Cantu Syndrome

A number sign (#) is used with this entry because of evidence that hypertrichotic osteochondrodysplasia (Cantu syndrome) is caused by heterozygous mutation in the ABCC9 gene (601439) on chromosome 12p12.

Description

Cantu syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. The hypertrichosis leads to thick scalp hair which extends onto the forehead and to a general increase in body hair. Some features are suggestive of a storage disorder, including macrocephaly and coarse facial features, with a broad nasal bridge, epicanthal folds, wide mouth, and full lips. About half of affected individuals are macrosomic and edematous at birth, whereas in childhood they usually have a muscular appearance with little subcutaneous fat. Thickened calvarium, narrow thorax, wide ribs, flattened or ovoid vertebral bodies, coxa valga, osteopenia, enlarged medullary canals, and metaphyseal widening of long bones have been reported. Cardiac manifestations such as patent ductus arteriosus, ventricular hypertrophy, pulmonary hypertension, and pericardial effusions are present in approximately 80% of cases. Motor development is usually delayed due to hypotonia. Most patients have a mild speech delay, and a small percentage have learning difficulties or intellectual disability (summary by van Bon et al., 2012).

Clinical Features

Cantu et al. (1982) described a brother and sister and 2 sporadic cases with a syndrome consisting of generalized congenital hypertrichosis, macrosomy at birth, narrow thorax, cardiomegaly, wide ribs, platyspondyly, hypoplastic ischiopubic branches, small obturator foramen, bilateral coxa valga, enlarged medullary canal, Erlenmeyer-flask-like long bones, and generalized osteopenia. No consanguinity was found in the 3 families. Garcia-Cruz et al. (1997) provided follow-up data on the 2 affected sibs and reported 4 additional patients.

Nevin et al. (1996) reported a sporadic case of the syndrome in a 16-year-old boy. His skeletal abnormalities were a narrow thorax with thin ribs, and mild shortening and cortical thinning of the long bones. Cardiomegaly was a major feature, along with recurrent pericardial effusion requiring the formation of a pleuropericardial window. Histologic examination revealed little evidence of myocardial pathology.

Robertson et al. (1999) reported 2 unrelated patients with Cantu syndrome (hypertrichosis, osteochondrodysplasia, and cardiomegaly). The cutaneous hypertrichosis and the skeletal changes were well documented by photographs of these patients. In the male patient, hypertrichosis was already striking at age 4 years. Limb radiographs showed Erlenmeyer flask-like deformities of the femora and the humeri; the radii and ulnae had similarly broad and undermodeled metaphyses and diaphyses, and bilateral coxa valga was present. The female patient had pulmonary hypertension of unknown cause, which was responsive to steroid therapy. She also had unusual, deep plantar creases, not previously reported in Cantu syndrome. Robertson et al. (1999) reviewed 14 published cases of Cantu syndrome, including their own. They found that all of the patients had cardiomegaly, with congenital concentric hypertrophic cardiomyopathy in 5 patients and pericardial effusion in 2. Broad ribs and metaphyseal flaring with enlarged medullary canal were observed in 12 cases. A coarse facial appearance suggesting a mucopolysaccharidosis and a broad flat nasal bridge were frequent findings, illustrated in the patients reported by Robertson et al. (1999).

Concolino et al. (2000) described an additional case of Cantu syndrome. The radiologic findings were unusual, namely proximal and distal megaepiphyses of long bones and advanced bone age. The female patient had a short neck, narrow thorax, and generalized hypertrichosis. The face was 'coarse' with prominent eyebrows, abundant and curly eyelashes, epicanthal folds, convergent strabismus, hypertelorism, flattened and broad nasal bridge, and long philtrum.

Engels et al. (2002) described an infant with the characteristic features of Cantu syndrome including macrosomia, macrocephaly, coarse facial appearance, and hypertrichosis. He also had generalized osteopenia, a narrow thoracic cavity with broad ribs, cardiac findings which resolved, and developmental delay. Previously undescribed findings included pyloric stenosis, elevated alkaline phosphatase levels, and calcification of the arteriae thalamostriatae on head ultrasound. Karyotype and FISH studies for subtelomeric chromosome aberrations were normal.

Scurr et al. (2011) studied 9 additional patients with Cantu syndrome, including the first reported African American patient, and provided long-term follow-up of the female patient reported by Robertson et al. (1999). Scurr et al. (2011) observed that the facial changes of Cantu syndrome are consistent and evolve over time: the face lengthens with age, with the forehead becoming tall and the chin prominent, and this lengthening makes the facial hair pattern much less striking. The flat nasal bridge becomes quite high and the supraorbital ridges become more prominent, giving the eyes a deep-set appearance. In addition, although about half of Cantu syndrome patients are macrosomic at birth, in childhood the patients usually have a fit, muscular appearance with little subcutaneous fat; however, after puberty, patients may tend to gain weight in a predominantly truncal distribution. Scurr et al. (2011) noted several new findings in some of their patients, including recurrent infections with low immunoglobulin levels and gastric bleeding. Cardiac manifestations included patent ductus arteriosus (PDA), septal hypertrophy, pulmonary hypertension, and pericardial effusion; 4 patients required surgical closure of the PDA and 1 patient underwent pericardectomy. Learning difficulties in these patients tended to be mild, and all attended normal school. Long-term follow-up suggested the emergence of a behavior phenotype involving anxiety and obsessive traits.

Inheritance

Autosomal recessive inheritance of Cantu syndrome had been suggested on the basis of sib recurrence in 1 family and consanguinity in another. Robertson et al. (1999) performed a segregation analysis based on all reported families and concluded that the data made autosomal recessive inheritance unlikely. They decided the most likely possibilities were a new dominant mutation or a microdeletion syndrome, sib recurrence possibly representing gonadal mosaicism.

Lazalde et al. (2000) also challenged autosomal recessive inheritance. They reported a Mexican family with this disorder. The 44-year-old father and his 2 children (a 14-year-old male and a 4-year-old female) showed the classic characteristics, but the father and the brother also had a previously unreported feature, thick calvarium. This was the first reported instance of male-to-male transmission of Cantu syndrome. Lazalde et al. (2000) suggested that together with the paternal age effect found in reported sporadic cases and the segregation analysis reported by Robertson et al. (1999), autosomal dominant inheritance is more likely than autosomal recessive inheritance. They suggested that the affected sibs reported by Cantu et al. (1982) could be explained by parental gonadal mosaicism.

Grange et al. (2006) reported a mother and 2 daughters with Cantu syndrome, consistent with autosomal dominant inheritance. All 3 patients had cardiac involvement, and symptomatic pericardial effusions requiring surgical intervention occurred in the mother and 1 of her daughters. Chromosome microarray analysis was normal in 1 of the girls.

Cytogenetics

Tan et al. (2005) reported a 16-year-old boy with features of Cantu syndrome who was found to have a distal 1p36 deletion (see monosomy 1p36 syndrome, 607872). The boy also had features not previously described in either syndrome, including hypercholesterolemia, type II diabetes, recurrent bony fractures, and nonalcoholic steatohepatitis. Tan et al. (2005) suggested that patients with Cantu syndrome with unusual or more severe features be analyzed for subtelomeric deletions.

Molecular Genetics

In 11 of 14 patients from 10 families with Cantu syndrome, including a mother and 2 daughters originally reported by Grange et al. (2006), van Bon et al. (2012) identified heterozygosity for 4 different missense mutations in the ABCC9 gene (601439.0004-601439.0007). Van Bon et al. (2012) observed no difference in severity of phenotype between the mutation-positive patients and the 3 patients in whom mutation in the ABCC9 gene was not found, 1 of whom was the patient previously studied by Engels et al. (2002).

Harakalova et al. (2012) performed exome sequencing in a 15-month-old boy with Cantu syndrome and his unaffected parents, and identified heterozygosity for a de novo missense mutation in the ABCC9 gene (601439.0005) that was confirmed by Sanger sequencing. Analysis of ABCC9 in 15 more patients, including 9 new patients and 6 patients previously reported by Scurr et al. (2011), 1 of whom was the female originally described by Robertson et al. (1999), revealed heterozygous missense mutations in 13 of the patients (see, e.g., 601439.0004, 601439.0005, and 601439.0008-601439.0011). Except for 1 mother-son pair, the mutation was shown to have arisen de novo in all of the patients for whom parental DNA was available.

Associations Pending Confirmation

For discussion of a possible association between Cantu syndrome and variation in the KCNJ8 gene, see 600935.0002 and 600935.0003.