ESPE Abstracts

Background: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. Mutations in the genes coding for transcription factors, such HESX1, involved in the development of the pituitary, determine a highly variable phenotype which may include severe midline defects, septo-optic dysplasia and other congenital abnormalities. A small number of HESX1 variants have been identified in humans. The phenotype shows always a GH deficiency, often associated with other pituitary hormone deficiencies in addition to ectopic posterior pituitary, mid-line abnormalities, micropenis, and polydactyly. We report a case of a newborn with congenital hypopituitarism due to a rare mutation of HESX1 who presented with hypoglycemia and micropenis at birth.

Case Report: The patient was born at term to consanguineous parents after an uncomplicated pregnancy. Presentation at birth: weight 2.850 kg, length 49 cm, head circumference 34.1 cm, large anterior and posterior fontanels, diastasis of rectus abdominal muscles, micropenis and bilateral cryptorchidism, jaundice and transient hypoglicaemia. Serum thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone (GH), testosterone, and insulin-like growth factor I (IGF-I) were undetectable. Free thyroxine was 1.10 ng/dl (0.89-1.76) and serum cortisol was 0.7 µg/dl (4.3-22.4), Ultrasound showed both testes located in the inguinal canal. The brain MRI showed the absence of the anterior pituitary with normal posterior pituitary and pituitary stalk, normal optical chiasm and no midline abnormalities. Hydrocortisone replacement (10 mg/m²/day) was started immediately followed by L-Thyroxine (9 µg/kg/day). At the age of 9 months, he started GH treatment. At the age of 2.7 years he underwent left orchidopexy. Right orchidopexy is scheduled. Genetic investigation identified a rare pathogenetic homozygous variant c.325C> T p. (arg109*) in HESX1, and a heterozygous variant of uncertain significance (c.19C> p. (arg7cys) in PROP1. This HESX1 variant was reported in only one patient who presented panhypopituitarism, hypoplastic adenohypophysis, ectopic neurohypophysis and interruption of the pituitary stalk. Our patient is currently on replacement therapy with L-Thyroxine (2.4 µg/kg/day), GH (0.023 mg/kg/day), hydrocortisone (12 mg/m²/day). During the 3 years follow-up he had a catch-up growth, no adrenal crisis, and just one hypoglycemic episode post surgery.

Conclusions: We reported a case of a rare homozygous pathogenic HESX1 variant characterized by hypopituitarism, absent anterior pituitary, normal posterior pituitary, stalk and optic nerves. These data might help to better understand the genotype-phenotype correlation in patients with homozygous HESX1 variants, which, according to the current knowledge is still not clear.