Hyperprolactinemia

A number sign (#) is used with this entry because of evidence that hyperprolactinemia (HPRL) is caused by heterozygous or compound heterozygous mutation in the PRLR gene (176761) on chromosome 5p13.

Description

Hyperprolactinemia unrelated to pregnancy occurs in approximately 0.1 to 0.3% of the general population and may result in infertility, hypogonadism, and galactorrhea. Such nonphysiologic hyperprolactinemia is caused mainly by drugs or by tumors in the anterior pituitary gland, primarily prolactinomas (see 102200). However, 10 to 60% of patients with hyperprolactinemia who undergo MRI have normal findings (summary by Newey et al., 2013).

Patients with hyperprolactinemia may also experience agalactia (Kobayashi et al., 2018).

Clinical Features

Newey et al. (2013) studied 3 sisters with familial idiopathic hyperprolactinemia. The proband was a 41-year-old woman with a 2-year history of oligomenorrhea and menorrhagia who was found to have hyperprolactinemia. Between age 18 and 31 years, she gave birth to 4 children, and at the cessation of breastfeeding after each pregnancy, she required dopamine agonist therapy to terminate persistent galactorrhea. She had no clinical features of hypopituitarism and was taking no medication; MRI of the pituitary was normal. A 38-year-old sister with a 3-year history of primary infertility and a 43-year-old sister with longstanding oligomenorrhea were both also found to have persistent hyperprolactinemia with a normal MRI of the pituitary gland. In addition, the proband's father and son were found to have persistent hyperprolactinemia. None of the affected family members had immunologic abnormalities.

Kobayashi et al. (2018) reported a 35-year-old woman with regular menstrual cycles who presented at age 28 with a 1-year history of infertility and was found to have hyperprolactinemia. Pregnancy was achieved on second intrauterine insemination; in the postpartum and puerperal periods, she had agalactia and experienced neither breast engorgement nor galactorrhea. A second pregnancy was achieved without infertility treatment, and again she had postpartum agalactia. Her prolactin levels remained elevated; brain MRI showed no evidence of a pituitary tumor. Her mother had no history of menstrual irregularities or infertility and had breast-fed each of her 3 children, but stated that she had been concerned about insufficient production of breast milk and supplemented with synthetic milk. Lactation ceased spontaneously within 3 months after each childbirth. The proband's father was healthy and fertile; both parents had normal prolactin levels, as did an unaffected sister and brother.

Molecular Genetics

In the proband of a 3-generation family segregating autosomal dominant hyperprolactinemia, who was known to be negative for mutation in the MEN1 (613733), AIP (605555), and PRL (176760) genes, Newey et al. (2013) identified heterozygosity for a missense mutation in the PRLR gene (H188R; 176761.0002). The mutation segregated with disease in the family and was not found in 110 ethnically matched controls or in more than 13,000 alleles from the NHLBI GO Exome Sequencing Project. The proband's 13-year-old prepubertal daughter, who carried the mutation but did not have hyperprolactinemia, was thought to represent age-related penetrance for the disease. Studies in transfected HEK293 cells demonstrated that H188R is a loss-of-function mutation. The H118R mutation is also denoted as H212R (Kobayashi et al., 2018).

Harris (2014), Grossmann (2014), and Molitch (2014) questioned the relationship between the H188R (H212R) loss-of-function mutation and the reproductive abnormalities and galactorrhea reported in the family studied by Newey et al. (2013). Newey et al. (2014) proposed the involvement of a hypothetical second receptor mediating peripheral effects of hyperprolactinemia as a possible explanation for the paradoxical occurrence of the loss-of-function mutation in PRLR with hyperprolactinemia and variable reproductive abnormalities, and cited previous studies associating prolactin levels with reproductive function (Bronstein, 2010; Garzia et al., 2004; Li et al., 2013). Newey et al. (2014) also noted that their results showed that the PRLR loss-of-function mutation cosegregated with familial hyperprolactinemia with odds of more than 125 to 1 favoring linkage, and that the mutation was associated with a phenotype similar to that in Prlr-null mice.

In a 35-year-old woman with hyperprolactinemia and agalactia, Kobayashi et al. (2018) sequenced the PRLR gene and identified compound heterozygosity for a nonsense mutation (R171X; 176761.0003) and a missense mutation (P269L; 176761.0004). The proband's parents were each heterozygous for 1 of the mutations, neither of which were found in her unaffected brother and sister. The authors noted that the 3 identified variant receptors (H212R, R171X, and P269L) exhibit similar residual signal-transduction function as well as absence of robust dominant-negative effects, and suggested that other factors that modulate prolactin receptor signaling might explain the difference in phenotype between this family and the family with PRLR-associated hyperprolactinemia reported by Newey et al. (2013).