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L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung's disease.

Jackson SR, Guner YS, Woo R, Randolph LM, Ford H, Shin CE - Pediatr. Surg. Int. (2009)

Bottom Line: X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis.Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene.A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mailstop #72, Los Angeles, CA 90027, USA.

ABSTRACT
X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis. Exceedingly rare is the concurrence of XLH and Hirschsprung's disease (HSCR) with a theoretical incidence of 1 in 125-250 million cases. Herein, we are describing a case of a patient with concurrent XLH and HSCR. The patient was delivered via cesarean section at 37 weeks gestation and underwent uneventful ventriculoperitoneal shunt placement. As a part of a workup for constipation, we performed a rectal biopsy, which was consistent with HSCR. Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene. A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. The association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Additional studies are necessary to fully elucidate the relationship between XLH and HSCR in the presence of L1CAM mutations.

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Related in: MedlinePlus

Plain radiograph demonstrating multiple, dilated loops of bowel
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Fig1: Plain radiograph demonstrating multiple, dilated loops of bowel

Mentions: With this report, we add to the literature with an additional case report of a patient with XLH and HCSR with an L1CAM mutation [1, 2, 13]. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. Defects in many genes have been implicated in HSCR, including RET proto-oncogene, endothelin receptor b, endothelin-3, SOX-10, and SIP1 [1] and L1CAM mutations alone certainly do not account for HSCR. Even so, the association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Perhaps, L1CAM acting as an X-linked modifier gene somehow allows for the manifestation of additional errors in genes known to be associated with HSCR [14]. While L1CAM mutation in the presence of XLH cannot independently predict HSCR, the multidisciplinary medical and surgical teams should proactively rule out the diagnosis of HSCR in the child with signs of feeding intolerance, vomiting, constipation or abdominal distention. A barium enema can quickly identify the presence of a small colon as well as rectal caliber change. Surgical consultation for suction or open rectal biopsy with acetyl cholinesterase activity level assay should be performed to confirm the diagnosis of HCSR. The goal of staged surgical intervention is to remove the aganglionic bowel segment with anastomosis of normal proximal bowel to rectal tissue just above the anus coupled with a diverting ostomy to allow healing of the fresh suture line. This ostomy is later reversed to re-establish bowel continuity. While it is obvious that additional studies are necessary to fully elucidate the true relationship between XLH and HSCR in the presence of L1CAM mutations, we are compelled to recognize the association in an effort to optimize outcomes in this rare, but all too often fragile patient population (Figs. 1, 2).Fig. 1


L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung's disease.

Jackson SR, Guner YS, Woo R, Randolph LM, Ford H, Shin CE - Pediatr. Surg. Int. (2009)

Plain radiograph demonstrating multiple, dilated loops of bowel
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2734257&req=5

Fig1: Plain radiograph demonstrating multiple, dilated loops of bowel
Mentions: With this report, we add to the literature with an additional case report of a patient with XLH and HCSR with an L1CAM mutation [1, 2, 13]. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. Defects in many genes have been implicated in HSCR, including RET proto-oncogene, endothelin receptor b, endothelin-3, SOX-10, and SIP1 [1] and L1CAM mutations alone certainly do not account for HSCR. Even so, the association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Perhaps, L1CAM acting as an X-linked modifier gene somehow allows for the manifestation of additional errors in genes known to be associated with HSCR [14]. While L1CAM mutation in the presence of XLH cannot independently predict HSCR, the multidisciplinary medical and surgical teams should proactively rule out the diagnosis of HSCR in the child with signs of feeding intolerance, vomiting, constipation or abdominal distention. A barium enema can quickly identify the presence of a small colon as well as rectal caliber change. Surgical consultation for suction or open rectal biopsy with acetyl cholinesterase activity level assay should be performed to confirm the diagnosis of HCSR. The goal of staged surgical intervention is to remove the aganglionic bowel segment with anastomosis of normal proximal bowel to rectal tissue just above the anus coupled with a diverting ostomy to allow healing of the fresh suture line. This ostomy is later reversed to re-establish bowel continuity. While it is obvious that additional studies are necessary to fully elucidate the true relationship between XLH and HSCR in the presence of L1CAM mutations, we are compelled to recognize the association in an effort to optimize outcomes in this rare, but all too often fragile patient population (Figs. 1, 2).Fig. 1

Bottom Line: X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis.Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene.A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mailstop #72, Los Angeles, CA 90027, USA.

ABSTRACT
X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis. Exceedingly rare is the concurrence of XLH and Hirschsprung's disease (HSCR) with a theoretical incidence of 1 in 125-250 million cases. Herein, we are describing a case of a patient with concurrent XLH and HSCR. The patient was delivered via cesarean section at 37 weeks gestation and underwent uneventful ventriculoperitoneal shunt placement. As a part of a workup for constipation, we performed a rectal biopsy, which was consistent with HSCR. Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene. A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. The association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Additional studies are necessary to fully elucidate the relationship between XLH and HSCR in the presence of L1CAM mutations.

Show MeSH
Related in: MedlinePlus