A Case of Turner’s Syndrome, with Apparently Normal Sex Chromatin and Chromosome Findings

Abstract

A case of an infertile female with 46 chromosomes and apparently normal sex chromatin is reported. The clinical findings resemble those of Turner’s syndrome with 45 chromosomes (designated as 45,X) and abnormal sex chromatin findings. A gonadal biopsy revealed streaked ovaries with fibrous connective tissue and no evidence of ovulation or primordial follicles. Chromosome studies of the peripheral blood lymphocytes, skin, and ovarian tissue revealed the presence of 46 chromosomes and an isochromosome of the long arm of the X chromosome, designated as 46,X,i(Xq). There was no evidence of chromosomal mosaicism.

This case emphasizes the importance of performing a complete chromosome analysis in patients who present with the clinical features of Turner’s syndrome, but who have apparently normal sex chromatin findings. The analysis can effectively rule out the syndrome, and can also provide a basis for prognosis and management of the patient, including genetic counseling of the family members.

Turner’s syndrome occurs with a frequency of approximately 1 in 2,800 female births. Patients with this condition are phenotypic females; however, the ovaries are not developed properly and thus the term gonadal dysgenesis is used. As a result of ovarian dysfunction, the estrogen levels are decreased and the gonadotropins are elevated. Due to the decreased estrogen levels, the clinical findings may include decreased secondary sex characteristics, primary amenorrhea, and premature menopause, as well as short stature, webbing of the neck, cubitus valgus, broad chest and widely spaced nipples, low posterior hair line, pigmented nevi, coarctation of the aorta, and renal anomalies. A few or all of these findings may be found in a patient with Turner’s syndrome.

One of the initial laboratory procedures used to confirm or rule out this diagnosis involves a sex chromatin determination from a buccal smear. Cells from the lining of the mouth are stained for the presence or absence of X-chromatin or Barr bodies, which represent a portion of an inactivated X chromosome. The typical Turner’s syndrome patient, who has 45 chromosomes and only one sex chromosome (an X), has no Barr bodies and is, therefore, X-chromatin negative.

This abnormal X-chromatin negative finding in the majority of Turner’s syndrome females is similar to the result found in a normal male, who also has only one X chromosome, and differs from the X-chromatin positive condition observed in the normal female, who has two X chromosomes. Occasionally, the patient with features of Turner’s syndrome is found to be X-chromatin positive. This apparently normal X-chromatin result in such a female may tempt one to eliminate Turner’s syndrome from consideration in the differential diagnosis. However, in cases such as this, a chromosome (karyotype) analysis is necessary in order to determine if the patient has more than one genetic cell line (i.e., is a mosaic) or has 46 chromosomes and an isochromosome of the X.

This report documents one of the atypical cases, a female who presented with the clinical features of Turner’s syndrome, but who was X-chromatin positive and who had 46 chromosomes, rather than being X-chromatin negative and having 45 chromosomes, as in the majority of the cases of Turner’s syndrome.

Case Report

The patient was a 35 year old white female, nulligravida, who was admitted to the hospital with the complaint of crampy, intermittent left lower quadrant pain accompanied with nausea, vomiting, and occasional diarrhea. She first experienced this problem approximately four months before admission, and stated that she had used antacids and tranquilizers to relieve the pain.

The past medical history revealed episodes of intermittent hematuria. A retrograde intravenous pyelogram demonstrated a bifid ureter and an upper collecting system on the right, which was thought to be the etiology of the hematuria. The patient also had a history of urinary tract infections during the past year which were treated with antibiotics.

On further questioning, it was found the patient had been amenorrheic for approximately one year, and before that had an irregular history of menstruation. The patient’s menarche was at 17 years, and her menses were three to six months apart before she experienced premature menopause approximately one year ago. She and her husband had attempted pregnancy for the past twelve years, but with no success. She had no history of abnormal Papanicolaou smears or pelvic pathology. The recent episode of amenorrhea had not been associated with dyspareunia or other signs of menopause. The family history was non­contributory. The patient’s parents were of a normal size with heights greater than the 50th percentile.

The general examination revealed a short stature of 145 cm (less than the 10th percentile) and a weight of 49 kg (10–20th percentile). The vital signs included a blood pressure of 128/90 mm Hg, an oral temperature of 37.0° C, and a pulse of 90. The skin revealed pigmented nevi of the upper body. The HEENT exam was normal except for some fullness of the neck, but there was no adenopathy and the thyroid was not palpable or tender. The chest showed small glandular breasts bilaterally and the lungs were clear to auscultation and percussion. The cardiovascular system revealed no heart murmur and the pulses were normal. The abdomen was soft, without abdominal masses but tenderness was elicited over the lower abdomen. The musculoskeletal system contained no gross deformities. The neurological exam was unremarkable. A pelvic examination revealed normal external genitalia, atrophic vaginal mucosal changes, a small atrophic cervix, and a very small anterior uterus. No ovaries or masses were palpable in the adnexal region. Due to the late menarche, oligomenorrhea, premature menopause, short stature, pigmented nevi, decreased secondary sex characteristics and renal anomalies, X-chromatin and chromosome studies were performed.

The admission hematocrit was 43% , hemoglobin of 13.6 gm/dl, and a WBC of 9,600, with 42% neutrophils, 2% bands, 48% lymphocytes, 2% eosinophils, and 6% monocytes. Electrolytes were all normal, as were calcium, phosphate, glucose, BUN, creatinine, uric acid, cholesterol, bilirubin, total protein, albumin, alkaline phosphatase, LDH, SGOT, and amylase. The FSH level was 30.6 mU/ml (upper limits of normal is 20 mU/ml). The lipid profile, protein electrophoresis, porphyrin screen, porphobilinogen, T₄, T₃ resin uptake, and Schilling’s test were normal. The urinalysis showed 3–6 RBC/HPF and 10 WBC/HPF, but the urine cultures were negative. The stool showed no trace of blood, ova, parasites, or cysts, and the cultures were negative. Routine chest and abdominal x-rays were normal, as were the UGI, small bowel series, barium enema, abdominal ultra­sound, and proctoscopy.

To aid in identifying the etiology of the patient’s abdominal pain, a laparoscopy and cystoscopy were performed. The cystoscopy showed normal mucosa with no signs of inflammation or abnormality, while the laparascopy revealed streaked ovaries bilaterally and an underdeveloped uterus. Because of the clinical findings, portions of ovary and umbilical skin from the abdominal wall were sent to Genetics for chromosome studies to rule out mosaicism and to Pathology for evaluation. Adhesions from the descending colon to the anterior abdominal wall were identified and lysed.

The patient was discharged after recovery from the abdominal complaints. It is thought the abdominal adhesions were the etiology of her discomfort. The microscopic hematuria present on admission resolved and no further urological evaluation was planned. The patient returned six months after discharge with no complaints and she was instructed on the signs of premature menopause due to Turner’s syndrome. She presently is considered in good health.

Results and Discussion

The first description of Turner’s syndrome characterized as having 45 chromosomes (designated at that time as 45,XO) was in 1959.¹ The first description of Turner’s syndrome associated with a female ­type and 46 chromosomes, including one normal X and one X chromosome similar in karyo length to the #3 chromosome, was in 1960.² The abnormal X was shown to be an isochromosome for the long arms of the X and the karyotype is designated as 46,X,i(Xq). The 46,X,i(Xq) patient with Turner’s syndrome is clinically undistinguishable from the typical Turner’s syndrome patient with what is now termed the 45,X karyotype. Schmid and others in 1974³ reported that 13% of patients with Turner’s syndrome have a 46,X,i(Xq) karyotype.

Other cases of the 46,X,i(Xq) karyotype in Turner’s syndrome have been reported.^{3, 4, 5, 6} The Turner’s syndrome phenotype can also appear with other chromosome arrangements. These include reports of 46,XXp-^{6, 7} (deletion of part of the short arm of one of the X chromosomes), 46,XXq-^{3, 6–10} (deletion of part of the long arm of one of the X chromosomes), 46,XXr^{3, 6} (one of the X chromosomes is in the configuration of a ring), mosaicism of the XX/XO type^{3, 6, 11} and an isolated report of the fusion of the short arms of one of the X chromosomes.¹²

To understand the etiology of the Turner’s syndrome phenotype in individuals with the 46,X,i(Xq) chromosome complement, isochromosome formation must be understood. An isochromosome is a chromosome in which both the long and short arms are identical. This phenomenon arises when during meiotic or mitotic division a chromosome and its centromere divide horizontally rather than longitudinally, thus producing two abnormal daughter chromotids, one containing only the short arms and one containing only the long arms. The short arm is designated as p, the long arms as q, and an isochromosome as i. Hence, an isochromosome for the long arm of an X is i(Xq).

If fertilization occurs between a gamete containing an isochromosome for the long arm of the X chromosome and a normal gamete, then effectively the individual developing from such a combination would have only one set of genes in the short arms (monosomy) and three sets of genes in the long arms (trisomy). Due to the monosomic condition of the genes on the short arms of the X, which is the same condition as in the classical 45,X chromosome complement, Turner’s syndrome occurs.

The karyotype studies of our patient can be found in Table 1. These studies revealed the presence of the abnormal female chromosome complement in the three tissue types studied (Figures 1 and 2). There was no evidence of either intratissue or intertissue chromosomal mosaicism. The buccal smear, stained with cresyl-echt violet for identification of the X-chromatin body, was X-chromatin positive, with 24% of the cells containing one abnormally large X-chromatin or Barr body, which represents a temporarily, physically inactivated portion of the X isochromosome (Figure 3). The normal female control was X-chromatin positive, with 29% normal sized X-chromatin bodies, while the normal male control was X-chromatin negative. Staining for Y-chromatin revealed our patient and the female control to be Y-chromatin negative, indicating the lack of a Y chromosome.

Table 1.

Karyotype Studies ^*

Origin of Tissue	Number of Metaphase Plates Analyzed	Number of Metaphase Plates With 46,X,i(Xq)
Blood lymphocytes	30	26
Skin	30	30
Ovary	30	26

^*Karyotypes were made from metaphase plates stained with conventional Giemsa and the Giemsa-Trypsin (GTG) banding techniques.

Figure 1.

Karyotype of ovarian fibroblast stained with Giemsa, showing the 46,X,i(Xq) pattern.

Figure 2.

Blood lymphocyte karyotype, banded with the Giemsa-Trypsin technique, showing the 46,X,i(Xq) pattern.

Figure 3.

Picture of buccal epithelial cells stained with cresyl-echt violet, showing the abnormally large X-chromatin or Barr body of the 46,X,i(Xq) karyotype (on the left), compared to the normal sized X-chromatin body of a normal female control (on the right).

The ovarian biopsy showed the most common features described in Turner’s syndrome: dense fibrous connective tissue consistent with ovarian stroma, no corpora albicantes, no primordial follicles, nor any other evidence of ovulation. The streaked ovary is a common finding in these individuals and causes hypoestrinism. Many of the phenotypic characteristics are reflections of the low estrogen levels. After puberty, the reduced levels of ovarian estrogen lead to elevated pituitary gonadtropin secretion, which was the case with our patient.

Our patient presented as a typical Turner’s syndrome with decreased secondary sex characteristics, short stature, fullness in the area of the neck, pigmented nevi, streaked ovaries, and renal anomalies. However, unlike the classical Turner’s syndrome patient, she was X-chromatin positive. This case emphasizes the importance of performing a complete chromosome analysis in patients who present with the clinical features of Turner’s syndrome, but who have apparently normal sex chromatin findings. The karyotype analysis can not only effectively rule out the syndrome, but can also provide a basis for prognosis and management of the patient, including genetic counseling of family members.

References may be obtained from the authors.