Keratoconus in association with Mullerian dysgenesis – A case report

Venugopal Anitha; Aditee Madkaikar; Aditya Ghorpade; Meenakshi Ravindran

doi:10.4103/ijo.IJO_2025_22

CASE REPORT

Year : 2023 | Volume : 3 | Issue : 2 | Page : 292-294

Keratoconus in association with Mullerian dysgenesis – A case report

Venugopal Anitha, Aditee Madkaikar, Aditya Ghorpade, Meenakshi Ravindran
Cornea, Anterior Segment, Refractive and Femto Surgeon; Cornea and Refractive Surgery; Cornea and Refractive Services; Paediatric and Strabismus Services, Aravind Eye Hospital, Post Graduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, India

Date of Submission	19-Aug-2022
Date of Acceptance	05-Jan-2023
Date of Web Publication	28-Apr-2023

Correspondence Address:
Venugopal Anitha
Senior Consultant, Cornea, Anterior Segment and Refractive Surgeon, Aravind Eye Hospital, Post Graduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_2025_22

Abstract

Keratoconus (KC) is a multifactorial disease with numerous associated systemic disorders. Hormonal dysfunction is commonly identified as a risk factor in the progression of KC. However, KC is very rarely known to be associated with congenital uterine anomalies. We present a case report of a 34-year-old female diagnosed with bilateral KC with hypoplastic uterus and septate vagina, albeit with normal sex hormonal parameters. Recognizing the existence of this rare association will encourage the diagnosis of such cases in futurity. Also, it is mandatory to do karyotyping in these cases to rule out the risk of developing gonadoblastoma.

Keywords: Genetic disorder, hypoplastic uterus, keratoconus, Mullerian duct anomalies

How to cite this article:
Anitha V, Madkaikar A, Ghorpade A, Ravindran M. Keratoconus in association with Mullerian dysgenesis – A case report. Indian J Ophthalmol Case Rep 2023;3:292-4

How to cite this URL:
Anitha V, Madkaikar A, Ghorpade A, Ravindran M. Keratoconus in association with Mullerian dysgenesis – A case report. Indian J Ophthalmol Case Rep [serial online] 2023 [cited 2023 Jun 4];3:292-4. Available from: https://www.ijoreports.in/text.asp?2023/3/2/292/374923

Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome, also referred to as Mullerian aplasia or dysgenesis or Mullerian duct anomaly (MDA), is a congenital condition characterized by aplasia of the uterus and upper part of the vagina with normal secretion of sex hormones, normal secretion of sex hormones, normal secondary sex characteristics and a normal female karyotype (46, XX).^[1],[2] Keratoconus (KC) is a complex corneal ectatic disorder characterized by the cone-shaped protrusion, and stromal thinning resulting in irregular corneal astigmatism.^[3] The etiologies of both these conditions are unknown, even though there is the possibility of a genetic link. Still, the specific genes responsible for these conditions have not yet been identified.^[1],[2],[3] KC in MDA has not been established in the literature, probably due to the rare occurrence of MDA (0.001%–10% in the general population) compared to KC (5.4 per 10,000 or 1 in 2000).^[1],[2] Here, we describe an intriguing, rare occurrence of KC in association with MDA, along with the literature review and the management outcomes.

Case Report

A 34-year-old female presented with blurring of vision in the left eye (LE) for 2 years. Her uncorrected visual acuity (UCVA) was 6/6 in the right eye (RE) and 6/18 in the LE, which improved to 6/9p with a − 2 cylinder at a 100° axis. Corneal topography ( Oculus Pentacam) in RE revealed a steep K of 48.2D, K max value 49.6D, thinnest location (TL) of 431μ, central steepening in axial curvature map, corresponding anterior elevation showing central island and central hotspot in the posterior elevation. LE revealed a steep K of 51.5 D, Kmax value of 57.5 D, TL of 418 μm, asymmetric bow tie with inferior steepening, and coincidence of the curvature's highest, thinnest, and steepest points, pachymetry, and elevation maps, respectively [Figure 1]. Both eyes were diagnosed with keratoconus and the patient was advised to undergo corneal collagen cross-linkage with riboflavin (CXL) in LE first. She did not have a history of eye rubbing, dry eyes, or any symptoms related to thyroid dysfunction. Further, her systemic history revealed primary amenorrhea. Her general examination was within normal limits. Her elder sister is married with two children. The patient was advised obstetrician (OG) consultation. Her ultrasonogram (USG) abdomen revealed normal liver, kidneys, and hypoplastic uterus (4.3 × 1.6 × 0.8), but the size of both ovaries (2.5 × 1.3) was within normal limits. Her per vaginal examination revealed a septate vagina, and she was diagnosed with Mullerian duct dysgenesis. Her prolactin level was mildly elevated (34 ng/ml; normal < 25 ng/ml) but was not considered significantly raised (>100 ng/ml). Her anti-Mullerian hormone level (2.5 ng/ml), thyroid stimulating hormone level (1.8 mIU/l), luteinizing hormone level (4.9 IU/l), and follicle-stimulating hormone (10.6 IU/ml) level were normal. Her serum estradiol (173 pg/ml) and serum progesterone (0.6 ng/ml) were normal with low serum testosterone (0.4 ng/ml). Her secondary sexual characteristics were intact with normal karyotyping (46, XX) [Figure 2]. She underwent an uneventful LE CXL [Figure 3]a. During her last visit, LE corneal stromal haze [Figure 3]b was noted with a stable ocular surface. She was advised to undergo RE CXL and regular follow-up with glasses for visual rehabilitation.

Figure 1: (a, b) Preoperative Pentacam images at the time of presentation

Click here to view

Figure 2:> Normal karyotyping analysis

Click here to view

Figure 3: First-day postoperative corneal image with edema after CXL; (b) shows a postoperative corneal image after 3 months. CXL = corneal collagen crosslinking

Click here to view

Discussion

The fallopian tubes, uterus, cervix, and the upper two-thirds of the vagina develop from a pair of Mullerian ducts and the ovaries, and the lower one-third of the vagina develops from ectoderm.^[1] The isolated MDA occurs with MRKH type 1, and renal (40%) and bone anomalies and congenital deafness occur in MRKH type 2.^[2] KC is a multifaceted disease with varied etiologies and pathogenesis.^[3],[4] It is known to occur in Turner's syndrome, characterized by ovarian dysgenesis, primary amenorrhea, underdeveloped secondary sexual characters, web neck, short stature, shield chest, and cubitus valgus.^[5] Our patient had MDA with hypoplasia of the uterus (4.3 long × 1.6 wide × 0.8 cm deep), septate vagina, and normal ovaries without any systemic abnormalities.^[1],[2] Karamichos et al.^[6] demonstrated the presence of gonadotropins and their receptors in the human cornea, and KC manifests prolonged hormonal abnormalities derived from the anterior pituitary. After the sex hormones bind to their receptors in the corneal epithelium, stromal keratocytes, and endothelium, the newly formed complex acts as a transcription factor to regulate the gene expression and stimulates the modulation of protein synthesis, causing the release of matrix metalloproteinase and activation of collagenases, changing viscoelasticity and increasing corneal distensibility, thus causing the progression of KC.^[4],[7] It has been reported that even stable KC in a 51-year-old woman progressed following 14 months of hormone replacement therapy for menopausal symptoms.^[7] Sex hormones play a pivotal role in the development and function of the uterus. Still, considering the normal levels of estradiol and progesterone in our patient, the probable etiology for uterine hypoplasia and KC progression in our case might be genetic. Several segmental deletions involved in MRKH syndrome have been identified in chromosomes 1 (1q21.1), 4 (4q34-qter), 8 (8p23.1), 10 (10p14-15), 16 (16p11.2), 17 (17q12), and 22 (22q11.21), and duplication was found on the chromosome X (Xpert-p22.32).^[3],[8] However, KC also has polygenic associations; one such significant association was found in isolated chromosomes 11 and 22, as in MRKH syndrome.^[1],[2],[3] Wingless-related integration site (WNT) signaling pathways are essential for normal embryonic and corneal development. The dysregulation and expression of WNT10A and WNT7B are known to be associated with KC, and WNT4 is associated with hyperandrogenism and MRKH syndrome.^[8] So, we have two common genetic associations between MRKH and KC from the literature.^[3.8] It is interesting to note that KC can progress in such genetic conditions without hormonal dysfunction. There exists a risk of developing gonadoblastoma with 46, XY karyotype in MDA, and prophylactic oophorectomy is indicated in such scenarios.^[9] Henceforth, a complete ocular, systemic evaluation, and karyotyping is imperative in patients with obstetric disorders. [Table 1] shows the literature review of various hormonal dysfunctions responsible for the pathogenesis of KC.

Table 1: Literature review on hormonal dysfunction and pathogenesis of KC

Click here to view

Conclusion

KC is a multifaceted disease with varied etiologies and pathogenesis. The systemic diseases associated with KC are accruing day by day. Even without hormonal influence, KC may progress in such genetic conditions. Hence, a complete ocular examination, estimation of serum hormonal levels, systemic evaluation, and karyotyping are requisites in such patients with obstetric disorders.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Selvaraj K, Selvaraj P, Suganthi K. Complex mullerian malformation: A rare case of hypoplastic noncavitated uterus in the middle with two rudimentary horns on either side. J Hum Reprod Sci 2020;13:235-8. [Full text]
2.	Bombard DS, Mousa SA. Mayer-Rokitansky-Kuster-Hauser syndrome: Complications, diagnosis and possible treatment options: A review. Gynecol Endocrinol 2014;30:618-23.
3.	Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297-319.
4.	Suzuki T, Kinoshita Y, Tachibana M, Matsushima Y, Kobayashi Y, Adachi W, et al. Expression of sex steroid hormone receptors in human cornea. Curr Eye Res 2001;22:28-33.
5.	Macsai M, Maguen E, Nucci P. Keratoconus and Turner's syndrome. Cornea 1997;16:534-6.
6.	Karamichos D, Barrientez B, Nicholas S, Ma S, Van L, Bak-Nielsen S, et al. Gonadotropins in keratoconus: The unexpected suspects. Cells 2019;8:E1494. doi: 10.3390/cells8121494.
7.	Coco G, Kheirkhah A, Foulsham W, Dana R, Ciolino JB. Keratoconus progression associated with hormone replacement therapy. Am J Ophthalmol Case Rep 2019;15:100519. doi: 10.1016/j.ajoc. 2019.100519.
8.	Loukovitis E, Sfakianakis K, Syrmakesi P, Tsotridou E, Orfanidou M, Bakaloudi DR, et al. Genetic aspects of keratoconus: A literature review exploring potential genetic contributions and possible genetic relationships with comorbidities. Ophthalmol Ther 2018;7:263-92.
9.	Esin S, Baser E, Kucukozkan T, Magden HA. Ovarian gonadoblastoma with dysgerminoma in a 15- year-old girl with 46, XX karyotype: Case report and review of the literature. Arch Gynecol Obstet 2012;285:447-51.
10.	Thanos S, Oellers P, Meyer ZU, Hörste M, Prokosch V, Schlatt S, et al. Role of thyroxine in the development of keratoconus. Cornea 2016;35:1338-46.
11.	Spoerl E, Zubaty V, Raiskup-Wolf F, Pillunat LE. Oestrogen-induced changes in biomechanics in the cornea as a possible reason for keratectasia. Br J Ophthalmol 2007;91:1547-50.
12.	Soeters N, Tahzib NG, Bakker L, Van der Lelij A. Two cases of keratoconus diagnosed after pregnancy. Optom Vis Sci 2012;89:112-6.
13.	Suzuki T, Kinoshita Y, Tachibana M, Matsushima Y, Kobayashi Y, Adachi W, et al. Expression of sex steroid hormone receptors in human cornea. Curr Eye Res 2009;22:28-33.
14.	Gupta PD, Johar Sr K, Nagpal K, Vasavada AR. Sex hormone receptors in the human eye. Sur Ophthalmol 2005;50:274-84.