Endocrine Abstracts

Introduction: Hyperprolactinemia is usually an acquired condition. Typical clinical manifestations include hypogonadism, infertility, and galactorrhea. Rarely, hyperprolactinemia has been attributed to a variant in the prolactin receptor gene (PRLR), presenting as agalactia, without hypogonadism, infertility, or galactorrhea.

Aim: In the current study we aimed to delineate the clinical phenotype and the genetic basis of marked hyperprolactinemia found in few females from one large kindred.

Methods: We have ascertained extended inbred kindred with multiple female subjects displaying presumably asymptomatic hyperprolactinemia. The family members underwent clinical, laboratory and imaging assessment. Whole exome sequencing has been used to obtain genetic molecular diagnosis of the proband. Segregation analysis was performed by Sanger sequencing.

Results: Fourteen family members, 7 females and 7 males of 3 different branches and of 2 generations were evaluated. Ethylene glycol precipitation and pituitary Magnetic Resonance Imaging revealed no evidence of macroprolactin or pituitary adenoma, respectively. Four females of reproductive age with elevated prolactin levels (X6-10 of the upper limit of norm), harbored a homozygous PRLR(NM_000949.7):c.1750del (p.Glu584AsnfsTer49) variant, predicted to change the amino acid (aa) sequence of the last 39 aa of the encoded PRLR, elongating it by additional 13 aa, thereby affecting its intracellular domain. All 4 had regular ovulatory cycles and no galactorrhea. Of these, 3 homozygous females conceived spontaneously. Of 3 who gave birth, only one nursed without difficulties, while 2 reported “lack of milk’ and did not have breast engorgement after stopping breastfeeding. All three postmenopausal women (one homozygous, one heterozygous, and one wildtype of the PRLR gene) had prolactin levels within the normal range. However, the homozygous postmenopausal woman had prolactin level X2 of ULN at menopause transition. She had 5 spontaneous pregnancies and successfully nursed all her children. All seven males (2 homozygous and 5 heterozygous) had prolactin level within the normal range and did not demonstrate any signs or symptoms related to hyperprolactinemia.

Conclusions: We describe a novel homozygous PRLR p.Glu584AsnfsTer49 variant predicted to affect the intracellular domain of the PRLR, resulting in significant, apparently asymptomatic hyperprolactinemia among females in their reproductive age, with a possible mild lactation difficulty. It might be suggested that the hyperprolactinemia largely compensate for the lower activity or stability of the PRLR.