Reproductive Health in Xeroderma Pigmentosum: Features of Premature Aging

Abstract

OBJECTIVE:

To assess the age at menarche and menopause of women with xeroderma pigmentosum, a DNA repair disease with premature aging, in a longitudinal natural history study.

METHODS:

We conducted a natural history study that reviewed medical records for gynecologic and reproductive health of all female xeroderma pigmentosum patients ages > 9 years examined at the National Institutes of Health (NIH). We performed gynecologic and laboratory exams on a subset. Women in a second subset, who could not be examined, were interviewed using a questionnaire. Women who were deceased or lost to follow-up formed a third subset.

RESULTS:

Sixty women with xeroderma pigmentosum > 9 years of age [median 29 yr, range 10 – 61 yr] were evaluated at the NIH from 1971 to 2018. Of these 60, 31 had history, questionnaire, record review, and gynecologic evaluation, 14 had record review and questionnaire interview by telephone, and 15 had only NIH record review. Menarche in women with xeroderma pigmentosum occurred at a median age of 12.0 years (range 9-17 years), which was comparable to the U.S. general population. Among the 18 patients with menopause, the median age at menopause of 29.5 years (range 18 to 49.5 years) was more than 20 years younger than in the U.S. general population (52.9 years). Premature menopause (before age 40 years) occurred in 14/45 (31%) of the women aged 18 years or older and primary ovarian insufficiency was documented in 9 of them. There were 32 live births in 21 of the women, 5 of whom subsequently developed premature menopause.

CONCLUSION:

Women with xeroderma pigmentosum in our study had a normal age at menarche, were fertile, but had increased incidence of premature menopause. Premature menopause, a symptom of premature aging, should be considered for gynecologic and reproductive health as well as implicating DNA repair in maintaining normal ovarian function.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, .

Precis:

Women with xeroderma pigmentosum, a rare DNA repair disease with premature aging, had normal menarche but reduced age at menopause.

INTRODUCTION

Xeroderma pigmentosum is a rare (1 per million people in the United States and Europe)(1) autosomal recessive disorder caused by mutations in any of 7 genes (complementation groups XP-A to XP-G) in the DNA nucleotide excision repair -transcription pathway or in polymerase eta (xeroderma pigmentosum variant), a bypass polymerase (2). Xeroderma pigmentosum is seen in higher frequencies in several parts of the world, such as 1 per 22,000 people in Japan (3) and 1 per 10,000 people in northern Africa (4). Clinical manifestations of xeroderma pigmentosum include acute burning of the skin on minimal sun exposure, features of premature aging including freckle-like (lentiginous) pigmentation on sun exposed skin before 2 years of age, and a 10,000-fold increased risk of skin cancer under age 20 years (2). Xeroderma pigmentosum patients have early onset of ocular abnormalities including ocular cancer (5). Approximately 25% of patients with xeroderma pigmentosum develop features of premature aging of the nervous system with neurologic degeneration characterized by progressive ataxia, loss of reflexes, cognitive decline, and accelerated age-related sensorineural hearing loss often requiring hearing aids (6-8).

We have been performing a longitudinal natural history study of xeroderma pigmentosum patients at the NIH for more than 40 years (6). Until recently, most xeroderma pigmentosum patients succumbed from cancer or xeroderma pigmentosum neurologic disease in the second or third decades of life (6). However, with better cancer treatments, improved methods of ultraviolet protection and better management of neurologic complications, xeroderma pigmentosum patients are living longer (7). Our goal was to assess the reproductive health of women in this study. We assessed their ages of menarche and menopause as well as their pregnancies and number of children.

METHODS:

The patients in this natural history study were evaluated under an IRB-approved protocol (99C-0099) at the National Cancer Institute of the National Institutes of Health (NIH) (5, 6, 8-10). Written informed consent was obtained from all participants or from the parents of minor patients. Patients were referred to NIH for evaluation and managed by outside health care providers. All females with a molecular or clinical diagnosis of xeroderma pigmentosum examined at NIH from 1971 to 2018 were ascertained using the NIH medical records system. Women who were >9 years old at the time of last observation were included in the present study. All outpatient gynecological evaluations were performed by one of the authors (MM) and included review of obstetric-gynecologic history, a questionnaire including information about menarche, childbearing and menopause, physical examination, and laboratory testing. Pelvic sonograms, thyroid ultrasound and dual energy x-ray absorptiometry (DXA) scans for bone density were performed on selected patients. Laboratory blood tests varied among the patients and included CBC, follicle stimulating hormone (FSH), serum estradiol, anti-mullerian hormone, intact parathyroid hormone, osteocalcin, bone specific alkaline phosphatase, thyroid stimulating hormone, free thyroxine, thyroglobulin, anti-thyroglobulin, serum human chorionic gonadotropin, luteinizing hormone, serum progesterone, prolactin, sex hormone binding globulin, total testosterone, free testosterone, 25 hydroxy-vitamin D, 1,25 dihydroxy-vitamin D, vitamin B12, folic acid, adrenal 21-hydroxylase antibody, immunoglobulin levels, hemoglobin A1C, and fragile X chromosome evaluation (expansion of CGG within the FMR1 gene). Where possible, we looked for evidence of primary ovarian insufficiency including patient-reported symptoms, laboratory findings and vaginal atrophy on examination. In addition, a subset of patients who had previously been seen at the NIH but had not had gynecology exams, was interviewed by telephone using a questionnaire to obtain data on gynecologic and reproductive health issues. All data was recorded on Excel spreadsheets and reviewed by two authors (MM and DT) for accuracy. Medical records from deceased patients and patients lost to follow-up were analyzed for gynecology reports, history of premature menopause and laboratory test results. These records consisted of electronic archived NIH medical records and stored outside medical records that had been requested for review. Ages at menarche and menopause between the xeroderma pigmentosum patients and U.S. Caucasian women (11, 12) were compared using Chi-square or Fisher exact tests. Results with a p value of <0.05 were regarded as significant.

RESULTS:

From 1971 to 2018, 85 female xeroderma pigmentosum patients were seen at the NIH as part of a DNA repair disease longitudinal natural history protocol. Of these, 6 patients did not meet the age requirement of at least 9 years of age at the time of the visit, 10 patients were found to have the overlap syndromes of either xeroderma pigmentosum-trichothiodystrophy or xeroderma pigmentosum-Cockayne syndrome (2) and were not included, and there was no gynecological information on 9 women. A total of 60 patients met the inclusion criteria (Table 1). Of these 60, 31 had obstetric–gynecologic history, questionnaire, record review, and gynecologic evaluation during their NIH visit, 14 had record review and questionnaire interview by telephone, and 15 had only NIH record review (these were primarily deceased patients).

Table 1.

Women with Xeroderma Pigmentosum >9 years old, 1971-2018 in NIH cohort Complementation Group^*

	TOTAL	XP-A	XP-C	XP-D	XP-E	XP-G	XP Variant	Unknown
Age at last observation (n)	60	7	27	13	2	1	4	6
Median (yr)	29	22	31	28	55.5	28	49	33
Age Range (yr)	10 - 61	12 - 44	10 - 61	14 - 52	52 - 59		39 - 60	12 - 57
Age at death (n)	12	2	5	3	0	0	0	2
Median (yr)	34		35	36
Age Range (yr)	24 - 49	24 - 44	28 - 49	28 - 45				24 - 28
Age at menarche known (n)	56	7	24	12	2	1	4	6
Median (yr)	12	12	12	12	14.5	11	12.3	11.5
Age Range (yr)	9 - 17	9 - 13	9 - 17	10 - 16	14 - 15		12 - 13	11 - 13
Age at non-surgical menopause known (n)	18	0	15	0	1	0	1	1
Median (yr)	29.5		28		49.5		47	38.5
Age Range (yr)	18 – 49.5		18 – 42
Primary ovarian insufficiency documented	9	0	9	0	0	0	0	0

^*Complementation groups correspond to different genetic mutations (see reference (2))

The 60 women with xeroderma pigmentosum included in the study ranged in age from 10 to 61 years, with a median age of 29 years (Table 1 and Figure 1A and B). The race or ethnicity was 80% Caucasian patients, 13% African-Americans, 3% Hispanic and 2% each Indian-American and Native American. The largest group of patients were in the XP-C complementation group (n=27, 45%), followed by XP-D (n=13, 22%) and a smaller number of patients with XP-A, XP-E, XP-G, XP-variant, or with an unknown complementation type (Table 1). This distribution of xeroderma pigmentosum patients is similar to that in Europe (13). Menarche occurred at a median age of 12.0 years (range 9–17 years), which is similar to the U.S. general population of 12.6 years (11) (Table 1 and Figure 2).

Figure 1.

Age distribution and age of menopause of women with xeroderma pigmentosum. A. There were 18 women who had menopause and 14 of them (78%) had premature menopause (before 40 years of age). B. There were 39 women aged 10 to 52 years who were still menstruating.

Figure 2.

Comparison of age at menarche in 56 women with xeroderma pigmentosum (solid curve) to 1,302 women in the U.S. general population (dashed curve). There was a similar median age of 12.0 years in both groups. (U.S. General population data from McDowell MA, Brody DJ, Hughes JP. Has age at menarche changed? Results from the National Health and Nutrition Examination Survey (NHANES) 1999-2004. J Adolesc Health 2007 Mar;40(3):227-31.).

There were 48 women aged 18 – 61 years. Three of them had surgically-induced menopause. Of the others, non-surgical menopause was reported in 18/45 (40%), with age at menopause ranging from 18–49.5 years (Table 1 and Figure 1A). Premature menopause (prior to age 40 years) occurred in 14/45 (31%) of the women aged 18 years or older representing 14/18 (78%) of the menopausal women (Figure 1A). Among 33 women in the cohort aged 18 to 39 years at last observation, 10 (30%) had premature menopause. Among the 15 women age 40 years and older at last observation, 4 (27%) reported premature menopause, 4 (27%) had menopause age 40 years or older, 3 had surgical menopause, 2 had died (10) and 2 did not report menopause (Figure 1A and B). Mutations in the XPC DNA repair gene were reported for 13 of the 14 women with premature menopause and 1 patient had an unknown xeroderma pigmentosum gene mutation. The proportion of women with premature menopause in this sample was significantly different compared to the general population (13) (p<0.001). In addition, among the 18 women with menopause, the median age at non-surgical menopause, 29.5 years old, was more than 20 years younger than the median age in the U.S. general population of Caucasians which is 52.9 years (12) (Figure 3).

Figure 3.

Comparison of ages of the proportion of women undergoing menopause in the xeroderma pigmentosum patient group (n=18) to the ages of the proportion of women undergoing menopause in the U.S. general population (n=1,533). The women with xeroderma pigmentosum reached menopause about 20 years earlier than the Caucasian controls (median 29.5 years compared with 52.9 years). (U.S. General population data from Gold EB, Crawford SL, Avis NE, Crandall CJ, Matthews KA, Waetjen LE, et al. Factors related to age at natural menopause: longitudinal analyses from SWAN. Am J Epidemiol 2013 Jul 1;178(1):70-83.).

Primary ovarian insufficiency was documented in 9 of the 18 menopausal women on the basis amenorrhea and 2 or more blood tests at least 4 months apart showing elevation of FSH (>40 mIU/mL). In addition, several also had reduced estradiol (< 20 pg/mL) and/or undetectable levels of anti-müllerian hormone (Appendix 1, available online at http://links.lww.com/xxx).

There were 45 pregnancies among 21 of the women. There was a range of 1 to 4 pregnancies per woman. They had 32 live births, 10 spontaneous abortions and 3 elective terminations. The women had 26 vaginal births and 6 cesarean deliveries. At the time of last live birth, the mothers with xeroderma pigmentosum ranged in age from 19 to 34 years. Premature menopause subsequently developed in 5 of these mothers with xeroderma pigmentosum at ages 26, 26, 29, 37 and 38.5 years. As expected for this recessive disorder, none of the children of the mothers with xeroderma pigmentosum had clinical features of xeroderma pigmentosum. The children would be obligate heterozygotes.

Twelve of the patients have died, with a median age of death of 34 years (range 24–49 years), underscoring the seriousness of the condition (Table 1). Premature menopause was diagnosed in 3 of the women who died (XP1BE, menopause 25 yr, death of uterine cancer at 49 yr (10); XP26BE, menopause 27 yr, death of cancer invasive to the brain at 33 yr (6); XP24BE, menopause 27 yr, death of glioblastoma at 35 yr (10)). Their cancer treatments occurred after the onset of premature menopause and included chemotherapy and radiation. Causes of death on the other 9 women were neurologic degeneration (n=3), cancer metastatic to the brain (n=2), pneumonia (n=1), drug overdose (1) and unknown (n=2)(6, 10).

DISCUSSION

In this cohort of 60 women with xeroderma pigmentosum, we report the finding of normal age of menarche, but premature menopause. Menopause is the permanent cessation of menses due to depletion of ovarian follicles (14). The mean (± SD) age at non-surgical menopause in the U.S. is 50± 4 years. Menopause before the age of 40 years is considered to be premature (14). Primary ovarian insufficiency is defined as a woman under age 40 years with amenorrhea or irregular periods for 4 months plus two elevated FSH values in the post-menopausal range (>40 mIU/mL) at least 1 month apart. Hypoestrogenism and reduced anti-mullerian hormone levels also support the diagnosis. The frequency of primary ovarian insufficiency for women in the general U.S. population is about 1% by the age of 40 years (14). In our study 31% (14/45) of the women with xeroderma pigmentosum aged 18 to 61 years at last observation had non-surgical menopause before 40 years of age (Figures 1A and 3). Nine of them have been documented as having primary ovarian insufficiency (Table 1 and Appendix 1 [http://links.lww.com/xxx]). The cause of primary ovarian insufficiency is not determined in about 90% of the women in the general population (14).

Premature menopause has been observed in other DNA repair diseases including Fanconi anemia, Bloom syndrome, Werner syndrome and ataxia-telangiectasia (15) but has not been generally recognized in xeroderma pigmentosum. Despite observing age at menarche similar to that of the general population, the median age at menopause of 29.5 years among the 18 women with xeroderma pigmentosum who reported menopause, was more than 20 years younger than the median age in the general population (11). Most of the patients with premature menopause in our cohort have mutations in the XPC gene (complementation group XP-C). However, XPC is the most common cause of xeroderma pigmentosum in the United States (6) and it is possible that patients with mutations in other nucleotide excision repair genes may also be affected. Additional data needs to be collected on xeroderma pigmentosum patients with mutations in other nucleotide excision repair genes. This study is limited by its small sample size, variable follow-up, and age at evaluation for menopause or no menopause.

We did not observe other known causes of primary ovarian insufficiency including fragile X syndrome or other chromosomal abnormalities, thyroid function abnormalities, adrenal abnormalities, hypo-parathyroidism, radiation, and chemotherapy (14, 16) in our patients. Premature menopause can be caused by an increased loss of follicles, more rapid destruction of follicles or failure of the follicles to respond to gonadotropins (14). Our index patient (XP24BE -Appendixes 2 and 3, available online at http://links.lww.com/xxx) had primary ovarian insufficiency and mutations in the XPC DNA repair gene (17). At autopsy she was found to have small ovaries with microscopic fibrosis and absent follicles (10). Normal ovaries are rapidly proliferating and have been reported to have among the highest levels of XPC mRNA (18). This may reflect a greater need for proofreading of newly replicated DNA strands and-or of repair of endogenous DNA damage. Thirteen of the 14 women with premature menopause in our study had mutations in the XPC gene (Tables 1 and Appendix 1 [Appendix 1 is available online at http://links.lww.com/xxx]). These are associated with low levels of XPC mRNA and reduced DNA repair (17). Thus, reduced levels of XPC protein may be another cause of primary ovarian insufficiency (14). Patients with Fanconi anemia have premature menopause with mutations in the inter-strand cross link repair pathway and patients with Bloom and Werner syndromes have mutations in RecQ helicase genes which are important for homologous recombination and non-homologous end joining (19). These observations suggest that maintenance of genome stability by multiple DNA repair pathways play a role in the maintenance of normal ovarian function. The exact mechanism underlying premature menopause in these women with defects in DNA repair is still under debate; however, there is evidence that the ovaries in women with Fanconi anemia may sustain unrepaired double strand breaks that over time result in loss of primary follicles (20). Since developmental abnormalities such as short stature, dysmorphic features and limb abnormalities can be seen in some patients with DNA repair disorders, there may be a decreased number of primary ovarian follicles, resulting in exhaustion of viable follicles at an earlier age (14).

The age when menopause begins may be an indicator of aging and of general health. Later age at menopause has been associated with clinical outcomes such as longer overall survival, greater life expectancy, reduced all-cause mortality, reduced loss of bone density and reduced fracture risk (See (21) and references therein). In our 18 post-menopausal xeroderma pigmentosum patients, the average age of cessation of menses was 29 years. With better management of skin cancers and good sun protection, these women are living active lives. Knowledge about the increased risk of early menopause for women with xeroderma pigmentosum may impact decisions regarding reproductive choice and timing of childbearing. Young women with xeroderma pigmentosum may benefit from increased surveillance of hormone levels and ultrasound testing in their 20’s to help identify diminished ovarian reserve and guide reproductive health recommendations and use of hormone replacement when indicated (16, 22). Specialists in obstetrics and gynecology who provide gynecologic care for women with xeroderma pigmentosum can play an important role in advising about these reproductive health issues and monitoring for adverse effects of premature menopause such as those on bone, cardiovascular system, stroke and malignancy (21).