(25) Chimeric Monochorionic Diamniotic 3 -Year-Old Female with Male Brother

Background: While traditionally monochorionic twins are understood to be monozygotic, researchers have identified atypical forms of twinning resulting in monochorionic dizygotic (MCDZ) twins. As a result, intrauterine twin-twin transfusion pathways can result in blood chimerism with one neonate subsequently having two blood cell lines.

Case: A 3-year-old female presented to the subspecialty combined clinic consisting of endocrinology, genetics, and pediatric and adolescent gynecology (PAG) physicians secondary to abnormal placental genetic testing noting monochorionic diamniotic (MCDA) twinning without placental fusion and subsequent concern for chimerism. The patient was born as a MCDA twin but was found to be non-identical to her twin brother. Her physical exam at the multidisciplinary clinic was grossly unremarkable with a normal thyroid without nodularity, normal appearing external female genitalia, no clitoromegaly, visible urethral and vaginal openings, no labial fusion, no palpable masses within the labia or inguinal canals, and tanner stage 1 for breast and pubic hair development. A transabdominal pelvic ultrasound showed a 3.5cm prepubertal uterus with suspected ovaries visualized bilaterally. Her labs were remarkable for a total testosterone < 2.5, dihydrotestosterone < 1.0, negative inhibin, LH < 0.09, FSH 3.17, and estradiol < 1. Interestingly, her karyotype identified normal male karyotype (46, XY) in 30 of 31 metaphase cells examined; in one cell there was a normal female karyotype (46, XX) resulting in chi, XY[30]/46,XX[1]. Microarray comparative genomic hybridization identified one copy gain involving 45 probes in the distal region of the long (q) arm of chromosome 4 at bands 4q35.1q35.2. Fluorescence in-situ hybridization (FISH) results suggested the patient has two cell lines: the major cell line (99%) was normal male (XY) signal patterns and the minor line (1%) had normal female (XX) signal patterns. The suspected clinical diagnosis is a confined hematopoietic chimerism in a MCDA dizygotic twin secondary to twin-twin transfusion physiology with her non-identical twin brother.

Comments: This case demonstrates a confined chimerism persisting into childhood with lab work (inhibin and testosterone) ruling out alternative single gene developmental sex disorders. Interestingly, this patient was phenotypically completely female with a presumable normal uterus despite her chimeric chromosome results. If the patient desires to assess whether her mosaicism is confined to the bone marrow, a skin biopsy FISH for X,Y would be indicated. Blood sampling from the brother would provide insight to verify chimerism secondary to twin-twin transfusion.