A Rare Co-occurrence of Intestinal Malrotation and Hirschsprung's Disease in a Neonate with 13q21.31q33.1 Interstitial Deletion Including the EDNRB Gene

Abstract

We report a rare co-occurrence of intestinal malrotation and Hirschsprung's disease (HSCR) in a male neonate with a large 38.8 Mb interstitial deletion of chromosome 13 extending from q21.31 to q33.1 including the EDNRB gene, who presented with craniofacial dysmorphic features and central nervous system malformations. The loss of EDNRB gene in addition to bilateral hearing loss and HSCR suggested an additional diagnosis of Waardenburg–Shah's syndrome. This case highlights the fact that prior knowledge of this rare association in infants with 13q deletion syndrome would enable early diagnosis and prompt interventions to prevent gastrointestinal complications.

Introduction

Even though the majority of Hirschsprung's disease (HSCR) occurs as an isolated entity, approximately up to 30% of cases of HSCR occur either in association with a genetic syndrome or with congenital anomalies of other organ systems. ¹ The occurrence of HSCR in association with distal 13q deletion, a characteristic dysmorphic syndrome, is well known. ^{2 3} Abnormalities in the genetic signaling mechanisms leading to the development of HSCR in infants with 13q deletion syndrome involving 13q22 locus have been elucidated. ^{4 5} In such deletions, haploinsufficiency of endothelin-B receptor ( EDNRB ) gene located at 13q22 leads to a defect in the formation of myenteric ganglion cells resulting in HSCR. ⁵ An association of HSCR with small intestinal malrotation has also been reported previously. ⁶ However, to the best of our knowledge, a co-occurrence of HSCR and small intestinal malrotation in association with partial deletion of 13q chromosome has been described in only two infants previously. ^{3 7} We report an additional case with a large interstitial deletion of chromosome 13q involving the EDNRB gene, who presented with a combined anomaly of small intestinal malrotation and HSCR. Our patient also presented with bilateral hearing loss, suggesting the additional diagnosis of Waardenburg's syndrome, type 4A (WS4A, Waardenburg–Shah's syndrome).

Case Description

A Caucasian male infant was born at 36 weeks of gestation at an outside hospital facility to a 35-year-old mother with an antenatal period that was complicated by poor prenatal care and maternal use of nonprescription methamphetamine. No maternal or paternal family histories of genetic and inherited metabolic disorders were disclosed. Following delivery, the infant required minimal neonatal resuscitative measures, including 1 minute of bag and mask ventilation. After stabilization, he developed moderate to severe respiratory distress, and he was transferred to the neonatal intensive care unit (NICU) on noninvasive respiratory support.

On arrival to the NICU, the patient was noted to have a significant craniofacial dysmorphism which included dysplastic and low set ears, a flattened and broad nasal bridge, hypertelorism, a broad forehead, a large anterior fontanel, mild bilateral ptosis, and bilateral wide sandal gaps. Further evaluation revealed appendicular and axial hypotonia, the presence of a Dandy–Walker variant malformation with mild ventriculomegaly but without hydrocephalus, hypoplasia of corpus callosum ( Fig. 1 ), and bilateral hearing loss as revealed by auditory brain stem response testing (tested twice). A GTG banding karyotype on peripheral blood at a band resolution of 525 showed a male genotype with an interstitial deletion of 13q, extending from q21.2 to q32.3 [46,XY,del(13)(q21.2q32.3)]. A chromosomal microarray analysis (CMA) confirmed the presence of a large interstitial deletion of the 13q21.31-q33.1 chromosomal region. International System for Human Cytogenetic Nomenclature (ISCN): arr[hg19] 13q21.31q33.1(64,825,656–103,641,349)x1. The deletion spans 38.8 Mb encompassing at least 122 genes including the EDNRB gene ( Fig. 2 ). Parental cytogenetic studies could not be completed.

Fig. 1.

Sagittal T1-weighted magnetic resonance images (MRIs) of the index case with 13q21.31q33.1 deletion depicting brain anomalies: ( A ) sagittal T1-weighted MRI showing hypoplasia of cerebellar vermis (white solid arrow) and mildly enlarged fourth ventricle with prominent posterior fossa cerebrospinal fluid space (empty white arrow); ( B ) sagittal T1-weighted MRI showing hypoplasia of corpus callosum (white solid arrow) and mildly enlarged lateral ventricles (empty white arrow).

Fig. 2.

Ideogram of chromosome 13 depicting the deleted region of the long arm of chromosome 13 extending from q21.31 to q33.1. All 122 genes that are deleted are also shown in the box. The major genes have been highlighted in bold letters.

The infant successfully passed meconium within the first 48 hours of life. However, when enteral feedings were initiated and advanced conservatively, he developed recurrent episodes of mild feeding intolerances, which precluded the attainment of full enteral autonomy. On the 11th postnatal day, the infant developed abdominal distension with nonbilious emesis. A plain abdominal radiographic evaluation revealed a nonspecific, mild gaseous distension of bowel loops. Contrast-enhanced upper gastrointestinal radiographic series revealed the presence of small intestinal malrotation with no volvulus ( Fig. 3 ). Ladd's procedure was performed without any serious complications. However, following a full surgical recovery, the patient continued to have persistent problems with tolerance to enteral feeding advancement with episodic abdominal distension and constipation needing rectal administrations of glycerin suppositories. Following several failed attempts to achieve advancement in enteral feeding, a contrast-enhanced lower gastrointestinal radiographic series revealed the presence of markedly reduced rectosigmoid ratio, raising the suspicion of HSCR ( Fig. 4 ). A rectal mucosal suction biopsy was inconclusive. Subsequently, rectal mucosal slit biopsy was performed and revealed the absence of ganglion cells with hypertrophy of neurons, confirming the histopathological diagnosis of HSCR. Feeding tolerance improved when treatment with rectal irrigations was initiated while waiting for the definitive treatment with single-stage surgical repair at a later postnatal age. Despite the optimization of enteral nutrition, the infant developed a severe postnatal growth restriction.

Fig. 3.

Contrast-enhanced fluoroscopic and radiographic images of upper gastrointestinal tract showing small intestinal malrotation in the index case: ( A ) fluoroscopic image depicting the ligament of Treitz at right of midline (black arrow); ( B ) radiographic image depicting the presence of proximal loops of small intestine occupying the upper right quadrant (black arrow).

Fig. 4.

Fluoroscopic image of water-soluble contrast enema showing dilated sigmoid colon and small rectum with reversal of rectosigmoid ratio which is suggestive of Hirschsprung's disease in the index case.

Discussion

Partial 13q monosomy or deletion syndrome was first described in 1963 ⁸ and is characterized by an interstitial or terminal deletion of 13q of various sizes leading to congenital anomalies with a variable degree of severity. Phenotypical manifestations and long-term prognosis among infants with partial 13q deletion syndrome varied depending on the length of the deletion and based on the presence or absence of 13q32 gene locus in the deleted segment. ⁹ The occurrence of partial 13q deletion syndrome is usually sporadic. However, a parental chromosomal translocation involving the 13q chromosomal region is found in 10% of cases. ¹⁰

Common gastrointestinal anomalies reported in partial 13q deletion syndrome include anorectal malformation, jejunal atresia, and HSCR. ^{3 7 8} Mechanism of the development of HSCR in association with partial 13q deletion syndrome has been well established. ^{2 4 5} The EDNRB gene located at 13q22 is deleted in partial 13q deletion syndrome and leads to abnormal development of the enteric nervous system, an underlying mechanism for the development of HSCR. ^{2 5} Our patient also presented with an unusual co-occurrence of intestinal malrotation and HSCR. This rare association has already been reported ( Table 1 ). ^{3 7} Lamont et al ³ reported the co-occurrence of HSCR with small intestinal malrotation in a neonate with interstitial deletion of a distal segment of chromosome 13q. Similar to the index case, the deleted region included a large segment of chromosome 13q involving the genomic region 13q21.2-q32.3. In addition, Shanske et al ⁷ have described a female infant with 13q14.3q22.2 deletion who was diagnosed and treated for HSCR during the neonatal period. Just like in our case, this infant had persistent gastrointestinal obstructive symptoms for which she underwent exploratory laparotomy. Small intestinal malrotation was diagnosed and repaired during the exploratory laparotomy. Hence, our case is the third case reporting this rare co-occurrence. The review of the deleted segments of 13q in all three cases suggests that the rare co-occurrence of small intestinal malrotation and HSCR can be associated with deletion of a narrow segment of 13q21.31–13q22.2, the segment which was common for all the three cases of 13q deletions ( Table 1 ).

Table 1. A rare co-occurrence of Hirschsprung's disease and intestinal malrotation in children with 13q deletions: genotype and phenotype aspects of two previously reported patients and our case.

Authors/reference	Lamont et al 3	Shanske et al 7	Current case
Deleted segment of 13q	q21.2-q32.3	q14.3-q22.2	q21.31-q33.1
Postnatal age at diagnosis of Hirschsprung's disease	First wk	Fourth wk	1 mo
Postnatal age at diagnosis of small intestinal malrotation	First wk	9 mo	Second wk
Craniofacial dysmorphism	Hypertelorism, prominent forehead, broad nasal bridge, ear anomalies	Hypertelorism, depressed nasal bridge, ear anomalies, dolichocephaly, large anterior fontanelle, mild proptosis	Hypertelorism, depressed nasal bridge, ear anomalies, large anterior fontanelle, mild bilateral ptosis
Brain malformations	Not reported	Not reported	Dandy–Walker malformation, hypoplasia of corpus callosum, cerebellar vermis hypoplasia
Hypotonia	Present	Present	Present
Hearing loss	Not reported	Present	Present
Postnatal growth restriction	Present	Present	Present

Mutations in the EDNRB gene or a deletion of the EDNRB gene are known to cause WS4A. This is a condition characterized by hypopigmentation of hair, skin (piebaldism), and irides, as well as sensorineural hearing loss, and HSCR. Even though rare, patients with 13q deletions involving the EDNRB gene and presenting with variable features of WS4A have been reported. Tüysüz et al ¹¹ reported three unrelated patients with variable features of WS4A associated with heterozygous 13q deletions involving the EDNRB gene. Two of these patients had deletions of chromosome 13q22.1-q31.3, one child manifesting with heterochromia iridis and HSCR, and the other with a mild unilateral hearing loss. In addition, they presented with short stature, dysmorphic features, and intellectual disabilities, common clinical features in patients with 13q microdeletions. Córdova-Fletes et al ¹² reported a female child with 13q21.32q31.2 deletion involving EDNRB gene who presented with cutaneous and iris pigmentary abnormalities but without hearing loss and HSCR. Matute et al ¹³ reported a similar mid-13q deletion syndrome involving EDNRB gene in a young adult with intellectual disability and heterochromia iridis along with bilateral deafness but without HSCR. Both the patients reported by Córdova-Fletes et al and Matute et al did not qualify to be diagnosed as WS4A as they did not have HSCR.

Lance et al ⁹ and Brown et al ¹⁴ have described three groups with distinctive genotypes and a wide range of phenotypic features in patients with 13q deletion syndromes. Our index case could be classified into group 2 as the deleted region included a large segment of 13q chromosome involving the critical region of 13q32. Phenotypically, our patient exhibited group 2 (brain malformations, gastrointestinal anomalies, and craniofacial dysmorphism) features predominantly as well as some overlapping group 3 (postnatal growth restriction) features. As phenotypic features evolve with time, a close follow-up is required to achieve a better genotype–phenotype correlation in our index case.

Several brain anomalies, including Dandy–Walker malformation, cerebellar vermis hypoplasia, and hypoplasia of corpus callosum were present in the index case. ZIC2 and ZIC5 genes are the possible candidate genes for the normal development of dorsal midbrain as suggested by the findings of the studies in zebrafish. ¹⁵ In a clinical context, in a case series of 14 children with variable length 13 q deletions, Ballarati et al ¹⁶ associated the development of Dandy–Walker malformation to the deletion of a narrow segment of 13q32.2–33.2. Mademont-Soler et al ¹⁷ were able to narrow further down the critical region associated with the development of Dandy–Walker malformation to 13q32.2–32.3, wherein the two candidate genes ZIC2 and ZIC5 are located. Hence, we speculate that in the index, case deletions of ZIC2 and ZIC5 ( Fig. 2 ) genes might have contributed to the development of Dandy–Walker malformation. Furthermore, heterozygous loss of ZIC2 gene in 13q deletion syndrome has also been implicated in the pathogenesis of holoprosencephaly. ¹⁸ Moreover, Mimaki et al ¹⁹ reported a rare association of holoprosencephaly and Dandy–Walker malformation in a neonate with 13q31.3q34 deletion with heterozygous loss of ZIC2 and ZIC5 genes. On the contrary, similar to the index case, Ballarati et al ¹⁶ reported three patients with 13q deletions involving the loci of ZIC2 and ZIC5 genes with only Dandy–Walker malformations without the development of holoprosencephaly.

In summary, our index case demonstrates the importance of a cytogenetic (karyotype) and molecular cytogenetic (CMA) evaluation in infants with HSCR with associated anomalies and dysmorphic features. Second, this report further reveals that EDNRB gene deletion causes variable manifestations of WS4A suggesting the need for continued developmental and hearing screening in affected children. Finally, as feeding intolerance in 13q partial deletion syndrome is common owing to gastroesophageal reflux and intestinal dysmotility, having prior knowledge of co-occurrence of HSCR and small intestinal malrotation in neonates with chromosome 13q partial deletion syndrome will promote early targeted investigation and prompt diagnosis so as to prevent the complications of late diagnosis.

Funding Statement

Funding None.