This case describes the presence of a GH-secreting pituitary microadenoma in a patient with KS, which was previously undiagnosed. Early recognition and hormonal treatment of KS can substantially improve patients’ quality of life and prevent serious consequences.7 The low rate of timely discovery and diagnosis results from diversity in clinical presentation of the patient and insufficient understanding of the classic endocrine negative feedback system by physicians. More emphasis should be placed on improving case identification of KS. We diagnosed him with KS based on his atrophic testicles, primary hypogonadism as revealed by hormonal examination, and a chromosomal aberration of 47,XXY.
In male individuals, hypogonadism can be divided into 2 types: hypogonadotropic hypogonadism owing to a lesion in the hypothalamic or pituitary region and hypergonadotropic hypogonadism from defects in the testes or in the androgen target tissues.8 The tumor mass effects and invasive alternative, pituitary hormone decline was frequently observed in the anterior lobe of the pituitary gland before and after trans-sphenoidal surgery, which leads to hypogonadotropic hypogonadism.9 Hypergonadotropic hypogonadism can result from testicular injury, tumour, or infection and genetic defects affecting testicular development (eg, KS), as well as chemotherapy, radiation treatment or alcohol abuse.8 KS is the most common genetic form of hypergonadotropic hypogonadism. According to patient's history and clinical examination, KS was given higher priority. For our patient, a low T concentration with elevated FSH and LH concentrations in this case provided a clue to KS diagnosis, and the confirmed diagnosis based on chromosome analysis.
The patient had typical features of acromegaly, and laboratory examination reveals a notable increase in the GH concentration. Furthermore, the imaging detected a pituitary adenoma and postoperative immunohistochemical findings confirmed the diagnosis of a pituitary GH-secreting microadenoma. Kontogeorgos et al10 defined pituitary gonadotropin-secreting adenomas as those with an FSH and/or LH expression level of >10%. In our patient, immunohistochemical staining was negative for FSH and weakly positive for LH. Gonadotropinoma or acromegaly combined gonadotropinoma should be excluded.
Acromegaly is a rare disease with unrestricted GH-induced secretion of IGF-1, leading to an increased prevalence of comorbidities.11 Treatment options include surgery, medical therapy, and radiotherapy. Trans-sphenoidal surgery is recommended as a priority treatment for many patients with acromegaly, particularly those with microadenomas.12 However, 40% to 60% of patients with acromegaly will experience persistent or recurrent disease following surgery, necessitating additional therapy.13 Somatostatin analogues are the first-line medical treatment for patients with acromegaly. Moreover, better prognosis of acromegaly depends upon early recognition, diagnosis, and management.5 A multidisciplinary management approach and close follow-up are thus necessary for acromegaly therapy.14
The patient's skin was black and rough, and his height was normal, which led to diagnostic confusion and resulted in misdiagnosis during his first treatment. His parents were normal in appearance, intelligence, and height (father, 170 cm; mother, 156 cm). The patient's mother stated that the development of the patient's language and motor ability was delayed and that his height growth was slow. As he reached maturity, the patient's language and motor ability became almost normal. At the age of 22 years, he was 160-cm tall and continued growing until he reached 172 cm. He had been a manual worker in an industrial company after his graduation from junior high school. He had a mild temperament with no violent behavior. He got married at the age of 25, and because of low sexual desire, he had received testosterone treatment for half a year.
A characteristic of KS is tall stature, but not all men with XXY actually develop this syndrome or its symptoms. Many autosomal genes are differentially expressed in patients with KS, which explains the diversity in clinical phenotype diversity among patients with KS.20,21 In fact, many men show no abnormalities at all. Some uncommon KS variants are associated with short stature (49,XXXXY).22 There are a few reported cases of KS and short stature secondary to GH deficiency.23–31 Complementary studies showed partial GH deficiency, but the reason for such an association is not clearly known.
We believe that the patient's height increase was a result of his GH-secreting pituitary adenoma, and the possibility that this patient with KS had short stature because of partial GH deficiency cannot be entirely ruled out. KS can stimulate tallness because of failure of the epiphyses to close. The gonadal steroids (estrogen, T) cause closure of the epiphyseal growth plates.32 On this basis, we hypothesized that the T treatment for low libido that the patient received after marriage might account for the closure of the epiphyses.
Prolonged target gland failure causes pituitary hyperplasia; several cases of gonadotrope cell hyperplasia were reported in patients with KS.33 Samaan et al34 have reported that reactive pituitary changes may accompany the gonadal failure present in these dysgenetic syndromes. It is reasonable to assume that because of the loss of negative feedback, chronic stimulation of adenohypophysial cells type results in hyperplasia.35 Whether hyperplastic gonadotroph cells can transform to adenoma and the underlying mechanism is still not clear.
KS is characterized by at least 1 supernumerary X chromosome in addition to the genes on the extra X chromosome, which may be inherited from either parent.36 Acromegaly is an acquired disorder related to excessive production of GH and characterized by progressive somatic disfigurement and systemic manifestations.37 The gsp gene mutation is the major intrinsic defect in the pathogenesis of acromegaly.38 In addition, acromegaly in the setting of germline AIP mutations has been reported in clinical studies worldwide.39,40 So we believe that the KS occurred before the acromegaly, and whether the formation of GH-secreting pituitary adenoma is because of a genetic abnormality linked to KS remains to be elucidated.
Timely diagnosis of KS is challenging itself, and the presence of a GH-secreting pituitary adenoma in this case suggests a rare combination. Further reports would be needed to confirm a possible association between KS and acromegaly. Better understanding of the classic endocrine negative feedback system is important for early diagnosis in KS. Our report also highlights the importance of complete pituitary hormonal screening and conventional pituitary MRI might be essential for the patients with KS to screen for the presence of pituitary adenoma.
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