Expanding the KMT2D-related Phenotypic Landscape: A Case of Kabuki Syndrome and Hirschsprungs Disease Presenting with Fetal Renal Fusion, Hyperechogenic Bowel, and Polyhydramnios

Dear Editor, Kabuki syndrome (KS) is a rare genetic disorder, characterized by distinctive facial features, delayed development, intellectual disability (ID), postnatal short stature, and a range of congenital abnormalities. Congenital Hirschsprung disease (HD) is characterized by the loss of nerves in partial intestinal tract. We report the case of KS with HD who presented prenatally with renal fusion, hyperechogenic bowel, and polyhydramnios. A 25-year-old primigravida woman had a normal cell-free DNA aneuploidy screen with a 12-week nuchal translucency of 1. 0 mm. At 22 weeks, the ultrasound showed renal fusion occurred at the lower pole of each kidney and hyperechogenic bowel Figure 1a and b. Amniocentesis showed normal cytomegalovirus polymerase chain reaction and chromosomal microarray. A follow-up ultrasound at 32 weeks showed polyhydramnios (amniotic fluid index 260 mm). Oral glucose tolerance test and hemoglobin A1c were both normal. Exome sequencing of the remaining fetal DNA detected a de novo pathogenic variant c. 11475₁1478delACAG (p. Gln3826fs*3) (Chr12: 49033227-49033230 on GRCh38) of KMT2D (NM₀03482. 4) Figure 1c, a variant has previously been reported in KS patients. 1Figure 1: A case of Kabuki syndrome and Hirschsprung’s disease caused by a KMT2D variant. (a) Fetal renal fusion at 22 weeks, showing the fusion of the lower poles of both kidneys in front of the descending aorta, with fused part measuring 3. 6 mm; (b) Echogenic bowel (arrow) at 22 weeks; (c) Schematic diagrams of the variant KMT2D c. 11475₁1478delACAG in the family members showing mutant allele in the fetus and wild allele in the parents; (d) Pathology (H and E) of colon section showed no ganglion cells in the submucosal plexus (left) (×10), compared with a control colon sample containing ganglion cells (arrows) in the plexus (right) (×20). LK: Left kidney; RK: Right kidneyA male infant was delivered at 39 weeks’ gestation, with a birth weight of 3. 0 kg and length of 47. 5 cm. The boy showed downward slanting of palpebral fissures, arched eyebrows, a broad nose with a depressed tip, large ears, excess nuchal skin, and abnormally short fifth digits of feet. Despite a patent anus, meconium was not passed until the 3rd day of life only after an enema. The diagnosis of HD was made after a series of examinations. Total colectomy with ileorectal anastomosis was performed, with pathology confirming aganglionosis Figure 1d. The boy presented with ID and behavioral problems at the follow-up of 24 months old. Congenital anomalies of the kidneys and urinary tract are the known manifestations of KS, such as hydronephrosis, renal agenesis, pelvic kidney, or fusion defects. The renal fusion identified in utero in our case led to the molecular diagnosis of KS. Gastrointestinal involvements are less common in KS patients. 2 The reported malformations include intestinal malrotation, abnormalities of the anus or rectum in the form of anal atresia, anovestibular fistula, and anteriorly placed anus. Our case is the first one with association between KS and HD. HD has also been associated with several syndromes such as trisomy 21, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, Shah-Waardenburg syndrome, and cartilage-hair hypoplasia. 3 However, prenatal diagnosis of HD is challenging. Jakobson-Setton et al. 4 reported 19 patients confirming the histopathological diagnosis of HD at the age of 1 day–15 months. Their prenatal anomaly scans revealed hyperechogenic bowel in three cases, with one complicated by polyhydramnios; none had sonographic evidence of bowel dilatation. The only clue in our case was the hyperechogenic bowel, a marker of chromosomal abnormalities, infections, cystic fibrosis, and bowel abnormalities. 5 Our case report indicates that as a nonspecific marker when cell-free DNA screening is normal, hyperechogenic fetal bowel, especially combined with polyhydramnios, can be associated with a pathologic condition, like HD. In an era of genomic sequencing, this soft marker might warrant HD suspicion even when a genetic syndrome has been diagnosed due to other fetal structural anomalies. Abbreviations DNA Deoxyribonucleic acid H and E Hematoxylin and eosin HD Hirschsprung disease ID Intellectual disability KMT2D Lysine methyltransferase 2d KS Kabuki syndrome LK Left kidney RK Right kidneyEthics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.