Cantu syndrome, or hypertrichotic osteochondrodysplasia, is a condition characterized by a range of severe and systemic defects in the body.
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It was first described in 1982 and is caused by mutations in two distinctive genes that code for the regulatory or pore-forming subunits of KATP channels in the heart. Only about 50 cases of this rare disorder have been reported the world over. Most have detectable mutations in the ABCC9 or (much rarer) KCNJ8 genes.
These mutations cause gain-of-function in the isoforms of the ATP-sensitive potassium channels called KATP , which are present mainly in heart muscle. This causes regulatory or pore-forming dysfunction of these channels, respectively, depending on the subunit encoded by the affected gene.
Cantu syndrome is transmitted in an autosomal dominant manner, so 50% of the offspring of an affected individual may potentially inherit the disease. Most cases are due to new mutations, however.
Cantu syndrome is characterized by a combination of:
- Generalized hypertrichosis (excessive hair growth) including thick hair over the scalp, and excessive hair over the forehead, back, face and limbs
- History of fetal macrosomia and/or polyhydramnios
- Coarse facial features, such as a broad nose, long philtrum, wide mouth, flaring nostrils, and epicanthal folds
- Macrocephaly, commonly present at birth or developing in childhood
- Patent ductus arteriosus (50%), which may sometimes be extremely large and may need early closure
- Pericardial effusion (20%)
- Skeletal abnormalities (osteochondrodysplasia), such as thickened skull, broad ribs, and scoliosis, which do not usually require treatment except for scoliosis, in some cases
- Lymphedema, which may be present at birth, but typically resolves without treatment
- Abnormal blood vessels, such as tortuous vessels in the retina, or convoluted arteriovenous communications in the lungs at multiple sites, or dilated and tortuous vessels within the central nervous system and systemic circulations, with kcnj8 mutations
- Behavioral problems, such as anxiety, mood fluctuations, or obsessive-compulsive disorder
- Intelligence is typically normal, but may be higher than usual or sometimes mildly subnormal
- Other manifestations, such as pulmonary hypertension, abnormal connective tissue with hyper-extensible joints and loose skin, little subcutaneous fat, gut abnormalities, such as umbilical hernia and upper gastrointestinal bleeds, craniosynostosis or premature fusion of cranial bones, and occasionally stunted growth due to growth hormone deficiency
- Fetuses with Cantu syndrome are at risk for developing macrosomia and polyhydramnios, with their related consequences, such as preterm labor, premature birth and increased operative deliveries.
- There are two other syndromes caused by ABCC9 mutations, namely, acromegaloid facial appearance (AFA) and hypertrichosis with acromegaloid facial features (HAFF).
Diagnosis and management
The diagnosis depends on the clinical symptoms and signs, and is confirmed by genetic testing for a mutation in ABCC9 or KCNJ8. The child must be evaluated for heart, and bone abnormalities other than those, which are obvious at presentation. Brain neuroimaging is required if the patient has persistent headaches or other neurologic symptoms.
Management is based on the symptoms. Hypertrichosis may be treated with depilatory therapies, whether mechanical (shaving) or more sophisticated methods. Heart defects and scoliosis must be treated as early as required. Edema may require compression stockings if persistent or troublesome.
Yearly follow ups are mandatory to monitor the heart size as well as function and other complications. Genetic counseling is offered to the family if one of the above mutations is detected in a proband. Some clinically unaffected parents may have germline or somatic mosaicism and may have thus escaped serious manifestations.