Nonimmune Hydrops and Left-Sided Cardiac Defect: Prenatal Presentation of Kabuki Syndrome

A 26-year-old gravida 5, para 1-0-3-1 woman was referred to our fetal center at 21 weeks and 1 day of gestation for a suspected fetal cardiac defect. Fetal echocardiography revealed findings consistent with unbalanced ventricles (right larger than left), a large atrioventricular septal defect, a small aortic valve diameter, and a small aortic arch with forward flow (Figs 1A–C, Video 1). In addition to the complex cardiac defect, ultrasonographic assessment revealed fetal growth restriction, increased nuchal fold, and elevated umbilical artery Doppler indices. Follow-up ultrasonography at 28 weeks’ gestation revealed new findings of polyhydramnios, ascites (Fig 1D), and pericardial effusion.A 37-year-old primigravida woman was referred to our fetal center at 21 weeks and 1 day of gestation because of concern for dilated bowel loops. Ultrasonographic findings were notable for suspected coarctation of the aorta, ventricular septal defect (VSD), and ventricular disproportion (Fig 2 A and B, Video 2). Follow-up ultrasonography at 24 weeks and 6 days’ gestation revealed bilateral hydronephrosis, large bowel loops, and an abnormal sacral spine (Fig 2 C and D). Fetal magnetic resonance imaging (MRI) performed at 34 weeks and 6 days of gestation was negative for brain, spinal, and diaphragmatic abnormalities, but did reveal ascites, bilateral hydroceles, bilateral hydronephrosis, dilated colon, and lack of visualization of the anus.At first presentation, the pregnant patient was counseled that the combination of right dominant atrioventricular septal defect, small aortic annulus, and small aorta could be considered a variant of hypoplastic left heart syndrome, which may possibly evolve and, hence, require single ventricular repair in the postnatal period. The family consulted with pediatric cardiology, pediatric cardiac surgery, neonatology, and genetics. After discussing with the family, the patient underwent amniocentesis, which revealed a normal female complement on chromosomal microarray. Several weeks later, when the fetus developed findings consistent with hydrops, additional testing with whole exome sequencing (WES) was offered as part of a hydrops research study. Samples were sent for WES, but results were not available until the postnatal period.Given the constellation of ultrasonography and MRI findings, the patient was counseled on the suspicion of VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) or Fanconi anemia. Diagnostic testing was recommended to the pregnant patient. She underwent amniocentesis, which revealed a normal male complement on chromosomal microarray. Fanconi anemia testing through expanded carrier screening was also negative. Despite the normal chromosomal microarray and given the multiple anomalies noted, the patient was offered WES, which she declined.Until 39 weeks’ gestation, the pregnant patient underwent follow-up ultrasonography every 2 weeks, which persistently revealed polyhydramnios, growth restriction, and a complex heart defect. A cesarean delivery was performed at 39 weeks’ gestation in a hybrid operating room because of the complex fetal cardiac defect. The infant was admitted to the intensive care unit after delivery.Postnatal echocardiography confirmed a hypoplastic left heart variant with double outlet right ventricle, large VSD, mitral stenosis/dysplasia, normal-sized aortic valve and aorta, and intact atrial septum. Immediately after birth, the infant underwent attempted balloon atrial septostomy, followed by cannulation for cardiopulmonary bypass, surgical atrial septectomy, patent ductus arteriosus (PDA) ligation, and right arterial line placement.On initial examination, atypical facial features were recognized, including low-set ears, hypertelorism, and lagophthalmos of the right eye. WES results became available on the day of delivery and revealed a heterozygous pathogenic variant in the KMT2D gene c.16360C>T (p.Arg5464Ter), consistent with a diagnosis of Kabuki syndrome (KS), which was consistent with the infant’s facial features. Parental testing was negative, indicating that this was a de novo variant.Throughout her postnatal course, she was noted to be persistently hypoglycemic, and laboratory results were consistent with hyperinsulinism. Immunologic evaluation during admission showed extremely low immunoglobulin (Ig) G levels with normal IgA and IgM levels, warranting repeated intravenous immunoglobulin administration, as needed, based on her IgG levels. She received multiple courses of antibiotics for episodes of bacteremia. Neurologically, she was determined to have hypotonia. In addition to multiple cardiac surgical repairs, she also underwent correction of malrotation by lysis of duodenal bands and reduction of midgut volvulus. She underwent Nissen fundoplication because of the reflux that was responsible for her inability to feed, and she received a gastric tube (G-tube) on which she was dependent for feeding.The patient remained admitted in the intensive care unit for 175 days, after which she was discharged from the hospital with scheduled follow-up with pediatric cardiology, endocrinology, gastroenterology, genetics, immunology, and pulmonology teams, in addition to home-care arrangements.At the time of this writing, the infant is 34 months old and meeting most developmental milestones. She continues to have episodes of hypoglycemia that are identified with continuous glucose monitoring. Her G-tube remains in place to quickly raise her blood glucose levels when needed, though she can feed orally. She also has difficulty mounting proper immune responses to infections and vaccinations; therefore, she remains on biweekly immunoglobulin injections. She otherwise is making remarkable progress with occupational therapy, speech therapy, and physical therapy teams.Prenatal ultrasonographic examinations were performed every 2 weeks, showing progressive development of the previous findings. A cesarean delivery was performed at 34 weeks and 6 days’ gestation because of non-reassuring fetal Dopplers (reverse A wave of the ductus venosus), abdominal ascites, and suspected heart failure.Postnatal evaluation confirmed hypoplastic aortic valve, VSD, sacral spine anomaly, bilateral urinary tract dilation, anal atresia, and imperforate anus. The differential diagnosis still favored the prenatal suspicion for VACTERL association. Pediatric genetics was consulted on the day of birth, expanding the differential diagnosis to include KS and CHARGE syndrome (coloboma, heart disease, atresia of the choanae, growth restriction and mental development, genital anomalies, and ear malformations and hearing loss), in addition to VACTERL association. Chromosomal breakage studies and gene panels for KS and CHARGE syndrome were sent to further evaluate etiology. The KS gene panel testing (KMT2D, KDM6A, CHD7) returned positive for a pathogenic heterozygous mutation in the KMT2D gene c.4843 C>T (p.Arg1615*), consistent with a diagnosis of KS.On examinations during admission, the infant had facial features consistent with KS, including long eyelashes; laterally thinned eyebrows with central notching on the right; eversion of the lower lids of eyes; low-set, posteriorly rotated, and prominent ears; short columella; and a thin upper lip.For his cardiac defect, he underwent end-to-side aortic arch advancement, VSD closure with pericardial patch, and PDA ligation. In addition, during his postnatal course, he received prophylactic antibiotics for grade 4 vesicoureteral reflux without outlet obstruction. He underwent spinal ultrasonography for a sacral dimple that showed concern for a tethered cord. Brain MRI showed a Dandy-Walker malformation. In addition to cardiac surgical repair, he also underwent a colostomy and mucous fistula placement for imperforate anus without complication. He was placed on parenteral feeding by G-tube because of feeding intolerance.The patient remained in the intensive care unit for 83 days, after which he was discharged from the hospital with scheduled follow-up with pediatric cardiology, endocrinology, gastroenterology, genetics, neurology, ophthalmology, immunology, and pulmonology teams, in addition to home-care arrangements.At the time of this writing, the patient is 18 months old and meeting some developmental milestones but still lagging on social-emotional milestones, language/communication milestones, and movement milestones. He is still unable to feed by mouth and requires continuous G-tube feedings. He can mount appropriate immune responses despite low levels of immunoglobulins. He also continues to struggle with hypotonia given his spinal cord tethering but is progressing well with assistance from the occupational therapy, speech therapy, and physical therapy teams.KS (OMIM #147920/#300867) is a rare genetic disorder, which is estimated to occur in 1/32,000 live births, (1) and was first described in 1981. (2) The etiology of this disorder is unknown and is characterized by the following 5 cardinal features (1): Dysmorphic facial features including eversion of the lower lateral eyelid, arched eyebrows, depressed nasal tip, prominent earsSkeletal anomaliesPersistent fingertip padsMild-to-moderate intellectual disabilityPostnatal growth deficiencyWith the advent of WES, causative mutations were found in the KMT2D (3) and KDM6A (4) genes, accounting for ∼75% and 3% to 5% of cases, respectively. (5) Although most of these mutations are de novo variants, some mutations can be inherited in an autosomal dominant (KMT2D) or X-linked dominant (KDM6A) fashion. (5) The current consensus guidelines for diagnosing KS include a pathogenic variant in KMT2D or KDM6A, in addition to the features previously described by Adam et al. (6)Early childhood outcomes in patients with KS are complex and require thorough anticipatory management by multidisciplinary care teams both before and after birth. It is thus crucial to develop early clinical suspicion for KS through prenatal ultrasonography and make use of the availability of genetic testing to confirm the diagnosis. As such, current efforts in diagnosing KS have focused on describing the marked heterogeneity in the prenatal and postnatal phenotypes associated with KS. (7)(8)(9)(10)(11)(12)(13) Some of the prenatal findings include increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios/oligohydramnios, and single umbilical artery. (9) In addition, nonimmune hydrops, while broad and nonspecific, has been suggested as a possible marker of KS. (8)The exact combination of fetal defects that constitutes a legitimate suspicion of KS has yet to be confirmed because several structural abnormalities described in fetuses with KS also overlap with other congenital diseases. In addition, the varied presentation of KS (9)(13) and the inability to recognize the distinctive facial features by prenatal imaging make the prenatal diagnosis difficult.When KS was first described by Niikawa et al, cardiac defects were not included in the “5 cardinal features” of KS, (1) yet cardiac abnormalities were noted to be present in 31% of affected patients. These included single ventricle with a common atrium, VSD, atrial septal defect, tetralogy of Fallot, coarctation of aorta, PDA, aneurysm of aorta, transposition of great vessels, and right bundle branch block. (1) The literature now suggests that cardiac defects are amongst the most common postnatal findings, present in 25% to 93% of patients with KS, (13) with left-sided obstructive lesions being most common. (5) In addition, cardiac defects have been found to be the most common prenatal finding in KS. (9) Furthermore, although polyhydramnios has been documented in cases of KS at a rate of ∼28.9%, (9) there is a growing body of literature that hydrops is also a common prenatal finding, affecting 12% to 20% of cases. (9)(13)Given the important implications for postnatal care and the advancement of prenatal genetic testing technology, we aim to reinforce consideration of genetic testing for KS, especially when faced with nonspecific prenatal findings in the setting of nonimmune hydrops and cardiac defects. As Wigby et al demonstrated in a recent retrospective review of 15 cases of KS diagnosed with whole genome sequencing, a molecular diagnosis was possible before clinical recognition of this rare disorder, enabling earlier diagnosis and change in management in 14 of 15 infants. (13)Although the focus of this report is the prenatal presentation of KS, it is worth briefly mentioning the persistent childhood issues of hyperinsulinemic hypoglycemia (case 1), hypogammaglobulinemia (case 1), and G-tube dependence (cases 1 and 2) in our patients. Similar cases of hypoglycemia have recently emerged in the literature, and different management options with maltodextrin (14) and lanreotide (15) have been described. Our patients were on neither therapy but rather managed with overnight continuous G-tube feedings. In addition, immune deficiencies because of hypogammaglobulinemia have been recognized as a frequent finding in KS, (16)(17)(18) occurring in 44% to 58% of affected individuals. (17) Treatment with prophylactic antibiotics and immunoglobulin substitution have been suggested, and our patient was similarly given maintenance subcutaneous immunoglobulin injections (Hizentra® CSL Behring AG, Bern, Switzerland). Finally, with respect to G-tube dependence, feeding difficulties have been documented in 62% to 100% of patients with KS, (13) with up to 12% requiring G-tubes according to a study. (19)In summary, based on our described cases and in concordance with the aforementioned published literature, we suggest that testing for KS be offered in the setting of cardiac defects, especially left-sided, with nonimmune hydrops. In addition, the varied clinical presentation justifies the importance of evaluating various other features in the fetus, including the kidney, spine, ears, and other facial features. In our cases, left-sided cardiac defects with hydrops were detected at 28 weeks’ gestation and 34 weeks’ gestation in cases 1 and 2, respectively, but confirmatory testing was not available until the postnatal period. Earlier genetic diagnosis would have allowed for earlier counseling, pregnancy decisions, and adequate multidisciplinary anticipatory management, as KS has severe implications on both pre- and postnatal outcomes.We suggest that testing for KS be offered in the setting of cardiac defects, especially left-sided, with nonimmune hydrops.The varied clinical prenatal presentation of KS justifies the importance of evaluating various other features in the fetus, including the kidney, spine, ears, and other facial features.Patients with KS face multiorgan system challenges and developmental delays that require longitudinal multidisciplinary therapeutic care and continuous follow-up.Early genetic diagnosis of KS allows for earlier pregnancy decisions, adequate multidisciplinary anticipatory management, and earlier parental counseling regarding the lifelong effects of KS and the importance of adequate psychosocial support in preparation for the birth and in the early childhood years.