Endocrine DOI 10.1007/s12020-015-0562-5
CLINICAL MANAGEMENT OF ENDOCRINE DISEASES
Kallmann syndrome patient with gender dysphoria, multiple sclerosis, and thrombophilia Aniruthan Renukanthan • Richard Quinton • Benjamin Turner Peter MacCallum • Leighton Seal • Andrew Davies • Richard Green • Jane Evanson • Ma´rta Korbonits
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Received: 18 December 2014 / Accepted: 21 February 2015 Ó Springer Science+Business Media New York 2015
Abstract One of the challenging issues in patients with complex problems is that the various diseases and their treatment can influence each other and present unusual hurdles in management. We investigated one such complex case. A 34-year-old XY male presented with azoospermia, detected on semen analysis for pre-orchidectomy sperm banking. He had a 20-year history of gender dysphoria and bilateral breast swelling. The patient suffered a deep vein thrombosis at the age of 19 years. Examination confirmed clinical features of Kallmann syndrome including unilateral cryptorchidism, micropenis, congenital anosmia, and bimanual synkinesis (mirror movements), with reduced serum testosterone and normal gonadotropin levels demonstrating hypogonadotropic hypogonadism. MRI showed missing olfactory bulbs. Osteopenia and reduced vitamin D levels of 21 nmol/L were identified. He was found to harbor a heterozygous factor-V-Leiden mutation. The genetic basis of Kallmann syndrome remains unknown: his screening tests A. Renukanthan M. Korbonits (&) Department of Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK e-mail: [email protected] R. Quinton Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK B. Turner Department of Neurology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
were negative for mutations in CHD7, FGF8, FGFR1, GNRH1, GNRHR, HS6ST1, KAL1, KISS1R, KISS1, NELF, PROK2, PROKR2, TAC3, and TACR3. The patient initially declined testosterone therapy with a view to undergo gender reassignment. Over the next 2 years, the patient experienced recurrent episodes of weakness and paresthesia, associated with classical MRI appearances of multiple sclerosis-related demyelination in the spinal cord and brain. Although it was difficult to elucidate an association between the patient’s gender dysphoria and untreated congenital hypogonadism, his desire to become female together with his co-existing thrombophilia, presented challenges to the administration of hormone treatment. Furthermore, we have considered an association between multiple sclerosis and hypogonadotropic hypogonadism. Keywords Kallmann syndrome Gender dysphoria Multiple sclerosis Thrombophilia L. Seal Department of Endocrinology, St George’s University of London, London, UK A. Davies Gender Identity Clinic Service, West London Mental Health NHS Trust, London, UK R. Green Faculty of Medicine, Imperial College London, London, UK J. Evanson Department of Neuroradiology, Barts Health NHS Trust, London, UK
P. MacCallum Department of Haematology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Introduction One of the exciting challenges in medicine is represented by patients with complex problems where the various diseases could influence each other. We present here such a case where congenital hypogonadotropic hypogonadism, gender dysphoria, thrombophilia, and multiple sclerosis are uniquely combined in a way that each of these diseases may significantly influence the others and provide challenges for diagnosis and management.
exceeded his height, this did not quite meet the formal definition of eunuchoid proportions (arm span [5 cm, greater than height) [4]. He had varicose veins on the right leg. He had a male-type distribution of sparse body hair and he had a female body habitus [narrow shoulders, wider hips, and bilateral gynecomastia (Fig. 1a)]. He had a micropenis and left-sided undescended testes. The right testis has a volume of 15 mL. He was found to have bimanual synkinesis (in keeping with a history of difficulty in learning the piano) and a shortened 4th metacarpal (Fig. 1b). Smell testing, using the University of Pennsylvania Smell Identification Test, confirmed anosmia.
Case analysis Investigations Clinical presentation A 34-year-old male presented to the endocrinology clinic with azoospermia, discovered on semen analysis (on two separate occasions) for pre-orchidectomy sperm banking as he was considering gender reassignment. Since childhood, and especially since he had experienced bilateral breast swelling, he felt comfortable in cross dressing and he had associated feelings of gender dysphoria (corroborated by psychological assessment and in keeping with the most recent criteria from the Royal College of Psychiatry [1], Endocrine Society [2] and World Professional Association for Transgender Health [3]). Although he desired a social gender role change, he was concerned that this might affect his employment circumstances and so was still living in a male-social role. His desire for hormonal and possible surgical therapy, to facilitate transition to the female role, led him to initiate sperm banking. Past medical history included a closed ventral septal defect (VSD) since birth, reduced hearing on the left, and a deep vein thrombosis (DVT) in his right leg at the age of 19, for which he received 6 months of anticoagulation. The patient had no relevant family history of hypogonadism or thrombophilia and his social history included alcohol problems and suicide in his father. He was treated for depression for 2 years and had several episodes of elated and low moods. On examination, he was found to have a height of 187 cm and an arm span of 190 cm. Although his arm span Fig. 1 Patient presenting features of Kallmann syndrome: a bilateral gynecomastia and b shortened fourth metacarpal (left image) compared to a normal hand (right image)
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Karyotype was XY. Testicular ultrasound confirmed the left-sided testes to be at the inguinal canal and of a much reduced volume (1.6 9 2.4 9 3.1 cm), in comparison with the volume of the right-sided testes (1.8 9 2.5 9 3.7 cm) located in the scrotal sac. The kidneys were normal on ultrasound. Initially, the patient had repeated low baseline total testosterone levels, which were 8, 2.7, and 5 nmol/L on three different occasions (9–27). He had inappropriately normal levels of serum luteinizing hormone (LH, 7.7 IU/L, normal range 1.7–8.6), and serum follicle-stimulating hormone was slightly elevated (FSH, 15 IU/L, normal range 2–12). He had a GnRH (gonadotropin-releasing hormone) test where he had 15-min sampling for 180 min: the FSH values were constant at 13 IU/L, the LH varied between 5.7 and 7.4 IU/L. He later had a second GnRH test at a different hospital, which showed baseline, 20 and 60 min LH of 5.5, 49, and 46 IU/L, and FSH of 13.3, 25, and 28 IU/L, respectively. Magnetic resonance imaging (MRI) showed an absence of olfactory bulbs (Fig. 2) explaining the patient’s anosmia. Mild hearing loss on the left was noted on hearing testing. DEXA (dual-energy X-ray absorptiometry) scan showed a T-score of -1.9 in the spine and -1.6 in the hip and the patient’s vitamin D level was found to be low (21 nmol/L). A thrombophilia screen identified a heterozygous factor-V-Leiden mutation. Detailed psychiatric assessment suggested the gender dysphoria to be present from early childhood. The patient
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Endocrine Fig. 2 MRI scans of the front lobe showing absent olfactory bulbs in the patient (a) and olfactory bulbs (indicated by black arrows) in a normal person (b)
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screened negative for mutations of genes associated with hypogonadotropic hypogonadism and Kallmann syndrome [W. Crowley Laboratory, Harvard Medical School [5, 6]: fibroblast growth factor 8 (FGF8), fibroblast growth factor receptor 1 (FGFR1), Kallmann syndrome 1 sequence, coding for anosmin-1 (KAL1), prokineticin 2 (PROK2), prokineticin receptor 2 (PROKR2), chromodomain helicase DNA binding protein 7 (CHD7), gonadotropin-releasing hormone 1 (GNRH1), gonadotropin-releasing hormone receptor (GNRHR), heparin sulfate 6-O-sulfotransferase 1 (HS6ST1), KISS1-metastasis suppressor (KISS1), KISS1 receptor (KISS1R), nasal embryonic luteinizing hormonereleasing hormone factor (NELF), tachykinin 3 (TAC3) and tachykinin receptor 3 (TACR3)]; further testing for is ongoing for AXL receptor tyrosine kinase (AXL), dual specificity phosphatase 6 (DUSP6), FEZ family zinc finger 1 (FEZF1), fibroblast growth factor 17 (FGF17), fibronectin leucine rich transmembrane protein 1 (FLRT3), homeobox expressed in ES cells 1 (HESX1), interleukin 17 receptor D (IL17RD), semaphorin 3a (SEMA3A), sex-
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determining region Y box 10 (SOX10), sprouty homolog 2 (SPRY2), and WD repeat-containing protein 11 (WDR11). Treatment Vitamin D replacement was initiated in the patient, but he initially declined testosterone therapy in view of possible gender reassignment.
Follow-up A few months after the initial workup, the patient presented with weakness of the left hand and paresthesia on the right torso. Over the next 2 years, he had developed another episode of weakness and paresthesia. Although lumbar puncture was attempted, it was unsuccessful and the patient declined further attempts. MRI scans showed inflammatory spinal lesions at C5–C7 (Fig. 3a) and 2 years later white matter lesions of the brain (Fig. 3b, c), in keeping with the
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Fig. 3 MRI scans showing cervical spine inflammatory MS lesion (a) and periventricular MS lesions (b, c). Arrows pointing to the lesions
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diagnosis of MS, which is currently under observation. Interestingly, the patient’s sister has recently presented with weakness and paresthesia to a neurologist, and the subsequent MRI scan identified lesions compatible with MS. Recently, 6 years after the initial presentation, the patient abandoned his plans for gender reassignment and accepted a prescription for testosterone treatment. He married a lady, whom he has been in a relationship with for 17 years; she is in her 60s. After 12 weeks of 10 mg percutaneous testosterone gel administration, his testosterone level has normalized to 15 nmol/L. He noted the increase in body hair growth and also an initial increase in gynecomastia and worsening of gender dysphoria, yet nevertheless elected to continue with testosterone replacement despite a degree of ambivalence.
Discussion The Spanish doctor Aureliano Maestre de San Juan described the first clinical features of Kallmann syndrome (small testes with absent olfactory bulbs in the brain) in 1856 [7] but the genetic nature of the syndrome was identified by Kallmann in 1944 [8]. Kallmann syndrome is thought to affect 1 in 48,000 individuals, more commonly in men [9]. The underlying mechanism implicated in Kallmann syndrome is a lack of migration of the GnRH neurons from the olfactory placode to the hypothalamus (causing reduced GnRH production leading to hypogonadotropic hypogonadism), lack of projection from the olfactory receptor neurons into the olfactory bulb, and in some patients atrophy of the olfactory bulb [10, 11]. Although our patient tested negative for 14 genes associated with Kallmann syndrome, a significant proportion of patients with this disease are currently lacking genetic alterations explaining their disease [5, 6, 12] and further testing is being conducted for another 11 genes. The genetic basis of idiopathic (or congenital) hypothalamic hypogonadism was formerly considered under simple Mendelian categories of X-linked and autosomal recessive, and autosomal dominant inheritance. However, it is becoming increasingly evident that the majority of cases result from oligogenic inheritance, with patients harboring two or more different disease-associated alleles, not necessarily of the same gene [6]. The patient presented with clinical features which were typical of Kallmann syndrome [11], including the features of hypogonadism, undescended testes, gynecomastia, anosmia, hearing impairment, bimanual synkinesis (involuntary mirrored movements of the upper limb), and a shortened fourth metacarpal [13]. Other possible features of Kallmann syndrome, which did not affect our patient, include color blindness, abnormal eye
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movements, abnormal visual spatial attention, agenesis of the corpus callosum, cleft lip/palate, agenesis of teeth (known as hypodontia), unilateral/bilateral renal agenesis, and obesity [11]. Our patient also had a VSD diagnosed at birth and although congenital heart defects are not typical features of Kallmann syndrome, there has been one previously reported case of a Kallmann syndrome patient with the FGFR1 mutation, who had a VSD [14]. Management of Kallmann syndrome involves the treatment of hypogonadism with testosterone and, if required, treatment of fertility with gonadotropins [11, 15]. The patient had two GnRH tests with different results. After the second GnRH tests, he had variable (low or low normal) basal testosterone levels. One possible explanation is that the patient may have had a partial reversal. This is a phenomenon, where idiopathic hypogonadotropic hypogonadism patients have normalization of serum testosterone levels as well as improvement in testicular volume and virilization following testosterone therapy [16–18], with most recent data estimating a lifetime incidence of reversal of 22 % [18]. It was first described by Bauman in 1986 [19] and was termed the ‘‘Bauman variant of Kallmann syndrome’’ [20], followed by description by Quinton et al. in 1999 and several reports since [16–18]. The current case raised several management issues: firstly, the patient’s gender dysphoria meant that he initially declined testosterone treatment due to concerns of its androgenic effects changing his body habitus. Secondly, if the patient was to prepare for male-to-female gender reassignment, in the past this would have raised issues with increased thrombosis risk in view of the patient’s thrombophilia and previous DVT; however, more recent regimens using transdermal estradiol have considerably reduced thrombosis risks compared with historical regimes, based on synthetic estrogen analogs (ethinyl estradiol) and equine-derived estrogen preparations. Furthermore, a question had arisen as to whether there could be an association between the patient’s Kallmann syndrome and multiple sclerosis. Kallmann syndrome and gender dysphoria In 1966, Burger-Prinz reported the case of a 23-year-old genetically male with anosmia, reduced sexual activity, reduced serum gonadotropins, and a lack of Leydig cells on testicular biopsy, which were in keeping with the diagnosis of Kallmann syndrome [21]. The patient had feelings of existing as ‘female’ since childhood and he desired gender reassignment. Gonadotropin administration resulted in increased testosterone levels and relieved the gender dysphoria [21]. The patient’s heterosexual interest increased and in a 17-year follow-up study, his gender dysphoria disappeared and he had engaged in a 10-year relationship
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with a female [22], who, interestingly similar to our case, was an older female. In 2001, Meyenburg [23] reported the case of a 58-yearold genetically male patient with a 20-year history of living as a female and gender dysphoria since the age of 4. Clinical features included anosmia, delayed puberty, impaired sexual function, eunuchoid appearance, bilateral undescended testes, scars from four previous gynecomastia operations, and reduced serum testosterone and gonadotropin levels. The patient was treated with estrogen therapy, bilateral inguinal orchidectomy, and psychotherapy but declined gender reassignment surgery and decided to live ‘in-between’ [23]. Our case is the third reported case in the literature of a patient with both Kallmann syndrome and gender dysphoria. Kallmann syndrome is a heterogeneous condition [11] and not all patients present typically, which can make the diagnosis difficult. The presence of gender dysphoria with Kallmann syndrome could be confounded by ‘diagnostic overshadowing’ [24] where the patient’s feelings of gender dysphoria could be attributable as secondary to the hypogonadism due to the Kallmann syndrome, rather than being primary in origin. It took for our patient 6 years following the formal diagnosis of hypogonadism before he decided to take gonadal hormone treatment. This hesitation can typically be observed in patients with gender dysphoria [1]. The most recent Royal College of Psychiatry 2013 guidelines define gender dysphoria as ‘‘the distress associated with the experience of one’s personal gender identity being inconsistent with the phenotype or the gender role typically associated with that phenotype’’ [1]. By this definition and according to the guidelines of the US Endocrine Society [2] and international WPATH (World Professional Association for Transgender Health) [3], the three reported cases have gender dysphoria. In our case, the patient had feelings of gender dysphoria noticed since childhood, possibly associated with the appearance of the bilateral gynecomastia and so it is difficult to elucidate whether they co-presented (i.e., the patient had primary gender dysphoria) or if the gender dysphoria was secondary to the eunuchoid features of Kallmann syndrome. If it was the latter, then treatment of the patient’s Kallmann syndrome with testosterone or gonadotropins could have potentially reversed the gender dysphoria (as it did so with Burger-Prinz’s patient). Expert psychiatric opinion confirmed that gender dysphoria was present though assessment also revealed the continuing uncertainty experienced by our patient as to whether full-time transition into the female gender role was ultimately the right pathway to take. Furthermore, it is important to note that according to the most recent DSD (disorder of sex differentiation) guidelines, Kallmann syndrome is not defined as a physical
intersex condition or DSD (a problem noted at birth, in which genitalia are atypical in relation to the chromosomes or gonads) [25]. Thrombophilia and gonadal hormone treatment According to the 2013 guidelines, the mainstay of the male-to-female patient hormonal management is estradiol treatment combined with suppression of androgen secretion [1]. Careful titration of the estradiol level into the upper part of the normal follicular phase range is suggested. Androgen suppression is achieved using depot GnRH analogs, and finasteride and low dose of older agents such as cytoproterone acetate or spironolactone can be added, if necessary [1]. Patients with heterozygous factor-V-Leiden mutations are known to spontaneously develop venous thromboembolism (VTE) in up to 36 % of the cases [26, 27]. The patient’s previous DVT would also have contributed to an increased risk for developing venous thrombosis, with a recent study finding 15 % of patients with an isolated DVT to have experienced a previous DVT [28]. Routine screening for thrombophilia in male-to-female transsexuals initiated on cross-hormone treatment is, however, not recommended except for patients with a personal or family history of VTE, such as our patient [2]. Initially our patient refused testosterone treatment but now, after 6 years, he has decided not to undergo gender reassignment and recently accepted prescription for testosterone. Testosterone replacement usually does not have an associated risk of venous thromboembolism. One study found that specifically in hypogonadal men, testosterone improved erythrocyte membrane lipid composition and suggested that this could help decrease any risk of thrombosis [29]. However, recent data suggest that in patients with thrombophilia, testosterone, via aromatization, predisposes to recurrent VTE events despite adequate anticoagulation, and therefore the study raised the issue about testosterone replacement in thrombophilia patients [30]. Following recognition of these cases of VTE while on testosterone therapy as being unrelated to polycythaemia, the FDA (US Food and Drug Administration) have now recently updated VTE as a general warning on all testosterone products [31]. Kallmann syndrome and multiple sclerosis MS is a chronic, inflammatory, demyelinating condition affecting the central nervous system [32]. It is estimated to affect 113 men and 286 women per 100,000 in the UK [33]. Our patient presented at the typical age at which MS patients present (between ages of 20 and 40) with a relapsing-remitting subtype of MS. Although MS is thought to have multifactorial etiology, genome-wide association
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studies and meta-analyses, using familial cases, have identified 57 genetic loci to be associated with the condition [34, 35]. As the patient’s sister has recently presented with MS, it suggests that there may be a genetic predisposition to the patient’s MS. Although we have not found any previous case reports of the coexistence of MS and Kallmann syndrome, a recent study has looked at the brain MRI scans of 45 male patients with Kallmann syndrome and identified one patient to have ‘‘multiple sclerosis-like white matter abnormalities’’ [36]. Interestingly, we also have another patient with MS and Kallmann syndrome (M. Korbonits, unpublished observation): this second patient presented at the age of 20 years with anosmia, bilateral undescended testis, eunuchoid proportions, and profound testosterone deficiency responding well to testosterone replacement therapy. This latter patient’s primary progressive MS started at the age of 45 years. Anosmin-1 and FGFR1 proteins are altered and known to contribute to the pathogenesis of Kallmann syndrome. They have now been linked to abnormalities in myelination and MS. It has been recently considered by Garcı´a-Gonza´lez et al. that myelination/demyelination defects could have a role in olfactory dysfunction and in causing the bimanual synkinesia and cerebellar symptoms in Kallmann syndrome [10, 37]. Furthermore, the myelinated lateral olfactory tract can show atrophy in Kallmann syndrome [10]. Both FGF2 and anosmin-1 are expressed in postmortem brain tissue of MS patients; anosmin-1was only raised in chronic MS lesions, whereas FGF2 was present in active MS lesions and peri-plaques [38]. Both anosmin-1 and FGF2 were found to interact with FGFR1 and influence migration of oligodendrocyte precursor cells in different ways, which has been thought to affect the remyelination of lesions [38]. To date, MS is still considered to have an autoinflammatory origin but there are differences in the pathological and radiological findings in the MS subtypes, showing the primary/secondary progressive subtypes to be more neurodegenerative (e.g., more cortical and white matter demyelination, axonal damage, spinal cord, and whole brain atrophy) [39]. It is not clear whether the increased neurodegenerative abnormalities in progressive MS disease contributes to hypogonadism but recent data have identified distinct immunological mechanisms in progressive MS (e.g., increased expression of specific serum adhesion molecules and leucocyte surface expression but intact blood brain barrier, in comparison with relapsing-remitting MS) [40], which could be influential in causing the worse hypogonadism in this subset of patients. On the other hand, there might be a possibility that the MS itself could arise from the state of pre-existing hypogonadotropic hypogonadism. MS is characterized by a predominance of T helper 1 (Th1) cytokines (such as TNF-
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a, interferon gamma, etc.) and lack of T helper 2 (Th2) cytokines (interleukin 10, interleukin 4, and interleukin 5). In experimental animal models of MS known as experimental autoimmune encephalomyelitis (EAE), testosterone and dihydrotestosterone have been shown to influence the balance of cytokines toward increased Th2 cytokine production and reduced Th1 cytokine production, and subsequently reduce mortality of these animals [41– 45]. Hence, in states of male hypogonadism such as Kallmann syndrome, the lack of testosterone could lead to a reduction in the production of Th2 cytokines and therefore contribute toward the pathogenesis of MS. Furthermore, some controversial studies found that testosterone treatment was beneficial in improving cognitive performance and slowing brain atrophy in a cohort of male patients with relapsing-remitting MS [46, 47]. In our case, the patient’s idiopathic hypogonadotropic hypogonadism was clearly due to congenital Kallmann syndrome. He also had a genetic predisposition to MS, whether the two together played a role in the manifestation in his MS remains an open question.
Conclusions In summary, this is a complex case of Kallmann syndrome and other comorbidities. The role of hypogonadism in male-to-female gender dysphoria is intriguing and remains to be controversial. In the past, thrombophilia presented a challenge in male-to-female gender reassignment, but modern regimens provide more acceptable options. Although MS is not the cause of this patient’s congenital hypogonadotropic hypogonadism, further research is needed to evaluate any association between Kallmann syndrome and MS. Managing this patient and his comorbidities required a multidisciplinary team, including originally a pediatric cardiologist and urologist, and more recently endocrinologist, psychiatric consultant-expert in gender reassignment, thrombophilia-expert, neurologist, neuroradiologist, and clinical geneticist to provide the patient with the possible management options and the opportunity to decide what was the most suitable treatment option for him. Acknowledgments We are grateful to the patient for allowing us to share the history and data of his diseases. Conflict of interest of interest.
The authors declare that they have no conflict
Informed consent Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
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CLINICAL MANAGEMENT OF ENDOCRINE DISEASES
Kallmann syndrome patient with gender dysphoria, multiple sclerosis, and thrombophilia Aniruthan Renukanthan • Richard Quinton • Benjamin Turner Peter MacCallum • Leighton Seal • Andrew Davies • Richard Green • Jane Evanson • Ma´rta Korbonits
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Received: 18 December 2014 / Accepted: 21 February 2015 Ó Springer Science+Business Media New York 2015
Abstract One of the challenging issues in patients with complex problems is that the various diseases and their treatment can influence each other and present unusual hurdles in management. We investigated one such complex case. A 34-year-old XY male presented with azoospermia, detected on semen analysis for pre-orchidectomy sperm banking. He had a 20-year history of gender dysphoria and bilateral breast swelling. The patient suffered a deep vein thrombosis at the age of 19 years. Examination confirmed clinical features of Kallmann syndrome including unilateral cryptorchidism, micropenis, congenital anosmia, and bimanual synkinesis (mirror movements), with reduced serum testosterone and normal gonadotropin levels demonstrating hypogonadotropic hypogonadism. MRI showed missing olfactory bulbs. Osteopenia and reduced vitamin D levels of 21 nmol/L were identified. He was found to harbor a heterozygous factor-V-Leiden mutation. The genetic basis of Kallmann syndrome remains unknown: his screening tests A. Renukanthan M. Korbonits (&) Department of Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK e-mail: [email protected] R. Quinton Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK B. Turner Department of Neurology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
were negative for mutations in CHD7, FGF8, FGFR1, GNRH1, GNRHR, HS6ST1, KAL1, KISS1R, KISS1, NELF, PROK2, PROKR2, TAC3, and TACR3. The patient initially declined testosterone therapy with a view to undergo gender reassignment. Over the next 2 years, the patient experienced recurrent episodes of weakness and paresthesia, associated with classical MRI appearances of multiple sclerosis-related demyelination in the spinal cord and brain. Although it was difficult to elucidate an association between the patient’s gender dysphoria and untreated congenital hypogonadism, his desire to become female together with his co-existing thrombophilia, presented challenges to the administration of hormone treatment. Furthermore, we have considered an association between multiple sclerosis and hypogonadotropic hypogonadism. Keywords Kallmann syndrome Gender dysphoria Multiple sclerosis Thrombophilia L. Seal Department of Endocrinology, St George’s University of London, London, UK A. Davies Gender Identity Clinic Service, West London Mental Health NHS Trust, London, UK R. Green Faculty of Medicine, Imperial College London, London, UK J. Evanson Department of Neuroradiology, Barts Health NHS Trust, London, UK
P. MacCallum Department of Haematology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Introduction One of the exciting challenges in medicine is represented by patients with complex problems where the various diseases could influence each other. We present here such a case where congenital hypogonadotropic hypogonadism, gender dysphoria, thrombophilia, and multiple sclerosis are uniquely combined in a way that each of these diseases may significantly influence the others and provide challenges for diagnosis and management.
exceeded his height, this did not quite meet the formal definition of eunuchoid proportions (arm span [5 cm, greater than height) [4]. He had varicose veins on the right leg. He had a male-type distribution of sparse body hair and he had a female body habitus [narrow shoulders, wider hips, and bilateral gynecomastia (Fig. 1a)]. He had a micropenis and left-sided undescended testes. The right testis has a volume of 15 mL. He was found to have bimanual synkinesis (in keeping with a history of difficulty in learning the piano) and a shortened 4th metacarpal (Fig. 1b). Smell testing, using the University of Pennsylvania Smell Identification Test, confirmed anosmia.
Case analysis Investigations Clinical presentation A 34-year-old male presented to the endocrinology clinic with azoospermia, discovered on semen analysis (on two separate occasions) for pre-orchidectomy sperm banking as he was considering gender reassignment. Since childhood, and especially since he had experienced bilateral breast swelling, he felt comfortable in cross dressing and he had associated feelings of gender dysphoria (corroborated by psychological assessment and in keeping with the most recent criteria from the Royal College of Psychiatry [1], Endocrine Society [2] and World Professional Association for Transgender Health [3]). Although he desired a social gender role change, he was concerned that this might affect his employment circumstances and so was still living in a male-social role. His desire for hormonal and possible surgical therapy, to facilitate transition to the female role, led him to initiate sperm banking. Past medical history included a closed ventral septal defect (VSD) since birth, reduced hearing on the left, and a deep vein thrombosis (DVT) in his right leg at the age of 19, for which he received 6 months of anticoagulation. The patient had no relevant family history of hypogonadism or thrombophilia and his social history included alcohol problems and suicide in his father. He was treated for depression for 2 years and had several episodes of elated and low moods. On examination, he was found to have a height of 187 cm and an arm span of 190 cm. Although his arm span Fig. 1 Patient presenting features of Kallmann syndrome: a bilateral gynecomastia and b shortened fourth metacarpal (left image) compared to a normal hand (right image)
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Karyotype was XY. Testicular ultrasound confirmed the left-sided testes to be at the inguinal canal and of a much reduced volume (1.6 9 2.4 9 3.1 cm), in comparison with the volume of the right-sided testes (1.8 9 2.5 9 3.7 cm) located in the scrotal sac. The kidneys were normal on ultrasound. Initially, the patient had repeated low baseline total testosterone levels, which were 8, 2.7, and 5 nmol/L on three different occasions (9–27). He had inappropriately normal levels of serum luteinizing hormone (LH, 7.7 IU/L, normal range 1.7–8.6), and serum follicle-stimulating hormone was slightly elevated (FSH, 15 IU/L, normal range 2–12). He had a GnRH (gonadotropin-releasing hormone) test where he had 15-min sampling for 180 min: the FSH values were constant at 13 IU/L, the LH varied between 5.7 and 7.4 IU/L. He later had a second GnRH test at a different hospital, which showed baseline, 20 and 60 min LH of 5.5, 49, and 46 IU/L, and FSH of 13.3, 25, and 28 IU/L, respectively. Magnetic resonance imaging (MRI) showed an absence of olfactory bulbs (Fig. 2) explaining the patient’s anosmia. Mild hearing loss on the left was noted on hearing testing. DEXA (dual-energy X-ray absorptiometry) scan showed a T-score of -1.9 in the spine and -1.6 in the hip and the patient’s vitamin D level was found to be low (21 nmol/L). A thrombophilia screen identified a heterozygous factor-V-Leiden mutation. Detailed psychiatric assessment suggested the gender dysphoria to be present from early childhood. The patient
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Endocrine Fig. 2 MRI scans of the front lobe showing absent olfactory bulbs in the patient (a) and olfactory bulbs (indicated by black arrows) in a normal person (b)
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screened negative for mutations of genes associated with hypogonadotropic hypogonadism and Kallmann syndrome [W. Crowley Laboratory, Harvard Medical School [5, 6]: fibroblast growth factor 8 (FGF8), fibroblast growth factor receptor 1 (FGFR1), Kallmann syndrome 1 sequence, coding for anosmin-1 (KAL1), prokineticin 2 (PROK2), prokineticin receptor 2 (PROKR2), chromodomain helicase DNA binding protein 7 (CHD7), gonadotropin-releasing hormone 1 (GNRH1), gonadotropin-releasing hormone receptor (GNRHR), heparin sulfate 6-O-sulfotransferase 1 (HS6ST1), KISS1-metastasis suppressor (KISS1), KISS1 receptor (KISS1R), nasal embryonic luteinizing hormonereleasing hormone factor (NELF), tachykinin 3 (TAC3) and tachykinin receptor 3 (TACR3)]; further testing for is ongoing for AXL receptor tyrosine kinase (AXL), dual specificity phosphatase 6 (DUSP6), FEZ family zinc finger 1 (FEZF1), fibroblast growth factor 17 (FGF17), fibronectin leucine rich transmembrane protein 1 (FLRT3), homeobox expressed in ES cells 1 (HESX1), interleukin 17 receptor D (IL17RD), semaphorin 3a (SEMA3A), sex-
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determining region Y box 10 (SOX10), sprouty homolog 2 (SPRY2), and WD repeat-containing protein 11 (WDR11). Treatment Vitamin D replacement was initiated in the patient, but he initially declined testosterone therapy in view of possible gender reassignment.
Follow-up A few months after the initial workup, the patient presented with weakness of the left hand and paresthesia on the right torso. Over the next 2 years, he had developed another episode of weakness and paresthesia. Although lumbar puncture was attempted, it was unsuccessful and the patient declined further attempts. MRI scans showed inflammatory spinal lesions at C5–C7 (Fig. 3a) and 2 years later white matter lesions of the brain (Fig. 3b, c), in keeping with the
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Fig. 3 MRI scans showing cervical spine inflammatory MS lesion (a) and periventricular MS lesions (b, c). Arrows pointing to the lesions
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diagnosis of MS, which is currently under observation. Interestingly, the patient’s sister has recently presented with weakness and paresthesia to a neurologist, and the subsequent MRI scan identified lesions compatible with MS. Recently, 6 years after the initial presentation, the patient abandoned his plans for gender reassignment and accepted a prescription for testosterone treatment. He married a lady, whom he has been in a relationship with for 17 years; she is in her 60s. After 12 weeks of 10 mg percutaneous testosterone gel administration, his testosterone level has normalized to 15 nmol/L. He noted the increase in body hair growth and also an initial increase in gynecomastia and worsening of gender dysphoria, yet nevertheless elected to continue with testosterone replacement despite a degree of ambivalence.
Discussion The Spanish doctor Aureliano Maestre de San Juan described the first clinical features of Kallmann syndrome (small testes with absent olfactory bulbs in the brain) in 1856 [7] but the genetic nature of the syndrome was identified by Kallmann in 1944 [8]. Kallmann syndrome is thought to affect 1 in 48,000 individuals, more commonly in men [9]. The underlying mechanism implicated in Kallmann syndrome is a lack of migration of the GnRH neurons from the olfactory placode to the hypothalamus (causing reduced GnRH production leading to hypogonadotropic hypogonadism), lack of projection from the olfactory receptor neurons into the olfactory bulb, and in some patients atrophy of the olfactory bulb [10, 11]. Although our patient tested negative for 14 genes associated with Kallmann syndrome, a significant proportion of patients with this disease are currently lacking genetic alterations explaining their disease [5, 6, 12] and further testing is being conducted for another 11 genes. The genetic basis of idiopathic (or congenital) hypothalamic hypogonadism was formerly considered under simple Mendelian categories of X-linked and autosomal recessive, and autosomal dominant inheritance. However, it is becoming increasingly evident that the majority of cases result from oligogenic inheritance, with patients harboring two or more different disease-associated alleles, not necessarily of the same gene [6]. The patient presented with clinical features which were typical of Kallmann syndrome [11], including the features of hypogonadism, undescended testes, gynecomastia, anosmia, hearing impairment, bimanual synkinesis (involuntary mirrored movements of the upper limb), and a shortened fourth metacarpal [13]. Other possible features of Kallmann syndrome, which did not affect our patient, include color blindness, abnormal eye
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movements, abnormal visual spatial attention, agenesis of the corpus callosum, cleft lip/palate, agenesis of teeth (known as hypodontia), unilateral/bilateral renal agenesis, and obesity [11]. Our patient also had a VSD diagnosed at birth and although congenital heart defects are not typical features of Kallmann syndrome, there has been one previously reported case of a Kallmann syndrome patient with the FGFR1 mutation, who had a VSD [14]. Management of Kallmann syndrome involves the treatment of hypogonadism with testosterone and, if required, treatment of fertility with gonadotropins [11, 15]. The patient had two GnRH tests with different results. After the second GnRH tests, he had variable (low or low normal) basal testosterone levels. One possible explanation is that the patient may have had a partial reversal. This is a phenomenon, where idiopathic hypogonadotropic hypogonadism patients have normalization of serum testosterone levels as well as improvement in testicular volume and virilization following testosterone therapy [16–18], with most recent data estimating a lifetime incidence of reversal of 22 % [18]. It was first described by Bauman in 1986 [19] and was termed the ‘‘Bauman variant of Kallmann syndrome’’ [20], followed by description by Quinton et al. in 1999 and several reports since [16–18]. The current case raised several management issues: firstly, the patient’s gender dysphoria meant that he initially declined testosterone treatment due to concerns of its androgenic effects changing his body habitus. Secondly, if the patient was to prepare for male-to-female gender reassignment, in the past this would have raised issues with increased thrombosis risk in view of the patient’s thrombophilia and previous DVT; however, more recent regimens using transdermal estradiol have considerably reduced thrombosis risks compared with historical regimes, based on synthetic estrogen analogs (ethinyl estradiol) and equine-derived estrogen preparations. Furthermore, a question had arisen as to whether there could be an association between the patient’s Kallmann syndrome and multiple sclerosis. Kallmann syndrome and gender dysphoria In 1966, Burger-Prinz reported the case of a 23-year-old genetically male with anosmia, reduced sexual activity, reduced serum gonadotropins, and a lack of Leydig cells on testicular biopsy, which were in keeping with the diagnosis of Kallmann syndrome [21]. The patient had feelings of existing as ‘female’ since childhood and he desired gender reassignment. Gonadotropin administration resulted in increased testosterone levels and relieved the gender dysphoria [21]. The patient’s heterosexual interest increased and in a 17-year follow-up study, his gender dysphoria disappeared and he had engaged in a 10-year relationship
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with a female [22], who, interestingly similar to our case, was an older female. In 2001, Meyenburg [23] reported the case of a 58-yearold genetically male patient with a 20-year history of living as a female and gender dysphoria since the age of 4. Clinical features included anosmia, delayed puberty, impaired sexual function, eunuchoid appearance, bilateral undescended testes, scars from four previous gynecomastia operations, and reduced serum testosterone and gonadotropin levels. The patient was treated with estrogen therapy, bilateral inguinal orchidectomy, and psychotherapy but declined gender reassignment surgery and decided to live ‘in-between’ [23]. Our case is the third reported case in the literature of a patient with both Kallmann syndrome and gender dysphoria. Kallmann syndrome is a heterogeneous condition [11] and not all patients present typically, which can make the diagnosis difficult. The presence of gender dysphoria with Kallmann syndrome could be confounded by ‘diagnostic overshadowing’ [24] where the patient’s feelings of gender dysphoria could be attributable as secondary to the hypogonadism due to the Kallmann syndrome, rather than being primary in origin. It took for our patient 6 years following the formal diagnosis of hypogonadism before he decided to take gonadal hormone treatment. This hesitation can typically be observed in patients with gender dysphoria [1]. The most recent Royal College of Psychiatry 2013 guidelines define gender dysphoria as ‘‘the distress associated with the experience of one’s personal gender identity being inconsistent with the phenotype or the gender role typically associated with that phenotype’’ [1]. By this definition and according to the guidelines of the US Endocrine Society [2] and international WPATH (World Professional Association for Transgender Health) [3], the three reported cases have gender dysphoria. In our case, the patient had feelings of gender dysphoria noticed since childhood, possibly associated with the appearance of the bilateral gynecomastia and so it is difficult to elucidate whether they co-presented (i.e., the patient had primary gender dysphoria) or if the gender dysphoria was secondary to the eunuchoid features of Kallmann syndrome. If it was the latter, then treatment of the patient’s Kallmann syndrome with testosterone or gonadotropins could have potentially reversed the gender dysphoria (as it did so with Burger-Prinz’s patient). Expert psychiatric opinion confirmed that gender dysphoria was present though assessment also revealed the continuing uncertainty experienced by our patient as to whether full-time transition into the female gender role was ultimately the right pathway to take. Furthermore, it is important to note that according to the most recent DSD (disorder of sex differentiation) guidelines, Kallmann syndrome is not defined as a physical
intersex condition or DSD (a problem noted at birth, in which genitalia are atypical in relation to the chromosomes or gonads) [25]. Thrombophilia and gonadal hormone treatment According to the 2013 guidelines, the mainstay of the male-to-female patient hormonal management is estradiol treatment combined with suppression of androgen secretion [1]. Careful titration of the estradiol level into the upper part of the normal follicular phase range is suggested. Androgen suppression is achieved using depot GnRH analogs, and finasteride and low dose of older agents such as cytoproterone acetate or spironolactone can be added, if necessary [1]. Patients with heterozygous factor-V-Leiden mutations are known to spontaneously develop venous thromboembolism (VTE) in up to 36 % of the cases [26, 27]. The patient’s previous DVT would also have contributed to an increased risk for developing venous thrombosis, with a recent study finding 15 % of patients with an isolated DVT to have experienced a previous DVT [28]. Routine screening for thrombophilia in male-to-female transsexuals initiated on cross-hormone treatment is, however, not recommended except for patients with a personal or family history of VTE, such as our patient [2]. Initially our patient refused testosterone treatment but now, after 6 years, he has decided not to undergo gender reassignment and recently accepted prescription for testosterone. Testosterone replacement usually does not have an associated risk of venous thromboembolism. One study found that specifically in hypogonadal men, testosterone improved erythrocyte membrane lipid composition and suggested that this could help decrease any risk of thrombosis [29]. However, recent data suggest that in patients with thrombophilia, testosterone, via aromatization, predisposes to recurrent VTE events despite adequate anticoagulation, and therefore the study raised the issue about testosterone replacement in thrombophilia patients [30]. Following recognition of these cases of VTE while on testosterone therapy as being unrelated to polycythaemia, the FDA (US Food and Drug Administration) have now recently updated VTE as a general warning on all testosterone products [31]. Kallmann syndrome and multiple sclerosis MS is a chronic, inflammatory, demyelinating condition affecting the central nervous system [32]. It is estimated to affect 113 men and 286 women per 100,000 in the UK [33]. Our patient presented at the typical age at which MS patients present (between ages of 20 and 40) with a relapsing-remitting subtype of MS. Although MS is thought to have multifactorial etiology, genome-wide association
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studies and meta-analyses, using familial cases, have identified 57 genetic loci to be associated with the condition [34, 35]. As the patient’s sister has recently presented with MS, it suggests that there may be a genetic predisposition to the patient’s MS. Although we have not found any previous case reports of the coexistence of MS and Kallmann syndrome, a recent study has looked at the brain MRI scans of 45 male patients with Kallmann syndrome and identified one patient to have ‘‘multiple sclerosis-like white matter abnormalities’’ [36]. Interestingly, we also have another patient with MS and Kallmann syndrome (M. Korbonits, unpublished observation): this second patient presented at the age of 20 years with anosmia, bilateral undescended testis, eunuchoid proportions, and profound testosterone deficiency responding well to testosterone replacement therapy. This latter patient’s primary progressive MS started at the age of 45 years. Anosmin-1 and FGFR1 proteins are altered and known to contribute to the pathogenesis of Kallmann syndrome. They have now been linked to abnormalities in myelination and MS. It has been recently considered by Garcı´a-Gonza´lez et al. that myelination/demyelination defects could have a role in olfactory dysfunction and in causing the bimanual synkinesia and cerebellar symptoms in Kallmann syndrome [10, 37]. Furthermore, the myelinated lateral olfactory tract can show atrophy in Kallmann syndrome [10]. Both FGF2 and anosmin-1 are expressed in postmortem brain tissue of MS patients; anosmin-1was only raised in chronic MS lesions, whereas FGF2 was present in active MS lesions and peri-plaques [38]. Both anosmin-1 and FGF2 were found to interact with FGFR1 and influence migration of oligodendrocyte precursor cells in different ways, which has been thought to affect the remyelination of lesions [38]. To date, MS is still considered to have an autoinflammatory origin but there are differences in the pathological and radiological findings in the MS subtypes, showing the primary/secondary progressive subtypes to be more neurodegenerative (e.g., more cortical and white matter demyelination, axonal damage, spinal cord, and whole brain atrophy) [39]. It is not clear whether the increased neurodegenerative abnormalities in progressive MS disease contributes to hypogonadism but recent data have identified distinct immunological mechanisms in progressive MS (e.g., increased expression of specific serum adhesion molecules and leucocyte surface expression but intact blood brain barrier, in comparison with relapsing-remitting MS) [40], which could be influential in causing the worse hypogonadism in this subset of patients. On the other hand, there might be a possibility that the MS itself could arise from the state of pre-existing hypogonadotropic hypogonadism. MS is characterized by a predominance of T helper 1 (Th1) cytokines (such as TNF-
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a, interferon gamma, etc.) and lack of T helper 2 (Th2) cytokines (interleukin 10, interleukin 4, and interleukin 5). In experimental animal models of MS known as experimental autoimmune encephalomyelitis (EAE), testosterone and dihydrotestosterone have been shown to influence the balance of cytokines toward increased Th2 cytokine production and reduced Th1 cytokine production, and subsequently reduce mortality of these animals [41– 45]. Hence, in states of male hypogonadism such as Kallmann syndrome, the lack of testosterone could lead to a reduction in the production of Th2 cytokines and therefore contribute toward the pathogenesis of MS. Furthermore, some controversial studies found that testosterone treatment was beneficial in improving cognitive performance and slowing brain atrophy in a cohort of male patients with relapsing-remitting MS [46, 47]. In our case, the patient’s idiopathic hypogonadotropic hypogonadism was clearly due to congenital Kallmann syndrome. He also had a genetic predisposition to MS, whether the two together played a role in the manifestation in his MS remains an open question.
Conclusions In summary, this is a complex case of Kallmann syndrome and other comorbidities. The role of hypogonadism in male-to-female gender dysphoria is intriguing and remains to be controversial. In the past, thrombophilia presented a challenge in male-to-female gender reassignment, but modern regimens provide more acceptable options. Although MS is not the cause of this patient’s congenital hypogonadotropic hypogonadism, further research is needed to evaluate any association between Kallmann syndrome and MS. Managing this patient and his comorbidities required a multidisciplinary team, including originally a pediatric cardiologist and urologist, and more recently endocrinologist, psychiatric consultant-expert in gender reassignment, thrombophilia-expert, neurologist, neuroradiologist, and clinical geneticist to provide the patient with the possible management options and the opportunity to decide what was the most suitable treatment option for him. Acknowledgments We are grateful to the patient for allowing us to share the history and data of his diseases. Conflict of interest of interest.
The authors declare that they have no conflict
Informed consent Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
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