics, Haeundae Paik Hospital, College of Medicine, Inje University, 1435, Jwa-dong, Haeundae-gu, Pusan 612-030, Korea. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 8 April 2014 DOI 10.1002/ajmg.a.36563
2118
PARK ET AL.
2119
FIG. 1. a: Facial photograph of the patient showing thick scalp hair with forehead hypertrichosis and a coarse facial appearance with fullness of upper eyelids, a wide nasal bridge, and thick vermillion of the upper and lower lips. b: Chest radiograph showing persistent cardiomegaly and bronchopulmonary dysplasia. c: Radiograph of the baby at 6 months of age showing broad ribs and a slightly narrow thorax. White arrows indicate delayed ossification of the humeral and femoral epiphyses compared with normal infants of the same age. The black line indicates the narrow interpedicular distance in the caudal lumbar spine.
Affected infants have thick scalp hair extending onto the forehead and heavy, generalized body hair. A coarse facial appearance is also typical, with a wide or depressed nasal bridge, epicanthal folds, and a wide mouth with thick vermillion of the lips. In addition, macrosomia and macrocephaly are also frequently observed. Grange et al. [2006] reviewed the cardiac manifestations of Cantu´ syndrome and suggested that cardiomegaly seems to be caused by increased cardiac muscle mass, not by a true cardiomyopathy. Most reported patients have shown normal ventricular function. A PDA is the only significant reported structural heart defect, and surgical ligation is needed in some cases. Pulmonary hypertension has also been observed in patients with Cantu´ syndrome, as in the patient described here. However, the cause of pulmonary hypertension in Cantu´ syndrome is unknown, and its long-term outcome cannot be predicted. Scurr et al. [2011] reported a patient with pulmonary hypertension who appeared to respond to steroid therapy and gradually improved; they suggested the possibility of inflammation as an underlying pathology of Cantu´ syndrome. However, no reported patient has been as severely affected as the patient reported here, and this patient’s pulmonary hypertension was not responsive to repeated steroid therapy. We could not determine the underlying pathphysiology of the patient’s pulmonary hypertension because we did not perform cardiac catheterization. Now that the genetic cause of Cantu´ syndrome is known, some of the manifestations may be explained as a consequence of ABCC9 dysfunction, although this does not explain all of the manifestations. Furthermore, the clinical course of the present patient was significantly different from that of the previously reported patients. It is not possible for us to determine if the cardiopulmonary complications are a direct consequence of the Cantu´ syndrome and ABCC9 dysfunction or if they are coincidental. Additional reports are necessary to affirm or refute this association. The known radiological features of osteochondroplasia in Cantu´ syndrome are a narrow thorax, wide ribs, coxa valga, osteopenia,
enlarged medullary canals with an “Erlenmeyer-flask” appearance, and metaphyseal widening of long bones [Rosser et al., 1998; Concolino et al., 2000]. Other described skeletal abnormalities include flattened or ovoid vertebral bodies, thickened calvaria, growth arrest in the metaphyses, and small terminal phalange of the thumbs and halluces [Engels et al., 2002; Czeschik et al., 2013]. The patient reported here had no features of osteochondrodysplasia of Cantu´ syndrome at birth; however, at 2–3 months of age, some characteristic findings were observed on radiologic examination, including wide ribs, delayed ossification of the humeral and femoral epiphyses, and narrow interpedicular distance of the caudal lumbar spine (Fig. 1c). Heterozygous missense mutations of ABCC9 cause Cantu´ syndrome [Harakalova et al., 2012]. The SUR2 protein encoded by ABCC9 is part of an ATP-sensitive potassium channel complex (ATP-sensitive meaning that KATP channels open and close in response to the intracellular ADP/ATP ratio) that functions primarily in the heart, skeletal muscle, and smooth muscle. The ABCC9 mutations may disturb the structure, thereby leading to dysfunction of the KATP channels. By electrophysiological measurements, ABCC9 mutations were found to reduce the ATP-mediated potassium channel inhibition, resulting in channel opening and eventually leading to the various clinical features of Cantu´ syndrome [Harakalova et al., 2012]. Cantu´ syndrome is a channelopathy and further understanding of the underlying pathologic mechanism may lead to effective therapeutic options [Bregje et al., 2012].
REFERENCES Bregje WM, 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. 2012. Cantu
2120 syndrome is caused by mutations in ABCC9. Am J Med Genet 90: 1094–1101. Cantu´ JM, Garcı´a-Cruz D, Sa´nchez-Corona J, Herna´ndez A, Nazara´ Z. 1982. A distinct osteochondrodysplasia with hypertrichosis— Individualization of a probable autosomal recessive entity. Hum Genet 60:36–41. Concolino D, Formicola S, Camera G, Strisciuglio P. 2000. Congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia (Cantu´ syndrome): A new case with unusual radiological findings. Am J Med Genet 92:191–194.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 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. 2012. Dominant missense mutations in ABCC9 cause Cantu´ syndrome. Nat Genet 44:793–796. Kurban M, Kim CA, Kiuru M, Fantauzzo K, Cabral R, Abbas O, Levy B, Christiano AM. 2011. Copy number variations on chromosome 4q 26-27 are associated with Cantu´ syndrome. Dermatology 223:316–320. Lazalde B, Sanchez-Urbina R, Nuno-Arana I, Bitar WE, Ramirez-Duenas M. 2000. Autosomal dominant inheritance in Cantu´ syndrome (congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly). Am J Med Genet 94:412–427.
Czeschik JC, Voigt C, Goecke TO, Ludecke HJ, Wagner N, Kuechler A, Wieczorek D. 2013. Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. Am J Med Genet Part A 161A:295–300.
Nevin NC, Mullholland HC, Thomas PS. 1996. Congenital hypertrichosis, cardiomegaly and mild osteochondrodysplasia. Am J Med Genet 66:33– 38.
Engels H, Bosse K, Ehrbrecht A, Zahn S, Hoischen A, Propping P, Bindl L, Reutter H. 2002. Further case of Cantu´ syndrome: Exclusion of cryptic subtelomeric chromosome aberrations. Am J Med Genet 111:205–209.
Robertson SP, Kirk E, Bernier F, Brereton J, Turner A, Bankier A. 1999. Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Cantu´ syndrome. Am J Med Genet 85:395–402.
Garcı´a-Cruz D, Sa´nchez-Corona J, Nazara´ Z, Garcı´a-Cruz MO, Figuera LE, Castanˇeda V, Cantu´ JM. 1997. Congenital hypertrichosis, osteochondrodysplasia, and cardiomegaly: Further delineation of a new genetic syndrome. Am J Med Genet 69:138–151.
Rosser EM, Kaarianen H, Hurst JA, Baraiser M, Hall CM, Clayton P, Leonard JV. 1998. Three patients with the osteochondrodysplasia and hypertrichosis syndrome—Cantu´ syndrome. Clin Dysmorphol 7:1–7.
Garcı´a-Cruz D, Mampel A, Echeverria MI, Vargas AL, Castanˇeda-Cisneros G, Cavalos-Rodriguez N, Patino-Garcia B, Sa´nchez-Corona J, Nazara´ Z, Garcı´a-Cruz MO, Castanˇeda V, Cardona EG, Marin-Solis B, Cantu´ JM, Nunez-Reveles N, Moran-Moguel C, Thavanati PK, Ramirez-Garcia S, Sanchez-Corona J. 2011. Cantu´ syndrome and lymphoedema. Clin Dysmorphol 20:32–37. Grange DK, Lorch SM, Cole PL, Singh GK. 2006. Cantu´ syndrome in a woman and her two daughters: Further confirmation of autosomal dominant inheritance and review of the cardiac manifestations. Am J Med Genet Part A 140A:1673–1680. 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
Scurr I, Wilson L, Lees M, Robertson S, Kirk E, Turner A, Morton J, Kidd A, Shashi V, Stanley C, Berry M, Irvine AD, Goudie D, Turner C, Brewer C, Smithson S. 2011. Cantu´ syndrome: Report of nine new cases and expansion of the clinical phenotype. Am J Med Genet Part A 155A: 508–518. Tan TY, Bankier A, Slater HR, Northrop EL, Zacharin M, Savarirayan R. 2005. A patient with monosomy 1p36, atypical features and phenotypic similarities with Cantu´ syndrome. Am J Med Genet Part A 139A:216– 220. 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. 2012. Cantu´ syndrome is caused by mutations in ABCC9. Am J Hum Genet 90:1094–1101.
