ESPE Abstracts

Background: Growth hormone deficiency in conjunction with the function loss of other anterior pituitary hormones is called combined pituitary hormone deficiency (CPHD). The most common congenital CPHD is caused by mutations in genes: PROP1, POU1F1, HESX1, LHX3, LHX4, OTX2, GLI2, and SOX3. POU1F1 mutations are extremely rare among the Indo-European ethnic type (1% of all cases of congenital hypopituitarism) and more common among the Turkic peoples (7.3%, according to Turkish researchers). Due to the migration and the influx of Azerbaijanis in particular, we can observe such cases more often in St. Petersburg in recent years.

Methods: 3 Azerbaijani boys (one of them born to consanguineous marriage) were examined using standard clinical and laboratory methods. The levels of blood glucose, TSH, free T4, GH, IGF-1, ACTH, cortisol, prolactin and liver function tests were evaluated. PROP1, POU1F1, HESX1, LHX3, LHX4, OTX2, GLI2, SOX3, ARNT2, GH1, GHRH, GHRHR, GHSR, IGSF1, PAX6, SHH gene mutations were investigated by a new generation sequencing (NGS) method.

Results: Patient№1 on the second day of life had persistant hypoglycemia, accompanied by convulsions. The patient had a craniofacial anomaly, shortening of the proximal extremities. By 1 month of life he had no growth increments. Patients №2 and №3 were hospitalized at the age of 1 month due to prolonged jaundice. Patients had general symptoms of hypothyroidism, craniofacial dysmorphisms. Unconjugated hyperbilirubinemia, hypoglycemia were diagnosed. After 1 month of life they had poor growth. The diagnosis of congenital hypopituitarism was completed with confirmation of FT4, GH, PRL deficiencies. Patients 2 and 3 had severe hypothyroidism while the patient №1 had moderate hypothyroxinemia. Homozygous mutations in POU1F1 were found in all infants: missense mutation s.793S> T: p.R265W (patient №1) is pathogenic and early described; frameshift mutations s.638_642delGGAAAp.R212KfsX12 (patient №2) and c.634_638delGAAAGp.R213KfsX12 (patsient№3). In the latter two cases mutations were not previously considered to be pathogenic. Replacement therapy with levothyroxine and then growth hormone led to the elimination of hyperbilirubinemia, hypoglycemia.

Conclusion: Infant jaundice and /or persistent hypoglycemia require CPHD exclusion, moreover male gender and Turkic ethnic type increase the risk of the POU1F1mutation. Thyrotroph dysfunction degree determines the severity of clinical and laboratory manifestations of the hypothyroidism syndrome and can be associated with the type of genetic defect.