Cardiac Defects in Patients with Kabuki Syndrome

heart normalKabuki syndrome, also known as Kabuki make-up syndrome and Niikawa-Kuroki syndrome, was initially described in 1981 by Niikawa and Kuroki [8]. Most patients have five cardinali features: distinct facial features, postnatal growth retardation, developmental delay or mental retardation, skeletal abnormalities and dermatoglyphic abnormalities which are referred to as a persistence of fetal fingerpads. At present, the diagnosis is made clinically. A prior review by the original investigators Niikawa and Kuroki reported a population of 62 patients with Kabuki syndrome and associated cardiac defects in up to 31% of patients [8]. Since then, there has been a series reported with 35 patients with an incidence of associated congenitali heart disease as high as 58% [3]. Overall, associated cardiac defects have been well documented [4,6,7,9,11].

As a brief review of the anatomy of the heart and circulation, the heart consists of four chambers (Figure 1). There are two right sided chambers which receive the blood from the body after it has delivered the oxygen to the tissues and then pumps it to the lungs to receive more oxygen. Then the blood with oxygen returns to the left sided chambers to be pumped to the body to deliver the oxygen to the tissues again. In a fetus, there is a communication between the right and left upper chambers and it usually closes after birth. Otherwise in a normal heart, there is no communication between the right and left sides. A fetus also has an extra blood vessel called a patenti ductus arteriosusi (PDA) that it uses in the womb to divert blood away from the lungs since it is not breathing and this vessel also usually closes after birth.

heart asdThe majority of the cardiac defects have been what are called ‘shunt lesions’, such as atrial and ventricular septal defects and patent ductus arteriosus, also known as ASD, VSD and PDA respectively [13] (Figures 2 ,3 and 4). VSDs and PDA can be detected by listening to the patient’s heart and hearing a certain type of murmur. The finding is confirmed by performing and ultrasound of the heart, also known as an echocardiogram. These are called shunt lesions because there is a communication between right and left sides of the heart and allows extra’ shunting’ of blood flow to the lungs. This results in excess blood flow to the lungs and depending on how much there is, may result in extra fluid in the lungs and dilation of the heart. These lesions, if they occur in isolation, are treatable either by cardiac catheterization device closure or with more traditional surgical closure. Device closure involves placing a catheter in the patient’s leg and using that catheter to enter the heart and place a device to close the hole for an ASD or to close off an open blood vessel in the case of a PDA. Surgery involves an incision on the chest and placement on a cardiac bypass machine for the surgery.

heart vsdThey have also been finding problems with the left sided heart structures in up to 29% of cases. One specific lesion that is found is called Coarctationi of the aortai (CoA) and is a narrowing of the aorta, or the large vessel that exits the heart to deliver blood to the body (Figure 5). This can result in diminished blood flow to the body and stress on the heart. This can be detected clinically if the patient has poor pulses or lower blood pressures in the lower body as compared to the upper body. This can also be diagnosed by echocardiographyi. Depending on the patient’s age and severity of the narrowing, this can be addressed either by a balloon or stent in the catheterization lab or, if needed, by surgical widening of the narrowed area. The balloon or stent procedure consists of introducing a catheter from the blood vessel in the patient’s leg to the area of narrowing and then inflating a balloon to dilate the narrowed area or using the balloon to place a stent to open up the narrowed area. The balloon and catheter are then removed. Surgical correction requires an incision in the chest and placement on cardiac bypass for the surgery. Coarctation of the aorta is also a common finding in patients with Turner’s syndrome leading some to hypothesize an overlap between Kabuki syndrome and Turner syndromei [1,5].

heart pdaThere are also more severe types of heart defects that can be found in patients with Kabuki syndrome including Tetralogy of Falloti (TOF) and Transposition of the Great Arteries (TGA). The most significant type of defect is referred to as a ‘single ventriclei physiology’ meaning that there is only one functioning ventricle instead of two. We did a case report of such a finding in three patients specifically with what is called Hypoplastic Left Heart Syndrome (HLHS) where the left side of the heart is significantly smaller and cannot function properly [14]. These patients cannot simply have a hole closed or a narrowing made bigger, they need multiple surgeries to eventually separate out the unoxygenated blood from the oxygenated blood. Fortunately, this finding is very rare, as only 5 such cases have been reported in the literature.

These are all considered congenital heart defects and occur when there is a problem with how the heart is formed very early on at about 6-8 weeks gestational age. Most of these defects can even be detected pre-natally by a specialized ultrasound focusing on the baby’s heart called a fetal echocardiogram after 20 weeks gestation age. Some lesions such as an ASD, PDA and CoA are harder to see pre-natally but can be diagnosed after the baby is born by ultrasound as well. Once the heart has finished forming, it is unlikely that further defect will occur. After the baby is born, another echocardiogram is performed to confirm any abnormal finding on the fetal echocardiogram. Since these are abnormalities of formation of the heart, no further defects should occur. How the baby does will depend on the specific cardiac defect and how they respond to any intervention that may be needed.

heart coarctationThe main difficulty with Kabuki syndrome is that it can be hard to diagnose as an infant whereas most of these cardiac defects are diagnosed either pre-natally or within the first month or so of life, often in the neonatal period. In fact, the features typical of Kabuki syndrome may be under-recognized and underappreciated in the neonatal period, only to become more pronounced with time and patient growth [12]. The cardiac disease often occurs before the diagnosis of the syndrome, thus we also propose that patients with left-sided heart defects, including HLHS, who have normal chromosomes, developmental delay and growth failure may benefit from periodic genetic evaluations during the first few years of life to assess for Kabuki syndrome and to assist parents in counseling and prognosis.






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