Mosaic 46, XY / 47, XXY With SRY Deletion in a Female With Complete Gonadal Dysgenesis: The Second Documented Case
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
This is the second documented case of a mosaic 46, XY/47, XXY phenotypic female with SRY deletion and complete gonadal dysgenesis.
Case Presentation
The patient, SK, was a 15 year old female with no significant medical history, who presented with primary amenorrhea and no breast development. More detailed history revealed one episode of vaginal spotting at age 10, scant axillary and pubic hair development at 11, and minimal breast development at 13 with none since. She had never had a growth spurt. She reported clear vaginal discharge from age 13, and denied acne or hirsutism.
Diagnostic Workup
On physical examination, SK was Tanner stage 1 for breasts, and 80th percentile for height. Initial diagnostic workup was significant for elevated Follicle Stimulating Hormone at 133.8mIU/L. Prolactin and Thyroid Stimulating Hormone were within normal limits, and blood pregnancy test was negative. Pelvic ultrasound showed a small, peripubertal uterus with thin endometrial stripe, no visualized right ovary, and a small hypoechoic ovoid structure within the left adnexa, likely a gonad/ovary.
Karyotype revealed 46, XY / 47, XYY (60:40) mosaicism. Chromosomal Microarray Analysis with FISH demonstrated a non-recurrent 3.2Mb deletion in the Y chromosome at Yp11.32, inside the pseudoautosomal region 1 and ranging from CRLF2 to ZFY, encompassing SRY. Notably, not all TSPY genes were encompassed in the deleted region.
Pelvic examination by adolescent gynecology showed Tanner Stage 4 pubic hair and typical female external genitalia with a small posterior labial adhesion, and 6cm vaginal length. Further laboratory evaluation revealed elevated repeat FSH at 116.7mIU/L and low estradiol at 16pg/mL, which confirmed primary gonadal failure. Testosterone was elevated at 1.05ng/mL. Bone age X-ray at 16 years and 3 months chronological age showed delayed bone age approximating 14 years. MRI of the abdomen and pelvis revealed a normal vagina and peripubertal sized uterus, and did not identify any gonadal structures.
Treatment and Management
Multiple lengthy discussions were had involving gynecology, psychology, and genetics to help the patient and family comprehensively understand her diagnosis. SK endorsed a definitive female gender identity, which informed the treatment course. She was started on hormone replacement therapy via transdermal estrogen patch. Gonadectomy and salpingectomy were performed due to risk of malignant transformation. Pathology reported two streak gonads composed primarily of viable gonadoblastoma tissue, with background ovarian stromal cells and rare tumor cells, with calcifications present. There were fallopian tubes and adjacent Wolffian structures present, without any invasive germ cell tumor component.
Outcome and Follow-Up
She recovered well postoperatively. Her height has plateaued, likely due to bone maturation and closure of growth plates. She has also since reported breast development and expressed desire to continue with estrogen.
Discussion
There are fewer than 20 documented case of 47, XXY individuals with SRY deletion and a female phenotype. Some of these patients have had symptoms associated with Klinefelter Syndrome, such as cognitive and intellectual challenges, and tumors commonly associated with Klinefelter Syndrome, neither of which were found in SK. One other case of a 46, XY/47, XXY mosaic has been documented, with a similar mosaicism ratio (55:45). The person detailed in that paper also had no significant past medical history, a female phenotype, and gonadoblastoma bilaterally. These cases raise interesting questions about whether a phenotypically female 47, XXY individual can be diagnosed with Klinefelter Syndrome, or whether it is a diagnosis exclusive to a male phenotype. It remains uncertain to what degree SK's mosaicism affected her presentation.
Conclusion
This is a unique case with interesting implications for the diagnosis of Klinefelter Syndrome and how mosaicism affects presentation. Additionally, it presents interesting questions about how, besides male-sex differentiation, the SRY region affects the development of people with a 47, XXY genotype.
This is the second documented case of a mosaic 46, XY/47, XXY phenotypic female with SRY deletion and complete gonadal dysgenesis.
Case Presentation
The patient, SK, was a 15 year old female with no significant medical history, who presented with primary amenorrhea and no breast development. More detailed history revealed one episode of vaginal spotting at age 10, scant axillary and pubic hair development at 11, and minimal breast development at 13 with none since. She had never had a growth spurt. She reported clear vaginal discharge from age 13, and denied acne or hirsutism.
Diagnostic Workup
On physical examination, SK was Tanner stage 1 for breasts, and 80th percentile for height. Initial diagnostic workup was significant for elevated Follicle Stimulating Hormone at 133.8mIU/L. Prolactin and Thyroid Stimulating Hormone were within normal limits, and blood pregnancy test was negative. Pelvic ultrasound showed a small, peripubertal uterus with thin endometrial stripe, no visualized right ovary, and a small hypoechoic ovoid structure within the left adnexa, likely a gonad/ovary.
Karyotype revealed 46, XY / 47, XYY (60:40) mosaicism. Chromosomal Microarray Analysis with FISH demonstrated a non-recurrent 3.2Mb deletion in the Y chromosome at Yp11.32, inside the pseudoautosomal region 1 and ranging from CRLF2 to ZFY, encompassing SRY. Notably, not all TSPY genes were encompassed in the deleted region.
Pelvic examination by adolescent gynecology showed Tanner Stage 4 pubic hair and typical female external genitalia with a small posterior labial adhesion, and 6cm vaginal length. Further laboratory evaluation revealed elevated repeat FSH at 116.7mIU/L and low estradiol at 16pg/mL, which confirmed primary gonadal failure. Testosterone was elevated at 1.05ng/mL. Bone age X-ray at 16 years and 3 months chronological age showed delayed bone age approximating 14 years. MRI of the abdomen and pelvis revealed a normal vagina and peripubertal sized uterus, and did not identify any gonadal structures.
Treatment and Management
Multiple lengthy discussions were had involving gynecology, psychology, and genetics to help the patient and family comprehensively understand her diagnosis. SK endorsed a definitive female gender identity, which informed the treatment course. She was started on hormone replacement therapy via transdermal estrogen patch. Gonadectomy and salpingectomy were performed due to risk of malignant transformation. Pathology reported two streak gonads composed primarily of viable gonadoblastoma tissue, with background ovarian stromal cells and rare tumor cells, with calcifications present. There were fallopian tubes and adjacent Wolffian structures present, without any invasive germ cell tumor component.
Outcome and Follow-Up
She recovered well postoperatively. Her height has plateaued, likely due to bone maturation and closure of growth plates. She has also since reported breast development and expressed desire to continue with estrogen.
Discussion
There are fewer than 20 documented case of 47, XXY individuals with SRY deletion and a female phenotype. Some of these patients have had symptoms associated with Klinefelter Syndrome, such as cognitive and intellectual challenges, and tumors commonly associated with Klinefelter Syndrome, neither of which were found in SK. One other case of a 46, XY/47, XXY mosaic has been documented, with a similar mosaicism ratio (55:45). The person detailed in that paper also had no significant past medical history, a female phenotype, and gonadoblastoma bilaterally. These cases raise interesting questions about whether a phenotypically female 47, XXY individual can be diagnosed with Klinefelter Syndrome, or whether it is a diagnosis exclusive to a male phenotype. It remains uncertain to what degree SK's mosaicism affected her presentation.
Conclusion
This is a unique case with interesting implications for the diagnosis of Klinefelter Syndrome and how mosaicism affects presentation. Additionally, it presents interesting questions about how, besides male-sex differentiation, the SRY region affects the development of people with a 47, XXY genotype.