Fertility outcomes and management of long-term pubertal testosterone replacement sequelae in Oliver-McFarlane syndrome: a case report and literature review

Introduction

Oliver-McFarlane syndrome (OMCS) is an extremely rare genetic condition first described in 1965, with fewer than 40 cases reported in the literature (1). The syndrome is caused by biallelic mutations in the PNPLA6 gene, which encodes neuropathy target esterase (NTE) (1). PNPLA6 is widely expressed in neural and endocrine tissues, including the developing eye, pituitary gland, and brain (2). Its impairment leads to a distinctive multisystem phenotype: the hallmark features of OMCS include congenital trichomegaly (abnormally long, thick eyelashes), severe chorioretinal dystrophy leading to progressive vision loss, and combined anterior pituitary hormone deficiencies (1). Growth hormone (GH) deficiency, thyroid-stimulating hormone (TSH) deficiency, and gonadotropin [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)] deficiency are commonly observed, resulting in short stature, delayed bone age, and absent puberty (1). Approximately 67% of reported OMCS cases have hypogonadotropic hypogonadism (HH) with delayed or absent sexual development (1).

Despite the well-documented association of OMCS with HH, the implications for fertility in male patients have not been explored in the literature. In fact, to our knowledge, no prior case report has detailed the fertility outcomes or management in a male with OMCS. Even long-term follow-up studies of OMCS patients have omitted reproductive details. Given that HH in other genetic syndromes (such as Kallmann syndrome or Boucher-Neuhäuser syndrome) can lead to infertility but is often treatable (3,4), it is important to investigate and document fertility potential in OMCS as well. Here, we present the case of a 33-year-old man with OMCS who presented with azoospermia, and we discuss the successful management of his infertility. This case suggests a possible association between OMCS and male infertility and highlights the potential clinical value of hormonal stimulation and microdissection testicular sperm extraction (micro-TESE) in this context. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0024/rc).

Case presentation

A 33-year-old male with genetically confirmed OMCS (compound heterozygous PNPLA6 mutations) was evaluated at The Andrology and Male Infertility Clinic, IVF Unit, Lady Davis Carmel Medical Hospital, Israel. He had developmental delay and classic OMCS manifestations from infancy, including micropenis, retinal dystrophy, sparse scalp hair, and trichomegaly (as illustrated in the clinical timeline (Figure 1).

Figure 1 Timeline of key clinical events. HH, hypogonadotropic hypogonadism; micro-TESE, microdissection testicular sperm extraction; OMCS, Oliver-McFarlane syndrome.

Micropenis was identified at 7 months of age and associated with congenital HH (CHH), for which he received brief testosterone therapy. During childhood, he developed retinitis pigmentosa and recurrent respiratory infections. Puberty failed to progress, and at 12.5 years he was found to have prepubertal testes (≈2 mL), delayed bone age, and low gonadotropins and testosterone. Testosterone replacement therapy (TRT) was initiated to induce virilization. Genetic testing later confirmed OMCS; karyotype was 46,XY. Despite androgen-induced secondary sexual characteristics, as expected testicular volume remained prepubertal and azoospermia persisted.

He continued long-term testosterone replacement into adulthood. At age 25 years, semen analysis showed azoospermia. At 29 years, while attempting conception, he was referred for fertility evaluation. Examination revealed eunuchoid habitus, small penis, and markedly atrophic testes (~4 mL), confirmed as hypoplastic on ultrasound. Baseline clinical, hormonal, and reproductive findings are summarized in Table 1. Testosterone was discontinued to allow hypothalamic-pituitary-gonadal axis recovery.

At age 31 years, laboratory testing confirmed persistent HH with very low testosterone and suppressed gonadotropins. Combined gonadotropin therapy with human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) was initiated, resulting in partial testosterone recovery, modest testicular growth (~6 mL), and a rise in inhibin B. However, repeated semen analyses over >18 months remained azoospermic. As shown in the longitudinal clinical course (Figure 1).

At age 33 years, following nearly two years of optimized gonadotropin stimulation, micro-TESE was performed. Focal spermatogenesis was identified, and motile spermatozoa were successfully retrieved bilaterally and cryopreserved for intracytoplasmic sperm injection. The couple subsequently proceeded to in vitro fertilization (IVF); treatment outcomes are pending at the time of reporting.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

We describe a unique case of male infertility in a patient with OMCS, illustrating the challenges and opportunities in managing HH due to this rare genetic condition. OMCS is distinguished by a triad of retinal degeneration, hair follicle abnormalities, and panhypopituitarism (1). In particular, gonadotropin deficiency (HH) is a common consequence of the PNPLA6 mutation, as PNPLA6 (NTE) is essential for normal development of pituitary gonadotroph cells (2). Our patient’s clinical course reflected this: he had signs of CHH from birth. He presented with micropenis, while cryptorchidism was notably absent. However, the presence of micropenis alone strongly suggested gonadotropin-releasing hormone (GnRH) deficiency. The presence of micropenis in infancy is a critical clue to CHH and is rarely seen in simple constitutional pubertal delay (5). In such cases, early intervention with low-dose testosterone can normalize penile growth (5), as was done for our patient. However, exogenous testosterone does not stimulate testicular growth or spermatogenesis; it in fact suppresses endogenous gonadotropins. Thus, while our patient’s adolescent TRT improved his virilization, it likely exacerbated testicular atrophy and delayed the initiation of spermatogenesis.

This case underscores an important consideration in the management of adolescents with CHH due to syndromic causes: the trade-off between inducing puberty with TRT versus fostering fertility potential with gonadotropins. Current guidelines suggest that if fertility is desired, treatment with hCG and FSH can not only induce secondary sexual characteristics but also stimulate testicular maturation, potentially preserving future fertility (4,5). Indeed, emerging evidence indicates that using FSH in the prepubertal or early pubertal period of boys with HH may expand the Sertoli cell population and spermatogonia, thereby improving eventual sperm production (5). In hindsight, our patient—whose OMCS was diagnosed in adolescence—might have benefited from early gonadotropin therapy instead of testosterone-only therapy, to better prime his testes for spermatogenesis. Unfortunately, at the time, the standard approach was testosterone supplementation for pubertal induction. This is effective for symptomatic androgenization, but as seen here, prolonged testosterone use led to severe testicular involution and azoospermia.

When the patient was ready to pursue paternity in adulthood, the reversal of his longstanding hypogonadism required prolonged gonadotropin stimulation. HH is an uncommon but treatable cause of male infertility (5). Unlike primary testicular failure, where intrinsic spermatogenic capacity is impaired, in HH the testicular tissue is fundamentally capable of spermatogenesis if provided with the missing hormonal signals. According to the American Society for Reproductive Medicine (ASRM), men with HH (whether due to congenital syndromes like Kallmann syndrome or acquired causes) should receive individualized hormonal therapy to induce spermatogenesis (4). In practice, this involves either pulsatile GnRH pumps or, more commonly, hCG injections to stimulate intratesticular testosterone (acting like LH) combined with FSH injections to directly stimulate the Sertoli cells. Our patient’s regimen of rFSH and hCG for over 18 months is in line with standard protocols for CHH. Spermatogenesis often requires 6–24 months of gonadotropin therapy in such patients, reflecting the slow initiation and progression of germinal epithelium development from a near prepubertal state (4). Published success rates are encouraging: roughly 75–80% of men with CHH will achieve sperm in the ejaculate with 1–2 years of therapy, and about 50% of couples achieve pregnancy over time (4).

Recent studies show that about 78% of men with pathologic gonadotropin deficiency achieve sperm in the ejaculate after a median of 18 months of gonadotropin therapy, with combined hCG/FSH being more effective than hCG alone (6). A prospective study found similar results, with most men achieving sperm within five months, though higher sperm counts required longer treatment (7).

Our patient did show biochemical evidence of testicular response (rising testosterone and inhibin B levels), but he did not have detectable sperm in semen even after 2 years. This could be attributed to several negative prognostic factors in his case, including the long duration of untreated HH and prior androgen exposure, very small baseline testicular volume, and the congenital absence of mini-puberty. He experienced more than a decade of minimal gonadotropin stimulation due to both the underlying HH and prolonged exogenous testosterone use, resulting in sustained suppression and a prolonged quiescent state of the testes that may have reduced the spermatogonial stem cell pool. Previous studies have shown that men with congenital or long-standing HH require a longer time to induce spermatogenesis compared with those with adult-onset disease (4), and prior androgen exposure is associated with delayed recovery of spermatogenesis. In addition, his baseline testicular volume at the initiation of gonadotropin therapy was approximately 4 mL, reflecting severe reduction in seminiferous tubule mass; clinical series indicate that larger baseline testicular volumes (e.g., >10 mL) predict a faster and more robust spermatogenic response (4), whereas very small testes are associated with poorer outcomes and may fail to achieve sperm concentrations sufficient for appearance in the ejaculate despite focal spermatogenesis. Finally, as in other men with CHH, the absence of neonatal mini-puberty likely impaired early Sertoli cell and germ cell establishment, which may further limit the maximal spermatogenic potential achievable later in life, even with appropriate hormonal therapy.

Despite these challenges, the outcome in this case was ultimately positive. When extended hormonal treatment did not yield ejaculated sperm, we pursued surgical sperm retrieval. In hypogonadotropic patients, micro-TESE can be an effective adjunct to retrieve sperm directly from the testes, as these patients often have isolated pockets of spermatogenesis. In our patient’s micro-TESE, the presence of motile sperm in testicular tissue confirmed that spermatogenesis had indeed been induced by the gonadotropin therapy—just not to the level of spilling over into the ejaculate. Sperm retrieval in men with HH who have had some hormonal priming is frequently successful, even if semen remains azoospermic (8). In non-syndromic HH cases, sperm retrieval rates approach 100% after adequate hormonal stimulation, given that the fundamental block is pre-testicular (endocrine) and not intrinsic testicular failure. Our case supports this: two years of gonadotropin therapy likely enabled the maturation of a small number of spermatogonial clones into sperm that could be surgically harvested. The use of microdissection technique was important, as it allowed us to visually identify and extract the fuller seminiferous tubules which were more likely to harbor sperm.

This case is, to our knowledge, the first documentation of successful fertility treatment in OMCS. It highlights several key learning points. First, multidisciplinary care is crucial—our patient’s journey involved pediatric endocrinologists, clinical geneticists, ophthalmologists, and reproductive urologists. Recognizing that a syndromic patient’s childhood hormonal treatments (like long-term testosterone) can impact future fertility is important for counseling families early on. Second, the case demonstrates the efficacy of combined FSH + hCG therapy in a CHH context: even though it did not produce an ejaculate sperm, it was a necessary bridge to create sperm that could be retrieved. Notably, had gonadotropin therapy not been used, micro-TESE would likely have found no sperm (in untreated CHH, the testis may be completely aspermatogenic). Thus, hormonal stimulation was a critical step in this patient’s fertility management. Third, it showcases the utility of micro-TESE in rare genetic syndromes. Most published data on micro-TESE outcomes focus on primary testicular failure (e.g., Klinefelter syndrome) or idiopathic azoospermia. In our patient with a “pre-testicular” cause of azoospermia, micro-TESE proved to be an invaluable tool to finalize sperm acquisition. We recommend considering micro-TESE in any HH patient who remains azoospermic after a reasonable trial of gonadotropin therapy, as it can uncover sperm that are not being emitted naturally.

Best practices for CHH include early gonadotropin-based therapy over testosterone alone in adolescents, since early FSH may improve future spermatogenic capacity (9). Combined hCG/FSH is preferred over hCG alone (6), and treatment should be tailored to testicular response, often requiring 12–24 months or longer. Micro-TESE should be considered for persistent azoospermia despite adequate hormonal stimulation (5,10). Multidisciplinary care is essential for optimal pubertal induction, fertility preservation, and assisted reproduction.

From a research perspective, this case expands the phenotype of OMCS. While OMCS has been known for pituitary hormone deficiencies, its impact on reproductive function in adulthood was previously unreported. Our patient’s successful sperm retrieval suggests that, despite the complex pathophysiology of PNPLA6 mutations, the spermatogenic apparatus can remain viable if appropriately stimulated.

Finally, this case emphasizes the importance of lifelong follow-up for patients with rare syndromic conditions. Early life treatment in OMCS focused on vision preservation and hormone replacement for growth and puberty. As these patients reach adulthood, new goals such as fertility and bone health become pertinent. A seamless transition from pediatric to adult endocrinology care could have benefited our patient by earlier planning for fertility preservation. In retrospect, banking sperm via testicular biopsy could have been attempted even in his late teens prior to prolonged TRT, although yield at that time might have been low given the state of his HH.

Limitations

This report is limited by its single-patient nature, which prevents generalization to all individuals with OMCS or CHH, as responses to therapy and surgical sperm retrieval vary with genetic background, testicular reserve, duration of hypogonadism, and prior treatments. The optimal approach to gonadotropin therapy in OMCS-related HH cannot be determined from one case, nor can we assess if alternative management strategies would have led to better outcomes. Long-term reproductive results, including fertilization, and pregnancy, are still pending. The rarity of OMCS precludes controlled studies, but further case reports are needed to inform evidence-based fertility management in this syndrome.

Conclusions

In conclusion, OMCS, due to PNPLA6 mutations, should be recognized as a rare but important cause of CHH in males. Alongside the classic features of retinal degeneration and trichomegaly, these patients can present with infertility secondary to HH. The encouraging message from this case is that such infertility is potentially treatable. A combination of hormonal therapy to induce spermatogenesis and microsurgical sperm retrieval can enable patients with OMCS to have biological children. Clinicians managing OMCS or CHH should counsel patients and families about this aspect and consider early fertility planning. This case also advocates for personalized approaches in puberty induction—balancing immediate developmental needs with long-term fertility outcomes.

Multidisciplinary follow-up from childhood through adulthood is essential in rare syndromes to address evolving objectives: metabolic/hormonal health, vision preservation, sexual function, and fertility should all be integrated into the care plan.

Acknowledgments

We would like to thank the embryology and andrology laboratory staff for their expertise in sperm processing and cryopreservation.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0024/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0024/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0024/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Xiao P, Gu Y, Qi X, et al. Novel variant in PNPLA6 gene causes Oliver-McFarlane syndrome in a Chinese family: 13 years follow-up. Front Genet 2025;16:1693876. [Crossref] [PubMed]
2. Hufnagel RB, Arno G, Hein ND, et al. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet 2015;52:85-94. [Crossref] [PubMed]
3. Boehm U, Bouloux PM, Dattani MT, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015;11:547-64. [Crossref] [PubMed]
4. Boeri L, Capogrosso P, Salonia A. Gonadotropin Treatment for the Male Hypogonadotropic Hypogonadism. Curr Pharm Des 2021;27:2775-83. [Crossref] [PubMed]
5. Chen YK, Huang IS, Chen WJ, et al. Reproductive outcomes of microdissection testicular sperm extraction in hypogonadotropic hypogonadal azoospermic men after gonadotropin therapy. J Assist Reprod Genet 2021;38:2601-8. [Crossref] [PubMed]
6. Muir CA, Zhang T, Jayadev V, et al. Efficacy of Gonadotropin Treatment for Induction of Spermatogenesis in Men With Pathologic Gonadotropin Deficiency: A Meta-Analysis. Clin Endocrinol (Oxf) 2025;102:167-77. [Crossref] [PubMed]
7. Gialouris JV, Conway AJ, Idan A, et al. Efficacy of Gonadotropin Therapy to Induce Spermatogenesis and Fertility in Men with Pathologic Gonadotropin Deficiency. J Clin Endocrinol Metab 2026;111:1450-8. [Crossref] [PubMed]
8. Dasgupta S, Le TS, Rambhatla A, et al. Medical treatment prior to micro-TESE. Asian J Androl 2025;27:342-54. [Crossref] [PubMed]
9. Dwyer AA, McDonald IR, Quinton R. Current landscape of fertility induction in males with congenital hypogonadotropic hypogonadism. Ann N Y Acad Sci 2024;1540:133-46. [Crossref] [PubMed]
10. Zachariou A, Zikopoulos A, Markou E, et al. Fertility Outcomes in Men with Nonobstructive Azoospermia Due to Hypogonadotropic Hypogonadism After Gonadotropin Therapy. J Clin Med 2026;15:1204. [Crossref] [PubMed]