ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2014) 36 P71 | DOI: 10.1530/endoabs.36.P71

A novel de novo heterozygous mutation in FGFR1 is associated with Hartsfield syndrome

Rathi Prasad1, Carole Brewer2 & Christine P Burren1

1Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, UK; 2Clinical Genetics Department, Royal Devon and Exeter Hospital, Exeter, UK.

Introduction: Hartsfield syndrome (#OMIM 615465) describes the rare co-occurrence of holoprosencephaly with ectrodactyly, associated with a spectrum of developmental defects including specific pituitary dysfunction.

Case report: Our patient, a male infant, had several congenital abnormalities: bilateral cleft lip and palate, right sided microtia, bilateral ectrodactyly of the hands and feet and semilobar holoprosencephaly. Aged 5 weeks he was noted to be hypernatraemic and paired serum/urine osmolalities (301 mOsmol/kg, 75 mOsmol/kg respectively) were indicative of cranial diabetes insipidus, with good response to DDAVP. He had microphallus and inguinoscrotal testes, with a poor response to LHRH stimulation (peak LH 0.7 IU/l, FSH 0.9 IU/l). His pituitary function was otherwise normal. His clinical features are consistent with Hartsfield syndrome. Novel homozygous/heterozygous mutations in FGFR1 have recently been associated with the condition in eight patients. Interestingly FGFR1 mutations have also been associated with Kallman’s syndrome, in which gonadotrophin deficiency is also a feature. FGFR1 encodes fibroblast growth factor (FGF) receptor 1. FGFs play a crucial role during embryonic development with downstream effects on cell motility, cell survival and cell mitosis. Fgfr1 deficiency in mice is reported to lead to olfactory bulb absence, failure of midline axonal migration, and a variety of limb defects. Direct Sanger sequencing of FGFR1 in our patient reveals a novel, de novo heterozygous missense mutation, c.1883A>G; p.Asn628Ser. Another heterozygous missense mutation at this site has previously been reported in association with the syndrome. The p.Asn628Ser mutation affects an amino acid residue located in the ATP binding pocket of the intracellular tyrosine kinase domain, with potential effect on FGFR1 kinase activity.

Conclusions: Identification of this novel mutation in FGFR1 in our patient provides further compelling evidence of the association of FGFR1 mutations with Hartsfield syndrome. This has informed genetic counselling and allowed for targeted surveillance of pituitary function in our patient.

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