CASE REPORT Bali Medical Journal (Bali MedJ) 2021, Volume 10, Number 2: 553-558 P-ISSN.2089-1180, E-ISSN: 2302-2914 Primary amenorrhoea caused by Turner syndrome: A case series

Published by Bali Medical Journal Hilwah Nora1*, Cut Nonda Maracilu2, Mohd Andalas3, Muhammad Hikmawan Priyanto4

ABSTRACT

Background: is a condition where women do not experience menstruation or the cessation of menstrual cycles at reproductive age. Amenorrhea is divided into primary and secondary. Turner syndrome is one example of gonadal dysgensis that cause the most common primary amenorrhea. It is represented by the absence of all or part of the normal second sex chromosome and physical features including short stature, webbed neck, cubitus valgus, pterygium colli, low hairline, edema of the hands and feet, and shield chest. Clinical pictures and karyotype of Acehnesse patients with Turner syndrome are presented in this study. The patients involved in the study were those who came to an endocrinology clinic in a tertiary care center. Case Presentation: We reported four cases of Turner syndrome which were confirmed from anamnesis, physical examination and chromosomal analysis at the Department of Obstetrics and Gynecology in the Fertility, Endocrine and Reproductive Division of RSUD Dr. Zainoel Abidin Banda Aceh. Conclusion: All patients with Turner syndrome had amenorrhea, short stature, bone deformity and underdeveloped primary dan secondary sexual characteristic. Only one case has monosomy X (45, XO), a mosaic chromosomal component was present in the rest of them (45, X with mosaicism).

1Consultant at Department of Obstetrics Keywords: Turner Syndrome, Primary amenorrhea, Gonad dysgenesis. and Gynecology, Faculty of Medicine, Cite This Article: Nora, H., Maracilu, C.N., Andalas, M., Priyanto, M.H. 2021. Primary amenorrhoea caused by Turner Syiah Kuala University, Dr. Zainoel syndrome: A case series. Bali Medical Journal 10(2): 553-558. DOI: 10.15562/bmj.v10i2.2407 Abidin-Banda Aceh General Hospital, Indonesia; 2Resident at Department of Obstetrics and Gynecology, Faculty of Medicine, INTRODUCTION have never experienced menstruation at age Syiah Kuala University, Dr. Zainoel 14 with secondary sexual characteristics Abidin-Banda Aceh General Hospital, Menstrual problems are more common in absence, or at age 16 with normal growth and Indonesia; younger people, especially in developing development of secondary sexual characteristics. 3Professor at Department of Obstetrics countries. This problem puts pressure on a and Gynecology, Faculty of Medicine, (2) Secondary amenorrhoea is defined as the person’s social, emotional and psychological ceasing of menstruation for at least 3 consecutive Syiah Kuala University, Dr. Zainoel life along with the emergence of gynecological Abidin-Banda Aceh General Hospital, months in women who have previously had problems.1 Women experiencing menstruation Indonesia; regular menstruation.3 In Rebar R (2018), some 4Faculty of Medicine, Syiah Kuala for the first time (called menarche ) is a sign of physicians will consider to start the evaluation University, Banda Aceh, Indonesia. entering puberty, an early sign of functioning of a girl with primary amenorrhoea at age 14, of the reproductive system and entering the especially if it has been more than 5 years since maturity stage of the sexual organs in the body, the first sign of pubertal development. Women many changes appear including physical and who are menstruating less than nine times in 12 *Corresponding author: mental changes which usually occur in the range Hilwah Nora; months (defined as ) should be of age 10-16 years or at early adolescence before evaluated like women who experience secondary Consultant at Department of Obstetrics entering the reproductive period. About 5.2 % and Gynecology, Faculty of Medicine, amenorrhea. These women usually experience of children’s menarche occurs in 17 provinces in Syiah Kuala University, Dr. Zainoel oligo or . Primary and secondary Abidin-Banda Aceh General Hospital, Indonesia under the age of 12. The difference in amenorrhea that occur as a result of artificial Indonesia; each country for the age of menarche is influenced action, for example, medicinal amenorrhea/ [email protected] by environmental conditions, nutritional status, 2 iatrogenic amenorrhea, cannot be included in the physical activity and genetic factors. evaluation results of women for amenorrhea.4 Amenorrhoea is the absence of menarche The prevalence of amenorrhoea without in women of reproductive age. Amenorrhoea Received: 2021-04-20 pregnancy, breastfeeding, or menopause is is classified into two, namely: (1) Primary 3-4%. Amenorrhoea reflects the failure of the Accepted: 2021-06-23 amenorrhea, defined as circumstances that Published: 2021-06-30 hypothalamic-pituitary-gonadal to induce

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cyclic changes in the that usually causes menstruation and can also occur due to lack of the presence of secondary sex organs or their obstruction tool genitalia. Amenorrhoea can result from abnormalities at any level of the reproductive tract.4 World Health Organization (WHO) estimates amenorrhoea is the 6th cause of infertility worldwide and affects women of childbearing age as much as 2-5%.5 Even so, amenorrhoea is not a diagnosis and is only a sign of a disease. Normally, menstruation occurs at 28 ± 3 day intervals with a normal range of 18-40 days in two-thirds of women. The three causes that need to be considered in categorizing amenorrhoea Figure 1. ( a ) Clinical photo of the patient; (b) Chromosome Analysis Results. are: (1) Anatomical condition, including pregnancy, which almost can be detected by physical examination alone; (2) Ovarian failure; (3) Chronic anovulation as a result from various endocrine disorders.4 Research on amenorrhoea has been conducted since a long time ago, stating that gonadal dysgenesis is the most common cause of primary amenorrhea. Turner syndrome by 43%, followed by Agenesis Mullerian as much as 15% and Delayed puberty as much as 14%. These three causes are the most common causes of gonadal dysgenesis that cause primary amenorrhea.6 Turner syndrome is a common condition in which a woman with a chromosomal abnormality originating from the absence of a second sex chromosome, either partial or total, with or without cell line mosaic, becomes X monosomy (45, X).7,8,9 Figure 2. (a) Clinical photo of the patient. ( b ) Results of chromosome analysis. This chromosomal abnormality affects approximately 1 in 2500 female patients.10 Typical abnormalities in Turner Syndrome system such as a malformation of the the next process is not followed by include short stature, gonadal dysgenesis koligentes duct in the nephron system and normal meiotic division, it will cause (usually reflecting ovarian failure),a hoof-like kidney shape that occurs in rapid oocyte cell loss. About 70-80% characteristic facial shape, webbed/ 3040% of patients. There are eye disorders of sufferers do not experience short neck, short hair, wide chest with such as epicanthus, ptosis, strabismus and puberty development and 90% of sufferers sparse nipple spacing, nevus throughout hyperopia, abnormalities in the hearing experience primary amenorrhoea.6 Cyclic the body, shorter IV metacarpals, small system (chronic otitis media and deformed replacement of estrogen and progesterone nails, shield-shaped chest, unfavorable ears) and immune disorders (autoimmune is required to induce the development of breast development, and cardiovascular thyroiditis). Turner Syndrome patients puberty starting at the age of 11 years. At anomalies. Many patients develop with epilepsy have also been reported to the age of 13-14 years, adolescent girls coarctation of the aorta, cardiovascular be associated with developing cortical with Turner Syndrome should undergo a abnormalities, lymphedema during malformations.6,11 process of counseling regarding options fetal life leading to cystic hygroma, and In Turner Syndrome, when the germ for fertility and other patients who have primary or secondary amenorrhoea. cells in the ovarian epithelium undergo a mosaic karyotype and who experience People with Turner Syndrome also migration which is then followed by spontaneous puberty accompanied by experience abnormalities in the urinary a normal mitotic division process but no increase in FSH or decrease in AMH,

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for pubic hair (no hair, figure 1a). The blood laboratory on July 4 2019 obtained Haemoglobin 14.6 gr/dl, Haematocryte 39%, leukocytes 7,400/m3, platelets 279,000 /m3, blood sugar levels at 111 gr /dl. Ultrasound examination revealed a rudimentary . From laboratory finding, the Anti Mullerian Hormone (AMH) level results were <0.01 ng/mL (normal value: 1.2-4.6 ng/ml). Her low AMH level showed a premature ovarian failure. Her abnormal chromosome result was mosaicism of 45X with another cell line: 45, X [19] / 46, X, i (X) (q10) [21] (figure 1b). Based on the history, physical examination and investigations, the patient was diagnosed with primary amenorrhoea e.c. Turner Figure 3. (a) Clinical photo of the patient. (b) Results of chromosome analysis. Syndrome. Case 2 A 22-year-old woman came complaining that she had never had a period. The patient also complained of the absence of secondary sex growth. Physical examination of the patient found: a. Posture short stature (height 140 cm, body weight was 30 kgs) accompanied with lumbar scoliosis, webbed neck, chest-shaped shield ( shield-like chest ). b. Undeveloped breast glands and areola follow the contour of the chest skin (Tanner stage I ) c. No pubic hair was found (Tanner stage I ). Gynecological examination found vulva urethra within normal limits, but the vaginal opening was not found. On Figure 4. (a) Clinical photo of the patient, (b) Results of chromosome analysis. ultrasound examination (USG) with a difficult impression of the uterus to be because it is currently starting to consider 138 cm, BMI 26.2 kg/m2 (short statue). assessed, the right and left ovaries are 6 plans for cryopreservation. Her forearm was angled out away from difficult to assess. From the karyotypic the body when the arm was fully extended examination results are 46, X, r? (X) [28} CASE PRESENTATION (cubitus valgus). She also had a shield / 45, X [12] (Figure 2a and 2b) . Case 1 chest and a low hairline. Assessment of maturation in secondary A 28-year-old woman came with a Case 3 sexual development recognized by complaint that she had never experienced A 28-year-old woman came with a Sexual Maturity Rating or Tanner Stage menstruation until 1 year ago after using complaint that she had never had a which is used to document and track the contraception pills which were obtained menstrual period. None of her family development and sequence of secondary by an obstetrician and gynecologist when members had the same case. On physical sex characteristics during puberty, she was 27 years old. Every time she took examination, we found a short stature with adolescence and adult. Tanner’s stage birth control pills, she got menstruation for a height of 125 cm, and a broad chest, and evaluates 6 days and changes sanitary napkins once sparse and straight armpit hair and pubic the growth of pubic hair and breast a day. No history of in hair (Tanner stage II). In gynecological development. This patient had Tanner her family. On physical examination, the status, the labia majora and minora were Stage 2 (breast bud only) for breast patient’s body weight was 50 kgs, height found within normal limits, intact hymen development and also Tanner Stage 1

Published by Bali Medical Journal | Bali Medical Journal 2021; 10(2): 553-558 | doi: 10.15562/bmj.v10i2.2407 555 CASE REPORT

Table 1. The 4 cases of Turner Syndrome Physical Examination Case Complaint Body Web Spine Elbow Breast Pubic Tanner Height (cm) Neck deformity Deformity Development Hare Stage 1 Amenorrhea 138 No No Yes Breast bud No Tanner 1 2 Amenorrhea 140 Yes Scoliosis Yes No No Tanner 1 Lumbalis 3 Amenorrhea 120 Yes Scoliosis Yes Breast Bud Scarce, Tanner 2 Lumbalis straight 4 Amenorrhea 132 Yes Scoliosis Yes Breast Bud Scarce, Tanner 2 Lumbalis straight

Table 2. Karyotypic examination results other characteristics.12,13 Turner syndrome Case Age (yo) Karyotype Type is associated with a variety of morbidities 1 28 45, X [19] / 46, X, i [X] (q10) [21] Mosaic that can affect nearly every system of the 2 22 46, X, r? (X) [28} / 45 , X [12] Mosaic body and become increasingly affected 3 28 45, X Monosomi during adult life such as linear growth 4 37 45, X [30] / 46, X, i (X) (q10) [10]. Mosaic failure, ovarian insufficiency (delayed puberty), sensorineural hearing loss, typical cardiovascular disease, skeletal and within normal limits. Case 4 anomalies, anomalies of the fingers and From the results of laboratory tests, the A 37-year-old woman came complaining kidneys, certain neurodevelopmental estradiol levels were low (10.1 pg / mL), that she never had menstruation. This profiles, and a constellation of other while the FSH and LH levels were high patient also had hearing problems disorders that are more common in Turner (FSH: 73.74 mIU / mL, LH: 23.02 mIU / (deafness). On physical examination, she Syndrome, including hypothyroidism and mL, Anti-Mullerian Hormone: <0.13 ng had a short stature with a body height of celiac disease. Of all the characteristics / mL) suggests premature ovarian failure. 132 cm, a webbed neck, and a shield-like above, the ones that stand out are Another examination performed was chest with a wide gap between the nipples, hypothyroidism, diabetes mellitus, a karyotype (45, X) indicating Turner scoliosis of the lumbar, and cubitus vagus. hypertension, and osteoporosis.12,13 Syndrome. Her secondary sexual characteristics The other result was the low level of The patient also performed an X-ray were Tanner Stage II for breast growth Anti Mullerian Hormone (AMH <0.01 of the antebrachial, lumbosacral, pelvic, with the areola widens, darkens slightly, ng / mL in case 1 and AMH<0.13 ng / and cruris where scoliosis was found and elevates from the rest of the breast mL in case 2). Decreasing AMH level in the lumbar spine tilted to the left and like a small mound. Her pubic hair grew was one of the signs of premature ovarian the pelvis in the form of an android type. sparse, straight, and only slightly curled, failure for reproductive-age females. From the MRI examination, it was found (Tanner stage II ). Ultrasound examination Turner Syndrome typically results in the that uterine hypoplasia. revealed a rudimentary uterus. The results most severe and irreversible premature The patient is also referred to the of laboratory examination found that TSHs ovarian failure, often clinically evident Eye and ENT department due to eye levels: 1,750, FT4: 100,78, the impression before menarche. Premature ovarian and hearing problems. From the ENT was within normal limits. The karyotypic failure (POF) is a primary ovarian examination, they found bilateral examination found mosaic chromosomes defect characterized by absent menarche sensorineural deafness and sclerosis of the with 45, X [30] / 46, X, i (X) (q10) [10]. (primary amenorrhea) or premature tympanic membrane of the left ear, but the depletion of ovarian follicles before the eye examination was within normal limits. DISCUSSION age of 40 years (secondary amenorrhea). From the results of the echocardiography Typically, in Turner Syndrome, We reported 4 cases of Turner Syndrome. examination, it was found that the function menopause precedes menarche, and there The most common complaint submitted of the four chambers of the heart was in is no evidence of ovarian function. POF by patients was amenorrhoea and good condition, left ventricular systolic is biochemically characterized by low physical examination reveals short stature function (Ejection Fraction (EF) 67%), left levels of gonadal hormones (estrogens and and underdeveloped secondary sexual ventricular diastolic function was good, inhibins) and high levels of gonadotropins development (table 1). the movement of the left ventricular wall (LH and FSH) as shown in case 3: FSH Turner Syndrome implies the presence was normokinetic with the conclusion of 73.74 mIU / mL, LH 23.02 mIU / mL. of physical characteristics such as short normal echocardiography results with EF The elevation of FSH is usually more stature, webbed neck, and lymphedema. 67%. The results of the examination of marked than that of LH and an FSH value The clinical manifestations of Turner TSH, T3, and T4 levels were within normal >30 U/L is indicative of ovarian failure. Syndrome can be extended to include limits (T3: 1.51; T4: 91.18 and TSH: 1.93) Beyond infertility, hormone defects may

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cause severe neurological, metabolic, or Other more complex karyotypes include ETHICAL CONSIDERATION cardiovascular consequences and lead to chromosomal translocations and mosaics the early onset of osteoporosis. 45, X / 47, XXX.12 This case series have obtained the ethical Uterine development is also altered In this study, the karyotypic examination approval from the Health Research Ethics in girls with Turner syndrome. USG that had been performed shows that only Commission of Faculty of Medicine of examination showed rudimentary uterus one patient had complete monosomy Univesity of Syiah Kuala – Dr Zainoel in cases 1 and 4, while in case 2 patient (45, X) while the rest have Turner mosaic Abidin Hospital. All patients and their uterus was difficult to assess. About half of (Table 2). In population about 40-50% of families have understood and agreed to the cases of primary amenorrhea are due women with Turner Syndrome present the publication of this article. to ovarian dysgenesis, which is revealed by with karyotype 45, X 15-25% have AUTHOR CONTRIBUTION the finding of streak ovaries accompanied mosaicism with 45, X / 46, XX about 20% by uterus hypoplasia at the ultrasound. of women have isochromosomes, and the All authors contributed to the study, Turner syndrome is associated with X ring chromosome is present in a few including literature research, data multiple skeletal abnormalities. Scoliosis women.14 As many as 10-12% of women collection, data analysis, and manuscript was found in all cases in this study but had a different amount of Y chromosome preparation only one case performed radiological material, while 3% were present with 45, examinations of lumbosacral and pelvic X / 46, XY.14,15 None of the patients with REFERENCES X-rays which found scoliosis of the lumbar mosaic karyotype in this study had a Y 1. Khudija A, Dar HZ, Heema, Farhat R, Unar vertebrae. Scoliosis occurs in around chromosome, most of the case have 45, X F, Shaikh AG. Raised BMI and Disturbed 10% of adolescent girls with Turner / 46, XX. Menstrual Cycle. APMC 2018;12(3):179- syndrome and may contribute to short All of the patients present to our health 81. stature. Scoliosis screening is therefore facility in Aceh in their post-adolescent 2. Herawati, Muchtar M, Sartika W, Syarwini. usually undertaken. Women with small age (22 yo to 37 yo). 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