First Reported Live Birth Following ICSI in a Man with Combined Complete AZFb and AZFc Y-Chromosome Microdeletions and 45,X/46,XY Mosaicism

Technical Summary: First Reported Live Birth Following ICSI in a Man with Combined Complete AZFb and AZFc Y-Chromosome Microdeletions and 45,X/46,XY Mosaicism

Problem Statement
Y chromosome microdeletions are the second most common genetic cause of male infertility, following Klinefelter syndrome. Specifically, complete deletions of the azoospermia factor b (AZFb) region are classically associated with meiotic arrest at the primary spermatocyte stage. Current international guidelines and published literature indicate an extremely poor prognosis for sperm retrieval in men with complete AZFb deletions, often resulting in non-obstructive azoospermia. Consequently, surgical sperm retrieval is generally not recommended, and donor sperm is the standard recommendation for family building. This case addresses a unique clinical scenario: a male patient presenting with a confirmed complete AZFb and AZFc microdeletion co-occurring with a mosaic 45,X/46,XY karyotype (mosaic Turner syndrome), a genetic profile traditionally considered incompatible with biological fatherhood via ejaculated sperm.

Methodology
The study reports a retrospective case management of a 32-year-old male and his 34-year-old female partner presenting with two years of primary infertility. The management strategy was driven by a multidisciplinary team (MDT) comprising reproductive medicine specialists, urological surgeons, endocrinologists, genetic counsellors, and senior embryologists.

• Genetic and Clinical Assessment: The male partner exhibited severe oligozoospermia, primary testicular dysfunction (low testosterone, elevated FSH), and reduced testicular volumes. Genetic testing confirmed a complete AZFb/AZFc microdeletion and 45,X/46,XY mosaicism. The female partner had a high ovarian reserve (AMH 48.2 pmol/L) and features of polyendocrine metabolic ovarian syndrome (PMOS).
• Treatment Protocol: The couple underwent Intracytoplasmic Sperm Injection (ICSI) using fresh ejaculated sperm. Due to the high risk of ovarian hyperstimulation syndrome (OHSS) and the scarcity of sperm, a "freeze-all" strategy was initially adopted.
• Laboratory Strategy: Given the extreme scarcity of viable sperm (often requiring two embryologists to search for hours to find sufficient numbers), the MDT implemented a tailored oocyte warming protocol. Instead of thawing all vitrified oocytes simultaneously, the number of oocytes warmed was strictly matched to the number of viable sperm identified on the day of treatment. This aimed to minimize oocyte wastage during cycles where sperm were absent.
• Counselling: Comprehensive genetic counselling was provided regarding the 100% transmission risk of the Y-chromosome microdeletion to male offspring (predicting future infertility) and the theoretical risks associated with the mosaic karyotype.

Key Results

• Initial Cycle: Ovarian stimulation yielded 30 oocytes (27 mature). After extensive laboratory processing, only nine motile sperm were identified. Nine oocytes were injected, resulting in two normal fertilizations; however, no viable blastocysts were formed.
• Subsequent Cycles:
  • One frozen oocyte warming cycle was cancelled because no viable sperm were found in the ejaculate on the scheduled day.
  • A subsequent cycle proceeded after rare viable sperm were recovered. Ten vitrified oocytes were warmed and injected. Four oocytes fertilized normally.
• Outcome: An early blastocyst and a partial morula were transferred, resulting in an uncomplicated singleton pregnancy. A healthy female infant was delivered at term with a birth weight of 3,856 g.
• Post-Treatment Management: The couple was advised to pursue further oocyte warming cycles while viable sperm remained available, rather than delaying treatment, due to the unpredictable nature of spermatogenesis and the risk of progression to complete azoospermia. Testosterone replacement therapy was deferred until the completion of family planning.

Key Contributions

1. First Reported Live Birth: To the authors' knowledge, this is the first reported successful live birth achieved using ejaculated sperm from a man with a confirmed complete AZFb and AZFc microdeletion in association with a mosaic 45,X/46,XY karyotype.
2. Validation of Residual Spermatogenesis: The case demonstrates that despite a genetic profile traditionally associated with maturation arrest and azoospermia, some individuals may retain sufficient residual spermatogenesis to produce rare, viable ejaculated sperm.
3. Operational Innovation: The paper highlights a specific laboratory management strategy—matching oocyte thawing to daily sperm availability—which proved critical in managing the high risk of oocyte wastage in the context of unpredictable sperm recovery.
4. Multidisciplinary Approach: The successful outcome is attributed to a collaborative MDT approach that balanced realistic prognostic expectations with individualized treatment planning, including complex genetic counselling and flexible laboratory protocols.

Significance and Claims
The authors claim that this report expands the current understanding of the reproductive potential associated with complete AZFb and AZFc microdeletions. While they explicitly state that this exceptional outcome should not alter current clinical guidelines or general counselling regarding the poor prognosis of complete AZFb deletions, the case serves as a proof of concept. It suggests that in carefully selected patients with demonstrable residual spermatogenesis, biological paternity may be achievable. The paper emphasizes that successful outcomes in such rare cases depend not only on the presence of viable sperm but also on meticulous laboratory techniques, flexible treatment planning, and close multidisciplinary collaboration. The authors maintain a modest tone, noting that while this case offers hope, it remains an outlier rather than a new standard of care for the broader population with similar genetic diagnoses.