Browsing by Author "Mortier, G."

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FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly
(British Medical Association, 2013) Simonis, N.; Migeotte, I.; Lambert, N.; Perazzolo, C.; de Silva, D.C.; Dimitrov, B.; Heinrichs, C.; Janssens, S.; Kerr, B.; Mortier, G.; Van Vliet, G.; Lepage, P.; Casimir, G.; Abramowicz, M.; Smits, G.; Vilain, C.
BACKGROUND: Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE andectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly. METHODS: We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome. RESULTS: We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies. CONCLUSIONS: Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmannsyndrome with or without additional features, to Hartsfield syndrome at its most severe end.
Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review
(Wiley-Blackwell, 2009) Vilain, C.; Mortier, G.; Van, G. V.; Dubourg, C.; Heinrichs, C.; de Silva, D.; Verloes, C. B.
We report on five male subjects with a triad of signs compatible with Hartsfield syndrome: ectrodactyly, holoprosencephaly, and mental retardation. Only six patients with this distinctive association have been reported over the past 20 years, all of them being males. Of the patients described here, some have unreported findings such as vermian hypoplasia in one and prolonged survival into adulthood in two. Two patients developed central diabetes insipidus. All were mentally retarded. No abnormalities were found at the cytogenetic level, including array CGH in two. No known genes for holoprosencephaly or ectrodactyly were found, including GLI2. The cause of Hartsfield syndrome is unknown. An X-linked defect is possible, although no recurrences have been described to date. Our observations almost double the number of cases. They underscore the usefulness of fetal brain imaging in the differential diagnosis of syndromal clefting diagnosed in utero, particularly when ectrodactyly-ectodermal dysplasia-clefting syndrome is suspected.