Background: Our patient, a male infant has bilateral cleft lip and palate, bilateral split hand and foot, semilobar holoprosencephaly and specific pituitary defects (cranial diabetes insipidus, gonadotrophin deficiency). He developed tumoral calcinosis at 16 months.
Objective and hypotheses: Our patients phenotype is suggestive of Hartsfield syndrome. We hypothesise that he harbours a FGFR1 mutation given recently published findings associating novel homozygous/heterozygous FGFR1 mutations with the condition. Tumoral calcinosis can be inherited in an autosomal recessive manner (loss of function mutations in FGF23, KLOTHO and GALNT3). The circulating factor FGF23 promotes phosphate excretion. Klotho directly converts the splice variant FGFR1 (IIIc) into the FGF23-specific receptor raising the possibility that an inactivating FGFR1 mutation may contribute to tumoral calcinosis development.
Method: Direct Sanger sequencing of FGFR1, incisional biopsy (histology consistent with tumoral calcinosis) and serum for bone biochemistry and C-terminal/ intact FGF23 levels was taken.
Results: Our patient has a novel, de novo heterozygous missense mutation, c.1883A>G; p.Asn628Ser, affecting an amino acid residue in the ATP binding pocket of the tyrosine kinase domain, with predicted impairment of FGFR1 kinase activity. Biochemical findings were consistent with familial tumoral calcinosis with normocalcemia, normal 1, 25(OH) Vitamin D, hyperphosphataemia, and low fractional excretion of phosphate. In comparison to other causes of familial tumoral calcinosis C-terminal FGF23 was only mildly raised (111 RU/ml, NR <100) and intact levels were within normal limits. Studies have implicated FGFR1 activation in regulating FGF23 gene transcription which may account for the paucity of elevation of FGF23 seen despite increased renal phosphate reabsorption.
Conclusion: This novel mutation in FGFR1 provides further compelling evidence of the association of FGFR1 mutations with Hartsfield syndrome. We also expand the phenotype with the first report of tumoral calcinosis with mildly raised C-terminal FGF23 levels, which may reflect loss of function of FGFR1.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology