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A novel mutation in the endothelin B receptor gene in a patient with Shah-Waardenburg syndrome and Down syndrome

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Editor—A case of Down syndrome, total gut Hirschsprung disease (HSCR), and segmental hypopigmentation is described in a neonate presenting with bowel obstruction. In addition to having trisomy 21, this patient was homozygous for a novel mutation in the endothelin B receptor (EDNRB) gene.

A term female infant with karyotype 47,XX,+21 presented on day 3 of life with bowel obstruction. She was of Somali origin and had large areas of segmental hypopigmentation affecting the left side of the face and trunk, the left upper limb, including the hair follicles, and had white scalp hair. At laparotomy she had an annular pancreas, duodenal web, and inspissated meconium in the ileum and colon, for which she underwent a duodenoduodenostomy. Histology of the rectal biopsy and appendix was inconclusive at this stage. Intestinal obstruction persisted and on day 20 she underwent a further laparotomy, which showed breakdown of the original anastomosis. Intraoperative frozen sections showed complete aganglionosis throughout the entire large and small bowel, sparing only the stomach and oesophagus; this is incompatible with life. An ileostomy was fashioned, intensive care was withdrawn, and the baby died the following morning. Necropsy confirmed total bowel aganglionosis. Her parents are not known to be consanguineous and there is no history of pigmentary disturbance or bowel disease in either them or her five sibs. Family genetic studies and clinical photographs were declined; a hearing assessment was precluded by her being ventilated and sedated for the duration of her life.

Shah-Waardenburg syndrome describes the association of HSCR with Waardenburg syndrome, and consists of deafness, pigmentary disturbance, and aganglionic megacolon. It is the result of defective development of two neural crest derived cell lineages: epidermal melanocytes and enterocytes.

A number of susceptibility genes for HSCR alone have been identified from the 5% of HSCR cases in whom there is an associated chromosomal or hereditary disorder and from HSCR affected kindreds.1Susceptibility to Shah-Waardenburg syndrome is conferred by mutations in three genes, the endothelin B receptor (EDNRB) gene at 13q22, its ligand the endothelin-3 gene (EDN3) at 20q13.2-13.3,2 and in the SOX10gene at 22q13.3

All exons of the EDNRB gene were amplified by polymerase chain reaction (PCR), and PCR products were sequenced using standard methods on a ABI PRISM 377 DNA sequencer.2 4 This infant appeared to be homozygous for a novel missense mutation in exon 2 (codon 186, GGA-AGA) of theEDNRB gene, a mutation that leads to the substitution of glycine with arginine (fig 1). As the family declined further genetic studies, it is not possible to rule out hemizygosity or disomy in this patient.

Figure 1

Sequence analysis showing nucleotides corresponding to codon 186 of the EDNRB gene. A DNA sample from the infant was used as a template in a PCR reaction in order to amplify exon 2 of the EDNRB gene. The resulting product was subsequently sequenced using standard methods. The electropherogram shows the presence of the Gly/Arg mutation at codon 186. The mutated nucleotide at codon 186 (A*GA) is marked with (*) to distinguish it from the wild type sequence (GGA).

The EDNRB gene codes for a G protein coupled transmembrane receptor protein which is necessary for the development of enteric neurones and epidermal melanocytes. The receptor ligand is endothelin-3, and mutations in this axis in both rodent models and humans result in a phenotypic spectrum comprising HSCR and pigmentary abnormalities.5 6 The Gly186Arg mutation is located in the third transmembrane domain of the endothelin-B receptor and disrupts receptor function, suggested by the finding that several other mutations in the transmembrane domains of the protein are known to cause a phenotype of aganglionosis and hypopigmentation; the human manifestations are the spectrum of Shah-Waardenburg phenotypes.7 The exact position of the mutation in the homozygous state is likely to produce the pleiotropic features observed in these patients.

There are case reports of patients with Down syndrome in association with both HSCR and/or Shah-Waardenburg determining genes.8 9 However, this patient had the coexistence of Down syndrome and a novel homozygous mutation of theEDNRB gene. This case emphasises that although HSCR has a well recognised association with Down syndrome, other causes of HSCR should be considered. Mutation analysis of known susceptibility genes might be helpful in cases of long segment HSCR, especially in those patients with pigmentary abnormalities and those with a positive family history of bowel dysfunction.


Standing Committee on Human Cytogenetic Nomenclature 2001-2006

Elections for the Standing Committee on Human Cytogenetic Nomenclature were held at the 10th International Congress of Human Genetics in Vienna, Austria, on 16 June 2001. The following members were elected for the period 2001-2006: Niels Tommerup (Denmark) (Chairman), Lynda Campbell (Australia), Christine Harrison (UK), David Ledbetter (USA), Albert Schinzel (Switzerland), Lisa Shaffer (USA), Angela Vianna-Morgante (Brazil). Issues regarding human cytogenetic nomenclature can be addressed to any member of the Committee.