Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.
The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.
Killoran
C E
CE
Genetic Disease Research Branch, NHGRI/National Institutes of Health, Bethesda, MD 20892, USA.
Abbott
M
M
McKusick
V A
VA
Biesecker
L G
LG
D000015:Abnormalities, Multiple / Q000235:genetics*; D001006:Anus, Imperforate / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D017689:Polydactyly / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013131:Spine / Q000002:abnormalities*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3
D004268:DNA-Binding Proteins; C108003:GLI3 protein, Xenopus; C065683:GLI3 protein, human; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D000074290:Zinc Finger Protein Gli3; D004247:DNA