ESPE Abstracts

Background: Congenital hypopituitarism (CH) is a group of disorders characterized by deficiencies in one or more hypophyseal hormones and a marked variability in genotype-phenotype correlations. Central diabetes insipidus (DI) is caused by a decreased release of ADH and results in a variable degree of polyuria. Their association is normally found in congenital cerebral midline abnormalities, such as septo-optic dysplasia.

Objective: Reporting a patient with CH and neurogenic DI and normal pituitary gland and midline brain structures in magnetic resonance imaging (MRI) without mutations in previously reported pathogenic variants known to cause hypothalamo-pituitary disease.

Method: Patient’s DNA was analysed with comparative genomic hybridization (CGH) array and exome sequencing.

Case Report: A two-day-old term male neonate (ovodonation pregnancy) was admitted after seizures and a cardiopulmonary arrest in the context of hypoglycaemia. Laboratory results (4 days after birth, glucose 24 mg/dl): cortisol 0.5 μg/dl, ACTH 11 ρg/ml, TSH 3.17 μg/dl, FT4 0.99 ng/dl and GH 7.2 ng/ml. In day 11 after birth polyuria (7.8 ml/kg/h) was detected (serum osmolality 312 mOsm, urine osmolality 84 mOsm/kg), with good response to subcutaneous desmopressin. Other laboratory findings (17 days of age): LH 6.25 μU/ml, FSH 1.25 μU/ml, testosterone 0.41 ng/ml, IGF-1 34 ng/ml (45-93) and IGFBP3 1.4 μg/ml (1.2-1.8). MRI showed subcortical and subependymal heterotopia, without any alterations of the hypophysis or other midline structures. Oral hydrocortisone and levothyroxine were started. During the clinical follow-up, a switch to oral desmopressin was made with poor clinical results, so subcutaneous administration is still ongoing.

Results: We identified a heterozygous frameshift insertion mutation (loss of function) in IRF2BPL c.320_321insGC; p.(GIn108Hisfs*45). Mutations in this gene have been reported to cause neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (OMIM#618088) and also changes in female pubertal-timing.

Discussion/conclusion: this patient presents with CH and DI without neuroimaging alterations in the typical structures when both conditions coexist. Furthermore, genetic analysis does not show mutations already linked to CH. Although the mutation found affects Wnt signaling pathway (mutations in this pathway have been described to produce CH), functional studies are required to determine its pathogenicity in CH. With the widespread use of next generation sequencing, more mutations in non-previously described genes associated with CH will appear and this will lead to achieve a better understanding of this complex group of disorders.