Background: Congenital hypopituitarism is a rare disease. Although our understanding of the involved transcription factors is improving, mutations in candidate genes are rarely identified. Extra-pituitary symptoms can point towards new genes of interest. FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), a rare affection that combines congenital alterations of eyelids with ovarian dysgenesis in some families. Moreover, we have previously reported the association of BPES with combined pituitary hormone deficiency (CPHD) in some rare non-related cases.
Objective and hypotheses: The main objective was to better define the possible molecular association between anomalies of eyelids, including BPES, but also other oculo-optic anomalies, and CPHD. Patients presenting these specific syndromes were selectively tested not only for FOXL2 mutations, but also for mutations in a series of genes already linked with CPHD.
Method: Our cohort consisted of 22 patients with CPHD and various ocular anomalies (of the eyelid, eyeball, and/or optic nerve), and presented various anomalies of pituitary gland documented by RMI. FOXL2 was screened in the patients with eyelid anomalies including BPES. HESX1 and OTX2 were screened for all patients. GH1, GHRHR, POU1F1, PROP1, LHX3, LHX4, PITX2, SOX3, PROKR2, GLI2, and/or ARNT2 were selected for screening by the GENHYPOPIT network based on clinical and radiological signs.
Results: A FOXL2 mutation was identified only in the two BPES patients among nine patients with eyelid anomalies. In addition, OTX2 was mutated in one patient presenting with septo-optic dysplasia and microphtalmia.
Conclusion: This study indicates a possible role of FOXL2 in hypothalamus and pituitary development. FOXL2 mutation is indeed the most frequent molecular anomaly within our cohort of patients with hypopituitarism and ocular anomalies. Further studies are necessary to determine if FOXL2 should be sequenced in CPHD patients presenting eyelid anomalies distinct from those observed in BPES.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology