Diagnosis and Treatment > Signs and Symptoms
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Summary
A 40-year-old man with achondroplasia presented with symptoms of hypogonadism, low libido and gynaecomastia. He was found to have hypergonadotropic hypogonadism, and karyotype and fluorescent in situ hybridisation analysis showed SRY-positive 46, XX disorder of sex development (DSD). He was tested to have the common activating mutation of the FGFR3 gene implicated in achondroplasia, indicating that he had the two rare conditions independently, with an extremely low incidence of 1 in 400 million. This, to the best of our knowledge, is the first report of an individual having these two rare conditions concurrently. This case highlights that individuals with achondroplasia should have normal sexual development, and in those presenting with incomplete sexual maturation or symptoms of hypogonadism should prompt further evaluation. We also propose a plausible link between achondroplasia and 46, XX DSD through the intricate interactions between the SRY, SOX9 and FGFR9 gene pathways.
Learning points:
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The SOX9 and FGF9 genes, which are upregulated by the SRY gene, are important in both sex determination in the embryo, as well as endochondral bone growth.
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Patients with achondroplasia should have normal sexual development and function in the absence of other confounding factors.
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Patients with achondroplasia who present with symptoms and signs of abnormal sexual development and/or hypogonadism should be appropriately investigated for other causes.
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Search for other papers by Conceição Canas Marques in
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Summary
Granular cell tumours (GCT) are rare, slow-growing, benign neoplasms that are usually located in the head and neck. They are more frequent in the female gender and typically have an asymptomatic clinical course, being diagnosed only at autopsy. Symptomatic GCT of the neurohypophysis are exceedingly rare, being less than 70 cases described so far. The authors report on a case of a 28-year-old male that presented to the Endocrinology clinic with clinical and biochemical evidence of hypogonadism. He also reported minor headaches without any major visual symptoms. Further laboratory tests confirmed hypopituitarism (hypogonadotrophic hypogonadism, central hypothyroidism and hypocortisolism) and central nervous system imaging revealed a pituitary macroadenoma. The patient underwent transcranial pituitary adenoma resection and the pathology report described a GCT of the neurohypophysis with low mitotic index. The reported case is noteworthy for the rarity of the clinicopathological entity.
Learning points:
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Symptomatic GCTs are rare CNS tumours whose cell of origin is not well defined that usually give rise to visual symptoms, headache and endocrine dysfunction.
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Imaging is quite unspecific and diagnosis is difficult to establish preoperatively.
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Surgical excision is challenging due to lesion’s high vascularity and propensity to adhere to adjacent structures.
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The reported case is noteworthy for the rarity of the clinicopathological entity.
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Search for other papers by Marcus Quinkler in
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Summary
DAX1 (NR0B1) is an orphan nuclear receptor, which plays an important role in development and function of the adrenal glands and gonads. Mutations in DAX1 cause X-linked adrenal hypoplasia congenita (X-linked AHC), which is characterized by adrenal insufficiency (AI) and hypogonadotropic hypogonadism (HHG). Affected boys present with adrenal failure usually in childhood and, later in life, with delayed puberty. However, patients with a late-onset form of X-linked AHC have also been described in the past years. We report a male patient who presented with symptoms of an adrenal crisis at the age of 38 years and was later diagnosed with HHG. Family history was positive with several male relatives diagnosed with AI and compatible with the assumed X-chromosomal inheritance of the trait. Direct sequencing of DAX1 of the patient revealed a hemizygous cytosine-to-thymine substitution at nucleotide 64 in exon 1, which creates a novel nonsense mutation (p.(Gln22*)). In order to compare the clinical presentation of the patient to that of other patients with X-linked AHC, we searched the electronic database MEDLINE (PubMed) and found reports of nine other cases with delayed onset of X-linked AHC. In certain cases, genotype–phenotype correlation could be assumed.
Learning points:
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X-linked AHC is a rare disease characterized by primary AI and hypogonadotropic hypogonadism (HHG). The full-blown clinical picture is seen usually only in males with a typical onset in childhood.
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Patients with a late-onset form of X-linked AHC have also been described recently. Being aware of this late-onset form might help to reach an early diagnosis and prevent life-threatening adrenal crises.
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Adult men with primary AI of unknown etiology should be investigated for HHG. Detecting a DAX1 mutation may confirm the clinical diagnosis of late-onset X-linked AHC.
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In relatives of patients with genetically confirmed X-linked AHC, targeted mutation analysis may help to identify family members at risk and asymptomatic carriers, and discuss conscious family planning.
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic–pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion.
Learning points:
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Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.
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In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.
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In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.
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Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.
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Search for other papers by S O Oyibo in
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Summary
Gonadotrophin therapy with human chorionic gonadotrophin and recombinant FSH is indicated for use in men with reduced spermatogenesis due to hypogonadotrophic hypogonadism (HH). Patients require regular monitoring for side effects and desired response to treatment. We present a man with HH, azoospermia and a history of previous anabolic steroid usage who had undergone gonadotrophin therapy, had subsequently achieved conception and has now fathered a child.
Learning points
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In total, 15% of couples do not achieve pregnancy within 1 year and seek medical treatment for infertility: male factors contribute to 50% of these.
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The evaluation of male infertility should include a full history and examination, an endocrine profile and a quality-controlled semen analysis.
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HH with defective spermatogenesis is an important cause of male infertility in a small percentage of cases.
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Gonadotrophin therapy requires regular monitoring for side effects and desired response to treatment.
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Any sustained rise in prostate specific antigen levels should prompt urological assessment for possible prostate biopsy.
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A multidisciplinary approach is required for gonadotrophin therapy, especially if assisted fertilisation techniques are required once, spermatogenesis is achieved.
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Summary
Erdheim–Chester disease (ECD) is a potentially fatal condition characterized by infiltration of multiple organs by non-Langerhans histiocytes. Although endocrine dysfunction has been reported in association with ECD, to date, there have been no previous reports of empty sella syndrome (ESS) associated with it. We report the case of a patient with ECD who had symptomatic ESS. A 55-year-old man of Chinese ethnicity initially presented with symptoms of heart failure, fatigue and knee joint pain. Physical examination revealed xanthelasma, gynaecomastia, lung crepitations, hepatomegaly and diminished testicular volumes. He had laboratory evidence of hypogonadotrophic hypogonadism, secondary hypoadrenalism and GH deficiency. Imaging studies showed diffuse osteosclerosis of the long bones on X-ray, a mass in the right atrium and thickening of the pleura and of the thoracic aorta on fusion positron emission tomography–computed tomography. Magnetic resonance imaging (MRI) of the brain showed an empty sella. The diagnosis of ECD was confirmed by bone biopsy.
Learning points
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ECD is a multisystemic disease that can affect the pituitary and other organs. The diagnosis of ECD is based on clinical and radiological features and histology, showing lipid-laden CD68+ CD1a− S100− histiocytes surrounded by fibrosis.
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The finding of xanthelasmas especially in the presence of normal lipid levels in the presence of a multisystem infiltrative disorder should raise the suspicion of ECD.
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Systemic perturbation of autoimmunity may play a role in the pathogenesis of ECD and is an area that merits further research.
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Summary
Testicular adrenal rest tumours (TARTs) are benign ACTH-dependent tumours that occur in males with congenital adrenal hyperplasia (CAH) and if left untreated can destroy testicular tissue. Corticosteroid suppressive treatment could result in the regression of these testicular tumours. We present a patient with bilateral large TARTs as a consequence of poor compliance to treatment and follow-up for his CAH, who consequently had to have bilateral orchidectomies and prosthesis replacement.
Learning points
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TARTs are frequently seen in males with CAH, and can be misdiagnosed as primary testicular cancer.
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Patient compliance to treatment and follow-up are necessary to reduce the risk of testicular damage as a result of TARTs in patients with CAH.
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Boys with CAH should have periodic ultrasonographic screening from before adolescent age for early detection of TARTs.
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Regular monitoring of renin, 17-hydroxyprogesterone and androgens levels is required to assess corticosteroid suppressive treatment.
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Patients with CAH should be offered psychological support and information concerning CAH support groups.
