ESPE Abstracts (2016) 86 P-P2-648

San Raffaele Hospital, Milan, Lombardy, Italy

Background: Congenital hypopituitarism is a rare cause of pituitary insufficiency (incidence: 12–42 new cases/million per year; prevalence: 300–455 cases/million). The aetiology remains largely unclear: the most frequently correlated genetic abnormalities are those involving transcription factors implicated in pituitary organogenesis. The phenotype and neuroradiological findings associated with the underlying genotype may be highly variable (from an isolated hypopituitarism to more complex conditions such as septo-optic dysplasia and holoprosencephaly).

Objective and hypotheses: i) Retrospective analysis of a population of pediatric patients with hypopituitarism in clinical, diagnostic and therapeutic terms; ii) assessment of the phenotypic characteristics and clinical findings in order to highlight common features that may suggest a diagnosis, a most likely genetic mutation and possible genotypic, phenotypic and neuroradiological correlates; iii) evaluation of the therapeutic response to GH replacement.

Method: Clinical, neuroradiological and molecular data were collected in 31 patients (M/F=15/16) with congenital hypopituitarism, 15 with neonatal diagnosis and 16 with delayed diagnosis, born from 1989 to 2014.

Results: Eighty-four percent of patients presented symptoms at birth: the most frequent were prolonged hypoglycemia (55%), prolonged jaundice (51%) and respiratory distress (49%). Micropenis and cryptorchidism were present in 47% of male patients. Genetic analysis showed correlated mutations only in 19% of cases (4 patients: mutation in HESX1, microdeletion in PROP1, mutation in GLI2, deletion 1q24.3q31.1 containing LHX4). Brain MRI showed: 84% adenopituitary hypo-aplasia, 77% pituitary stalk hypoplasia/interruption/absence, 74% ectopic neurohypophysis, 22% septo-optic dysplasia, normal in 3%.

Table 1. (for abstract P2-648)
Neonatal diagnosis (48%)Delayed diagnosis (52%)Peculiar phenotypic traits%
Median age at diagnosis0.1 years (1.2 months)3.16 yearsDepressed nasal bridge26
Hormones deficiencyGH+TSH+ACTH 97%GH+TSH+ACTH 90%Prominent forehead23
Median cortisol levels (ng/ml)1047.5 (P<0.0001).Low-set ear23
Response to GH replacement (mean dose 0.21 mg/kg per week)ΔHt after 2 year: +1.6 SDSΔHt after 2 year: +1.79 SDSCleft lip and palate9
ΔHt final height: +2.61 SDSΔHt final height: +3.35 SDS

Conclusion: The clinical suspicion should be placed at birth in those symptomatic children. MRI evaluation is fundamental in order to predict the endocrinological phenotype and the underlying genotype. The evidence of common traits in these patients make the hypothesis of a common genetic alteration more likely; however other genes still remain to be identified and other factors (such as environmental) could contribute to the pathogenesis of this complex condition.

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