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Kimberly Voon Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia

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Bronwyn G A Stuckey Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
Keogh Institute for Medical Research, Nedlands, WA, Australia
School of Medicine, University of Western Australia, Nedlands, WA, Australia

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Summary

With rising rates of adoption and surrogacy, induced lactation is likely to become increasingly relevant, allowing women who did not undergo pregnancy to breastfeed. We describe the case of a woman with complete androgen insensitivity syndrome (CAIS) on conventional oestrogen therapy who was expecting a child via surrogacy and who wished to breastfeed. The woman was commenced on supplementary oestrogen therapy, domperidone and breast stimulation by mechanical breast pump 8 weeks prior to the delivery of her child. Following delivery, the patient produced a small, unquantified amount of milk, allowing her to suckle the infant for a short period of time. Induced lactation is possible in chromosomally XY individuals. It has been most successful in cis-women and transwomen, both of whom have had progesterone/progestogen exposure to the breast. We suggest that the addition of a progestogen to our patient’s treatment regimen, either as part of her original hormone therapy or part of the lactation induction program, would have improved her changes of establishing successful lactation.

Learning points

  • Induced lactation is possible in chromosomally XY individuals with the use of pharmacological and non-pharmacological therapies.

  • There are no standardised guidelines regarding the optimal regimen for induced lactation.

  • Progesterone exposure to the breast is essential for ductal branching and alveolar maturation.

  • In the published literature, induced lactation is more successful in transwomen and other XY individuals who have had prior progesterone exposure.

  • The addition of progestogen to our patient’s treatment regimen would have improved her chances of establishing successful lactation.

Open access
Bronwyn G A Stuckey Keogh Institute for Medical Research, Nedlands, Western Australia, Australia
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
School of Medicine, University of Western Australia, Nedlands, Western Australia, Australia

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James D Nolan Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

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David M Hurley Department of Endocrinology and Diabetes, Royal Perth Hospital, Perth, Western Australia, Australia

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Graeme B Martin School of Agriculture and Environment, University of Western Australia, Nedlands, Western Australia, Australia

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Summary

A 33-year-old man with Kallmann syndrome had received pulsatile GnRH as an infant for the treatment of cryptorchidism. As an adult, his treatment for fertility with gonadotrophins was unusually rapid compared with expectations, with a total sperm count of 25 million after only 12 months of gonadotrophin therapy. We propose that pulsatile GnRH treatment as an infant induced minipuberty and facilitated his successful, rapid response to therapy. We also propose that identification of the absence of minipuberty in infants with clinical signs suggesting congenital hypogonadotrophic hypogonadism (CHH) is an opportunity for intervention with pulsatile GnRH yielding benefits for fertility decades later.

Learning points

  • Absence of minipuberty in males with CHH results in low Sertoli cell numbers and delayed response to induction of spermatogenesis in adulthood.

  • Presentation with 'red flags' for androgen deficiency including cryptorchidism at birth, with or without micropenis, should prompt screening for CHH and minipuberty by measurement of gonadotrophins and testosterone in the first 2 months after birth.

  • Pulsatile GnRH therapy in patients with CHH, given prior to age of attainment of Sertoli cell maturation, can replicate the normal physiology of minipuberty, thereby priming the testis for future fertility.

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M Lockhart Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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E Ali Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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M Mustafa Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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W Tormey Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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S Sreenan Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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A Saaed Ophthalmological Surgery Department, Hermitage Medical Clinic, Lucan, Ireland

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JH McDermott Academic Department of Endocrinology and Pathology, Connolly Hospital Blanchardstown/RCSI, Lucan, Ireland

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Summary

A patient treated with intramuscular testosterone replacement therapy for primary hypogonadism developed blurred vision shortly after receiving his testosterone injection. The symptom resolved over subsequent weeks and recurred after his next injection. A diagnosis of central serous chorioretinopathy (CSR) was confirmed following ophthalmology review. A decision was made to change the patient’s testosterone regime from this 12-weekly intramuscular injection to a daily topical testosterone gel, given the possibility that peak blood levels of testosterone following intramuscular injection were causing his ocular complaint. His CSR did not recur after this change in treatment. CSR secondary to testosterone therapy is a rare finding but has been reported previously in the literature.

Learning Points

  • Blurred vision in patients treated with testosterone replacement therapy (TRT) should prompt an ophthalmology review.

  • The potential for reduced risk of central serous chorioretinopathy (CSR) with daily transdermal testosterone remains a matter of conjecture.

  • CSR is a rare potential side effect of TRT.

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Sue Sleiman Clinical Andrology Laboratory, NSW Health Pathology, Concord Hospital, Sydney, New South Wales, Australia

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Feyrous Bacha Clinical Andrology Laboratory, NSW Health Pathology, Concord Hospital, Sydney, New South Wales, Australia

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David J Handelsman Clinical Andrology Laboratory, NSW Health Pathology, Concord Hospital, Sydney, New South Wales, Australia
ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia

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Summary

We report the successful delivery of a healthy baby after intracytoplasmic sperm injection (ICSI) with frozen-thawed autologous sperm, cryostored for 26 years, the longest successful autologous sperm cryostorage reported. Sperm was cryostored for a 15-year-old boy at the time of his cancer diagnosis. Semen samples were frozen with cryoprotectant, using a graduated vapour-phase nitrogen protocol. Straws were stored in a large vapour-phase nitrogen tank until transfer for use. The couple underwent a single ICSI–in vitro fertilisation procedure using the frozen-thawed sperm with a transfer of five fertilised embryos, resulting in the live birth of a healthy baby boy. This reinforces the importance of offering sperm cryopreservation to men who have not completed their family prior to gonadotoxic treatment for cancer or other diseases. As practical, low-cost fertility insurance, it should be offered to any young man who can collect semen and it provides essentially unlimited duration of fertility preservation.

Learning points

  • Gonadotoxic chemo or radiotherapy treatment for cancer or other diseases usually causes temporary or permanent male infertility.

  • Sperm cryostorage serves as a practical, low-cost insurance to facilitate future paternity.

  • All men who have not completed their families and are scheduled for gonadotoxic treatments should be offered sperm cryostorage.

  • There is no lower age limit for young men who can collect semen.

  • Sperm cryostorage offers essentially indefinite duration for the preservation of male fertility.

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Beryl Lin Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

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Stephen M Twigg Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Sydney Medical School (Central), University of Sydney, Sydney, NSW, Australia

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Summary

Functional hypogonadotropic hypogonadism is a relatively common condition in middle-aged to elderly men that can significantly impair quality of life. Besides lifestyle optimisation, androgen replacement remains the mainstay of treatment; however, its adverse effects on spermatogenesis and testicular atrophy are undesirable. Clomiphene citrate is a selective oestrogen receptor modulator that acts centrally to increase endogenous testosterone without affecting fertility. Although it has demonstrated effectiveness in shorter-duration studies, its longer-term outcomes are less well-documented. In this study, we report the case of a 42-year-old male with functional hypogonadotropic hypogonadism who sustained an excellent dose-dependent, titratable clinical and biochemical response to clomiphene citrate with no known adverse effects for 7 years to date. This case highlights that clomiphene citrate has potential as a safe and titratable longer-term treatment option, and the need for further randomised control trials in therapy options to normalise androgen status.

Learning points

  • Functional hypogonadotropic hypogonadism is a relatively common, but likely underdiagnosed, condition in middle-aged to older males.

  • Testosterone replacement is the current mainstay of endocrine therapy but can cause sub-fertility and testicular atrophy.

  • Clomiphene citrate is a serum oestrogen receptor modulator that acts centrally to increase endogenous testosterone production without affecting fertility.

  • It has potential as a safe and efficacious longer-term treatment option that can be titrated to increase testosterone and relieve clinical symptoms in a dose-dependent manner.

  • Longitudinal prospective studies as randomised control trials evaluating alternatives to exogenous testosterone are required.

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Jananie Suntharesan Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Louise Apperley Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Senthil Senniappan Department of Endocrinology, Alder Hey Children’s Hospital, Eaton Road, Liverpool, UK

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Summary

A male phenotype accompanied by a 45,X karyotype is rare. It may occur due to Y chromosomal translocation or insertion to X/autosome. Clinical presentation may vary depending on the presence of the Y chromosomal locus and the degree of loss of autosome material. 45,X males can present with short stature and Turner syndrome phenotype due to haploinsufficiency of genes which are normally expressed in both X and Y chromosomes. The presence of the sex-determining region Y (SRY) gene leads to the differentiation of bipotential gonads to testis. Most individuals go through puberty normally, but some may need pubertal induction for delayed puberty. Rarely some can have a pubertal arrest. The risk of gonadoblastoma is minimal in these individuals due to functioning testicular tissue. The azoospermia factor (AZF) region is found on the long arm of the Yq chromosome and is needed for spermatogenesis. In a 45,X male with unbalanced translocation of Y chromosome, spermatogenesis can be affected due to the lack of AZF leading to Sertoli cell-only syndrome. This will have an implication on fertility in adult life. We present a 14-year-old boy with developmental delay, learning difficulties and subtle dysmorphic features who was diagnosed with 45,X,der(2)t(Y:2)(?:p25). Fluorescence in situ hybridisation analysis revealed translocation of SRY (Yp11.3) to the terminal part of the short arm of chromosome 2 resulting in the deletion of most of the Y chromosome (Yp11.2-q12) and part of chromosome 2(2p25.3). This is the first case where SRY translocation to chromosome 2 presents with the above clinical presentation.

Learning points

  • 45,X karyotype is rare in male.

  • It may occur due to SRY translocation or an insertion to X/autosome.

  • SRY gene translocation to chromosome 2 has been not reported in the literature.

  • Clinical presentation can be varied due to degree of loss of chromosomal material.

  • Due to loss of AZF region found on the long arm of the Yq, spermatogenesis can be affected. Loss of 2p25 leads to learning difficulty and obesity.

Open access
Mami Kobayashi Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
Department of Pediatrics, The University of Tokyo Hospital, Tokyo, Japan

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Hideaki Yagasaki Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan

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Kei Tamaru Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan

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Yumiko Mitsui Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan

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Takeshi Inukai Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan

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Summary

Prader–Willi syndrome (PWS) is a genetic imprinting disorder that is characterized by obesity, short stature, and hypogonadism. Hypogonadism is characterized by normal luteinizing hormone (LH), high follicle-stimulating hormone (FSH), low testosterone, low inhibin B, and relatively low anti-Müllerian hormone (AMH). Only a few cases of central precocious puberty (CPP) have been reported in PWS, and follow-up for CPP with PWS is not established. Hence, we present a boy with PWS accompanied by CPP. Gonadotropin-releasing hormone analog (GnRHa) therapy was started at 7 years of age, CPP was adequately arrested, and GnRHa therapy was discontinued at 11.3 years of age. Growth hormone (GH) therapy was started at 12 years of age due to inadequate growth. He grew close to his final height, and his testes developed with normal LH, increased FSH, normal testosterone, and reduced AMH corresponding to puberty at 13.5 years of age. The features of 16 patients with PWS with CPP, including our patient, were summarized. Out of seven male patients, five were treated with GnRHa, as well as four out of nine female patients. Out of 16 patients, 6 were assessed with pubertal development over 13 years of age. Pubertal development was considered to be restored in four patients who had GnRHa therapy discontinuation. We should carefully follow-up on pubertal development in CPP. GnRHa therapy is useful for adequate puberty blockage, and pubertal development could be restored with GnRHa therapy discontinuation.

Learning points

  • Pubertal development in Prader–Willi syndrome (PWS) varies from hypogonadism to precocious puberty.

  • Pubertal development assessment based on clinical features and hormone levels is needed in central precocious puberty (CPP) treatment with PWS.

  • Gonadotropin-releasing hormone analog (GnRHa) therapy is useful for CPP with PWS, and pubertal development can be restored with GnRHa therapy discontinuation.

Open access
Laura Marino Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Andrea Messina Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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James S Acierno Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Franziska Phan-Hug Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Nicolas J Niederländer Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Federico Santoni Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Stefano La Rosa Department of Laboratory Medicine and Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland

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Nelly Pitteloud Department of Service of Endocrinology, Diabetes, and Metabolism, Faculty of Biology and Medicine, University of Lausanne, Lausanne University Hospital, Lausanne, Vaud, Switzerland

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Summary

Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens.

Learning points

  • N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome.

  • Surgical removal of testosterone-producing gonads can result in loss of libido.

  • Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS.

  • A previously unreported AR mutation – p.Glu2_Met190del (c.2T>C) – is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

Open access
Mariana Aveiro-Lavrador Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Center, Coimbra, Portugal

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Adriana De Sousa Lages Endocrinology Department, Braga Hospital, Braga, Portugal

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Luísa Barros Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Center, Coimbra, Portugal

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Isabel Paiva Endocrinology, Diabetes and Metabolism Department, Coimbra Hospital and University Center, Coimbra, Portugal

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Summary

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life.

Learning points

  • Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis.

  • CAH may be divided into two major forms: classic and non-classic CAH.

  • If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood.

  • Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients.

  • Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.

Open access
Tetsuji Wakabayashi Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Akihito Takei Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Nobukazu Okada Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Miki Shinohara Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Manabu Takahashi Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Shuichi Nagashima Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Kenta Okada Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Ken Ebihara Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Shun Ishibashi Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Summary

The underlying genetic drivers of Kallmann syndrome, a rare genetic disorder characterized by anosmia and hypogonadotropic hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GNRH)-producing neurons during embryonic development, remain largely unknown. SOX10, a key transcription factor involved in the development of neural crest cells and established as one of the causative genes of Waardenburg syndrome, has been shown to be a causative gene of Kallmann syndrome. A 17-year-old male patient, who was diagnosed with Waardenburg syndrome on the basis of a hearing impairment and hypopigmented iris at childhood, was referred to our department because of anosmia and delayed puberty. As clinical examination revealed an aplastic olfactory bulb and hypogonadotropic hypogonadism, we diagnosed him as having Kallmann syndrome. Incidentally, we elucidated that he also presented with subclinical hypothyroidism without evidence of autoimmune thyroiditis. Direct sequence analysis detected a nonsense SOX10 mutation (c.373C>T, p.Glu125X) in this patient. Since this nonsense mutation has never been published as a germline variant, the SOX10 substitution is a novel mutation that results in Kallmann syndrome and Waardenburg syndrome. This case substantiates the significance of SOX10 as a genetic cause of Kallmann syndrome and Waardenburg syndrome, which possibly share a common pathway in the development of neural crest cells.

Learning points

  • Kallmann syndrome and Waardenburg syndrome possibly share a common pathway during neural crest cell development.

  • SOX10, a key transcription factor involved in the development of neural crest cells, is a common causative gene of Kallmann syndrome and Waardenburg syndrome.

  • Careful evaluation about various phenotypic features may reveal the unknown genetic drivers of Kallmann syndrome.

Open access