Asymptomatic Familial Hyperprolactinemia Caused by a Unique Bi-allelic Variant in the Prolactin-Receptor Gene - Endo Annual 2022 The 50th Annual Meeting of The Israel Endocrine Society

Yoav Natif ¹ Marina Shwartz ^2,3 Nadav Agam ^2,3 Ohad S Birk ^2,3 Merav Fraenkel ^4,5 Uri Yoel ^4,5

¹Goldman School of Medicine, Ben-Gurion University of the Negev
²Genetics Institute, Soroka University Medical Center
³Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev
⁴Endocrinology, Soroka University Medical Center
⁵Faculty of Health Science, Ben-Gurion University of the Negev

Introduction:
Rare cases of inherited hyperprolactinemia, related to prolactin receptor (PRLR) gene variants, present as agalactia, without hypogonadism, infertility or galactorrhea.

Aim:

To delineate the clinical phenotype and the genetic cause of familial hyperprolactinemia.

Methods:

Family members underwent clinical, laboratory and imaging assessment. Whole exome sequencing was used to obtain genetic molecular diagnosis of the proband. Segregation analysis was performed by Sanger sequencing.

Results:

We ascertained extended inbred kindred with multiple female subjects displaying presumably asymptomatic hyperprolactinemia. Seven females and 7 males, of 3 different branches and 2 generations, were evaluated. Four females of reproductive age had hyperprolactinemia (X6-10 of the upper limit of norm). All 4 had regular ovulatory cycles and no galactorrhea, and 2 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. Macroprolactin and prolactinoma were excluded. The four affected females harbored a homozygous PRLR(NM_000949.7):c.1750del (p.Glu584AsnfsTer49) variant, predicted to change the last 39 amino acids of the encoded protein and elongate it by additional 13 amino acids, affecting the intracellular domain of PRLR. Notably, two homozygous and 5 heterozygous males had prolactin levels within the normal range, without signs or symptoms of hyperprolactinemia.

Conclusions:

We describe a novel homozygous PRLR p.Glu584AsnfsTer49 variant predicted to affect the intracellular domain of prolactin receptor, resulting in significant asymptomatic hyperprolactinemia among females in their reproductive age, with a possible mild lactation difficulty, suggesting very mild phenotype attributed to this particular PRLR variant.