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Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13
  1. P Debeer1,3,
  2. C Bacchelli2,
  3. P J Scambler2,
  4. L De Smet3,
  5. J-P Fryns1,
  6. F R Goodman2
  1. 1Centre for Human Genetics, University of Leuven, Leuven, Belgium
  2. 2Molecular Medicine Unit, Institute of Child Health, London, UK
  3. 3Department of Orthopaedics, University Hospital Pellenberg, Pellenberg, Belgium
  1. Correspondence to:
 Dr F R Goodman, Room 213, Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK;

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Hox genes encode a highly conserved family of transcription factors with fundamental roles in body patterning during embryogenesis.1 Studies in mouse and chick have shown that the 5‘ HoxD and HoxA genes are critical for vertebrate limb and urogenital tract development.2 In humans, mutations in HOXD13 and HOXA13 cause the rare dominantly inherited limb malformation syndromes synpolydactyly (SPD, MIM 186000) and hand-foot-genital syndrome (HFGS, MIM 140000), respectively. SPD is characterised by syndactyly between the third and fourth fingers and between the fourth and fifth toes, with variable digit duplication in the syndactylous web. Most cases result from expansions of a polyalanine tract in the N-terminal region of HOXD133–6 but frameshifting deletions have been identified in three families with an atypical foot phenotype.7,8 HFGS is characterised by short thumbs and halluces, hypospadias in males, Müllerian duct fusion defects in females, and urinary tract malformations in both sexes. Most cases result from nonsense mutations in HOXA13, but two polyalanine tract expansions and one missense mutation have also been described.9–11

Here we report two Belgian families, one with the first missense mutation to be identified in HOXD13 and the other with only the third polyalanine tract expansion to be identified in HOXA13. Remarkably, intermarriage between the two families has resulted in a girl heterozygous for both mutations, the first human HOXD13/HOXA13 double heterozygote to be reported. Her digital abnormalities are strikingly more severe than those in carriers of each individual mutation, suggesting that the two mutations act synergistically.


The proband

The proband (fig 1) was born with severe bilateral hand abnormalities (fig 2A-F). She had complete cutaneous syndactyly between the third and fourth fingers, duplication of the distal and proximal phalanges of the fourth fingers, and a rudimentary extra central metacarpal. In addition, both …

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