KLINEFELTER’S SYNDROME AND THALASSEMIA MAJOR-A RARE ASSOCIATION

1. Consultant Endocrinologist, Sanjeevani Thyroid, Sugar and Hormones Clinic, Kompally, Hyderabad, Telangana. (Ex. Consultant Endocrinologist, Yashoda Hospital, Secunderabad). 2. Senior Consultant, Department of Endocrinology, Yashoda Hospital, Secunderabad, Telangana. 3. Senior Resident, Department of Endocrinology, Yashoda Hospital, Secunderabad, Telangana. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History Received: 16 February 2020 Final Accepted: 18 March 2020 Published: April 2020

956 gonadotropic hormones and this might be due to short time interruption of iron chelating therapy. Conclusion: In our patient delayed puberty was due to KS. Association of KS with thalassemia major is very rare. To our knowledge this is the first case report on KS associated with thalassemia major.

Case details:
A 18-year-old boy presented with poor development of secondary sexual characteristics. He was born out of nonconsanguineous marriage, full term of normal vaginal delivery and without significant perinatal adverse events. At birth, both testes were in scrotal region, penis was of normal length and no genital ambiguity was present. Milestones were as per chronological age. At 4 years of his age, while evaluating for easy fatigability, weakness and tiredness, he was found to have anemia. On further evaluation he was diagnosed as thalassemia major.
Diagnosis of Beta thalassemia major was made after hemoglobin electrophoresis (HbA2-1.2%, HbF-20.8%) and DNA analyzed by sequencing for beta globulin gene which revealed compound heterozygous for IVS1-5(G-C) and poly A (T-C) mutations.
Parents were evaluated and both were found to have thalassemia trait.
He was requiring blood transfusion since then and presently he is on blood transfusion once in 2weeks. He underwent spleenectomy 4 years back. From last three years he has noticed the enlargement of both breast, which are not painful, and not having any discharge.
On examination, his weight was47kg, height-158cm, body mass index (BMI)-18.8kg/m 2 , arm span-159cm, upper segment (US)-73.5cm, lower segment (LS)-84.5cm. His anthropometry is suggestive of long legs, which is typical of KS. On further examination, he was found to have bilateral gynaecomastia, short stretched penile length (SPL) (8cm), small testes and firm in nature (3ml volume on Prader's orchidometer), Tanner staging of pubic hair -P3 (curly hair distributed in inverted triangle) and axillary hair A1 (axillary hair absent). Skin complexion was normal and brown in color. On systemic examination, he only had hepatomegaly and other systems were normal.
Investigations are shown in table no: 1. Hormonal profile revealed low testosterone, elevated gonadotropic hormones suggestive of primary hypogonadism. Other hormonal evaluation (serum prolactin, thyroid profile, serum estradiol and serum cortisol) was normal. On further testing, his karyotypewas47,XXY, and Klinefelter syndrome was confirmed.Biochemical investigations revealed iron over load as he had stopped iron chelating therapy few months prior to testing. Other laboratory tests showed Hb-11.7g%, and renal and liver function tests were normal. It is very rare to have association with Thalassemia. To our knowledge there is only one case report in this regard. That too it was Thalassemia intermedia 2 . This would be the first case report to reveal association with β-thalassemia major.
Thalassemia is known to be associated with several endocrinopathies. These include hypogonadism, diabetes, hypoparathyroidism, hypothyroidism, adrenal insufficiency and growth hormone deficiency. Among these hypogonadism is the most common endocrine disorder. Hypogonadotrophic hypogonadism occurs more often than primary hypogonadism 5 . Gonadotropic cells show more affinity towards iron that make them more susceptible than other pituitary cells.
A recent study from UK showed that 75% of patients had at least one endocrine disorder. Hypogonadism was found in 67%, diabetes in 41%, hypoparathyroidism in 17%, and hypothyroidism was seen in 14% of the subjects 6 . Any individual with thalassemia who presents with features of delayed puberty, central hypogonadism is likely the possibility.
However,our patient had primary hypogonadism due to KS. His testes size was small and firm in nature and also his 958 lab tests were showing elevated FSH and low testosterone. This pattern suggests primary hypogonadism. And it was further supported with his karyotype, 47,XXY (KS) that primarily causes testicular failure.
Lab results were showing iron overload as he had stopped iron chelating treatment recently. Because of the short duration of interruption of therapy, iron overload might have not shown the impact on gonadotropic cells, yet.
Klinefelter syndrome associating with thalassemia is rare. That too associating with thalassemia major is not reported so far. Early recognition and treatment of hypogonadism will help in induction of secondary sexual charactersand also improve the quality of life. In Klinefelter syndrome apart from giving treatment for hypogonadism, we have to look for the detection and management of associated conditions, which is very important.
In thalassemia patients also, we have to look for the development of endocrine abnormalities secondary to iron overload. Special focus has to be given to children as these endocrine disordersare going to affect their growth and development significantly.

Conclusion:-
In our patient, delayed puberty was due to KS. Association of KS with thalassemia major is very rare. To our knowledge this is the first case report on KS associating with thalassemia major.