We describe the rare case of an adult man with normal virilization affected by both Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, consulting for painful gynecomastia. A complete clinical workup included endocrinological, genetic, sexological evaluation and testis histology. Genetic analyses included karyotype, CYP21 sequencing and the CAG and GGC repeat polymorphism in the androgen receptor gene. KS was diagnosed by karyotype analysis (47,XXY), the testis biopsy revealed Leydig cell hyperplasia. The CAH was diagnosed by the direct detection of a I2 homozygous mutation in the CYP21 gene. The hormonal analysis revealed a mild hypergonadotropic hypogonadism, serum levels of androstenedione and ACTH above the normal range and a slightly reduced cortisol response with exaggerated 17-OH progesterone increase to ACTH stimulation. Cortisone acetate treatment disclosed a clinically relevant pre-existent hypogonadism in the relatively short time of 6 months, thus suggesting that the reduction in adrenal steroids impaired the balance in the androgen status previously created by the two syndromes. Only the combined therapy with cortisone acetate and testosterone restored a normal androgenization and a male sexual behavior. The simultaneous occurrence of KS and CAH is extremely rare. The clinical phenotype of our patient was characterized by mild symptoms of the two syndromes, probably because the high levels of adrenal androgens due to CAH counterbalanced the partial androgen deficiency due to KS.

Rheumatic diseases and Klinefelter's syndrome.Autoimmun Rev. 2006 Nov;6(1):33-6. Epub 2006 Apr 19.

The Klinefelter's syndrome (KS) is not a rare gonosomal aberration occurring in males. The disorder is characterized by microorchidism. Another typical although not constant symptom of this disorder is gynecomastia with almost normal male secondary sex characteristics. The etiology of the disease remains unexplained. Previous studies have shown that this disorder is a genetic chromosomal abnormality associated with the presence of one additional chromosome due to abnormal division. Thus, the affected individual has 47 chromosomes with the resulting chromosomal constellation of XXY (classical form) or 46,XY/47,XXX (mosaic form). Large population studies estimate the incidence of KS at 1:1000 live born male babies [Hammerton JL, Canning N, Ray M, et al. A cytogenic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet 1975;8:223-243]. The locomotor apparatus of persons affected by the syndrome is characterized by acromicria, clinodactyly, concrescence of thoracal vertebral bodies and spinal osteoporosis in not only individuals of older age but also in younger persons. In 1960s and 1970s, reports were published on the concurrence of the KS with autoimmune diseases. The aim of our article is to discuss case reports on the KS published by authors from our institute as well as to present an overview of the reports published so far, mainly abroad.

Social Behavior and Autism Traits in a Sex Chromosomal Disorder: Klinefelter (47XXY) Syndrome.J Autism Dev Disord. 2008 Mar 7.

Although Klinefelter syndrome (47,XXY) has been associated with psychosocial difficulties, knowledge of the social behavioral phenotype is limited. We examined specific social abilities and autism traits in Klinefelter syndrome. Scores of 31 XXY men on the Scale for Interpersonal Behavior and the Autism Spectrum Questionnaire were compared to 24 and 20 control men respectively. XXY men reported increased distress during social interactions and less engagement in specific social behaviors. In the XXY group, levels of autism traits were significantly higher across all dimensions of the autism phenotype. These findings call for a clinical investigation of vulnerability to autism in Klinefelter syndrome. Klinefelter syndrome might serve as a model for studying a role of the X chromosome in social behavioral dysfunction and autism-like behavior.

Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome.Clin Endocrinol (Oxf). 2007 Dec;67(6):863-70. Epub 2007 Jul 20.

OBJECTIVE: To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome. Design Retrospective chart review. Patients A total of 29 boys with Klinefelter syndrome with up to 12.3 years follow-up. MEASUREMENTS: Clinical features and serum hormone levels were analysed during follow-up. RESULTS: Of the 29 patients, 16 were prepubertal and 13 had already entered puberty at their first visit. Fifteen patients were followed up through late puberty. Before puberty, LH, FSH, testosterone, anti-Müllerian hormone (AMH) and inhibin B were within the expected range in almost all cases. However, levels of the inhibin alpha-subunit precursor Pro-alphaC were in the lowest levels of the normal range in most cases. During puberty, FSH levels increased earlier and more markedly than LH. Inhibin B and AMH declined to abnormally low or undetectable levels in advanced pubertal stages. Although testosterone and Pro-alphaC levels were within the reference ranges in most cases, they were abnormally low for the observed LH values. CONCLUSIONS: In Klinefelter syndrome, a mild Leydig cell dysfunction is present from early childhood in most cases and persists throughout puberty. Sertoli cell function is normal until mid puberty, when a dramatic impairment is observed.

Klinefelter's syndrome associated with mixed connective tissue disease (Sharp's syndrome) and thrombophilia with postthrombotic syndrome.J Dtsch Dermatol Ges. 2005 Aug;3(8):623-6.

A 43-year-old male with eunuchoid body proportions and a history of deep venous thromboses in the right leg presented with recurrent ulcers in the right perimalleolar region for 6 years. Karyotyping revealed a 47 XXY Klinefelter's syndrome, while serologic testing showed protein S deficiency, hyperhomocysteinemia and positive lupus anticoagulant. He also had mixed connective tissue disease (Sharp's syndrome) with acrosclerosis, proximal finger edema, Raynaud's phenomenon, and high titers of ANA and U1-RNP-antibodies, as well as osteoporosis. There is evidence that patients with Klinefelter's syndrome are prone to develop connective tissue diseases and thrombophilia as a result of low androgen levels. Substitution of testosterone in Klinefelter's syndrome can have a favorable therapeutic effect on the associated connective tissue disease, thrombophilia and osteoporosis.

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