Content area
Full Text
In 1998, Mowat et al 1 described six patients with a mental retardation syndrome recognised by its characteristic facial appearance in association with Hirschsprung disease (HSCR). One of their patients had a cytogenetic deletion of 2q22-23 and they noted a previously published patient with a 2q22 deletion and similar clinical features. Based on this they proposed that this syndrome was either caused by microdeletion in chromosome 2q22-2q23 or a de novo mutation of a gene within this region. In 2001, the cause of this syndrome was found to be deletions or intragenic mutations of the ZFHX1B gene. 2, 3 To date, 45 microdeletion/mutation positive cases have been reported. 2- 10 Several other clinical reports published before the ZFHX1B gene discovery describe patients with syndromic HSCR who probably also have this syndrome. 11, 12 All mutation positive cases show a similar facial appearance to the original patients. 1- 12 Although most patients were ascertained on the basis of HSCR, several series have now reported mutations in patients without HSCR. 4, 6, 8, 10 Recognition of the characteristic facies with or without Hirschsprung disease (HSCR) has important implications for genetic counselling. All reported cases of this syndrome have been sporadic, resulting from de novo deletion or heterozygous mutation of the ZFHX1B gene. It is important to distinguish this syndrome from the Goldberg-Shprintzen syndrome, 16 which has some clinical overlap but may have an autosomal recessive basis. Although the molecular basis of Goldberg-Shprintzen syndrome has not yet been established, characterisation of the ZFHX1B gene suggests clinical and genetic heterogeneity for the phenotypes of HSCR associated with mental retardation and microcephaly.
CLINICAL FEATURES (TABLE 1)
Table 1 Clinical features in patients with deletion or mutation of the ZFHX1B gene
Our series (n=21) | Lurie et al 9 (n=1) | Amiel et al 5 (n=8) | Yamada et al 6 (n=10) | Zweier et al 4 (n=4) | Garavelli et al 7 (n=1) | Frequency (n=45) |
|
Male/female | 15/6 | M | 3/5 | 7/3 | 4/0 | M | 31/14 |
Typical face (photograph seen) | 21/21 | 1/1 | 5/5 | 5/5 | 3/3 | 1/1 | 100% |
Moderate to severe MR | 21 | 1/1 | 8/8 | 10/10 | 4/4 | 1/1 | 100% |
Seizures/abn EEG | 15/3 | 1/1 | 6/7 | 8/10 | 3/4 | 1/1 | 90% |
Microcephaly (<3rd centile) | 16/20 | 1/1 | 7/7 | 10/10 | 2/4 | 0/1 | 84% |
HSCR proven | 13/21 | 1/1 | 7/8 | 4/10 | 2/4 | 1/1 |
|
Abnormal male genitalia |