Severe clinical course of Hirschsprung disease in a Mowat-Wilson syndrome patient

Abstract

We present a clinical case of a female infant with multiple anomalies and distinctive facial features, with an exceptionally severe clinical course of Hirschsprung disease. The girl was also diagnosed with Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene. Moreover, molecular karyotyping revealed a deletion involving further genes (KYNU, ARHGAP15, and GTDC1).Mowat-Wilson syndrome (MWS) is a recently delineated syndrome with multiple congenital anomalies and mental retardation (Amiel et al. 2001;Cacheux et al. 2001;Mowat et al. 1998;Wakamatsu et al. 2001;Zweier et al. 2002). MWS is characterized by distinctive facial features, short stature, and structural anomalies, including Hirschsprung disease (HD), genitourinary anomalies, congenital heart defects, agenesis or hypogenesis of the corpus callosum, and eye defects, as well as moderate to severe intellectual disability and severe speech impairment. We present a young female with a clinical diagnosis of MWS, confirmed by molecular analysis, presenting a severe course of HD.The proband was born to a G2,P1 healthy mother at 36 weeks of gestation. The parameters at birth were: weight 2600 g, length 52 cm, OFC 31 cm. Heart murmur, delayed meconium passage, and enterocolitis, were diagnosed after birth. Echocardiography showed a Fallot tetralogy. Radiographic barium enema studies suggested HD, which was confirmed by immunohistochemistry.During the operative procedure a short segment of aganglionosis was found and sigmoid colostomy was created. The postoperative course was complicated by multiple eventrations and severe sepsis. At the age of 18 months, the Duhamel procedure was planned. However, during the operation the Swenson procedure was performed, because of severe adhesions and difficult tissue preparation. The course of the disease was complicated again by leakage at the level of colorectal anastomosis, which required temporal protective ileostomy. Two days later the girl was reoperated because of severe haemorrhage from the rectum and through the peritoneal drain, but the source of bleeding was not found and she developed a sepsis. Ten days later ileal mechanical obstruction occurred. The ileostomy was closed 2 months later. The subsequent course was complicated by an incisional hernia. No congenital and acquired immunological defects were detected. However, hepatic cell lesion and a-1 antitrypsin deficiency (ATD) were revealed. The microscopic evaluation Abstract. We present a clinical case of a female infant with multiple anomalies and distinctive facial features, with an exceptionally severe clinical course of Hirschsprung disease. The girl was also diagnosed with Mowat-Wilson syndrome, confirmed by molecular analysis as a heterozygous deletion of the ZEB2 gene. Moreover, molecular karyotyping revealed a deletion involving further genes (KYNU, ARHGAP15, and GTDC1).

Severe intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report

“…This deletion segment overlaps with our case in an ~ 1.2 Mb [143,468,147–144,750,000] comprising KYNU, ARHGAP15 and GTDC1 (Table 1). The authors speculate that those genes could play a crucial role in the process of tissue regeneration [19]. While many candidate genes have been studied to investigate their role in birth defects such as omphalocele and hypospadias/cryptorchidism [23-25], the clinical observations in our patient suggests the assignment of such malformations to the genes in the region 2q22.2–2q22.3.…”

“…A child with MWS presenting with delayed psychomotor development, hypotonia, a variety of dysmorphic features, genitourinary anomalies and a severe course of HD has been described with a deletion at 2q22.2 to 2q22.3 [143,468,147–147,106,860] [19]. This 3.6 Mb aberration included ZEB2 and three other genes not currently associated with disease- KYNU, ARHGAP15 and GTDC1 -all encoding for proteins involved in ubiquitous and non-specific pathways [20-22].…”

“…It has previously been mentioned as possibly participating in a three-gene interaction influencing hypospadia, cryptorchidism and/or omphalocele [19]. However, a polymorphism in KYNU has also been linked to essential hypertension in a group of Han Chinese [26].…”

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

“…ArhGAP15 is a Rac-specific GAP that negatively regulates Rac1/3 activity 17 , 18 . In human, loss of ArhGAP15 has been associated to cognitive disorders, in the Mowat-Wilson disease, characterized by severe neurological and cognitive deficits, severe ID and speech impairment, and in most cases epilepsy 19 – 22 . In the most severe variants of the Mowat-Wilson syndrome, the loss of ArhGAP15 accompanies the deletion of Zeb2 , the known disease gene.…”

Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons and causes cognitive deficits

“…Thus, in human, both hyper- and hypo-activation of Rho-GTPases, due to mutations of regulatory proteins, are directly linked to ID via altered synaptic networks and plasticity 21 . Loss of ArhGAP15 has been documented in a rare variant of the Mowat-Wilson disease, characterized by severe neurological deficits, severe ID, speech impairment and autism 32 33 . The loss of ArhGAP15 accompanies the loss of the recognized disease gene Zeb2 34 , nonetheless it might contribute to the severity of these conditions or, alternatively, ArhGAP15 could act as a modifier gene.…”