Case Study: Hematologic malignancy in a patient with Klinefelter’s Syndrome: An Uncommon Association


A 30-year-old male who had diabetes for a year and a half attended my clinic and had other co-morbid conditions like hypertension, hypothyroid and hypogonadism. Clinically, his appearance fits in to Klinefelter’s syndrome (KS) as he had gynecomastia, scant pubic hair and small testes. Six months back, on one occasion, he had high blood pressure and raised creatinine, and he was diagnosed with acute renal failure. Later, he had a nose bleed for which he underwent a battery of tests consisting of complete blood count, bleeding time, clotting time, bone marrow aspiration and bone marrow biopsy. In the intervening period, he was given a trial of B12 injection in terms of megaloblastic anemia. But there was no improvement, so investigation was reviewed and treatment was planned, which proved he had myelodysplastic syndrome because of the drastic falling of Hb thrombocytopenia.

Literature on Klinefelter’s and myelodysplastic syndrome was reviewed. There was a constant association of DM and other malignancies like Hodgkin and non-Hodgkin disease, and myeloproliferative disorder. Diabetes is associated with certain cancers like pancreatic and endometrial cancer. Even the therapy for diabetes is associated with certain cancers, e.g., Glargine with pancreatic cancer, and Pioglitazone with bladder cancer.

Only Metformin and insulin analogues are exceptions. Insulin resistance and thyroid deficiency has fallen on the hemopoietic system, resulting in myelodysplastic syndrome, as per the general understanding.


This case is important because of the serious problem of symptoms in a young 30-year-old male who already had diabetes. Incidentally, he was screened and found to have a complex of Klinefelter’s syndrome with hypertension, diabetes and hypothyroidism as co-morbidities.

With thorough investigation in a private multi-specialty hospital, he was found to have a serious problem of myelodysplastic syndrome, which is a malignant hematological condition. This combination of so many co-morbid conditions make a 30-year-old male’s life miserable, while his quality of life can be kept in a reasonable and sound way by the team work of hematologist, oncologist, diabetologist, and lastly, a primary care physician who makes a vital contribution in maintaining the disease.

Case Presentation

A short-statured man, with the main complaint of fatigue on examination, was found to have an absence of pubic hair, auxiliary hair and small testes which gives an idea of hypogonadism. His CVS and RS were not contributory. P-A Examination also did not give any clues, except DM, hypertension and hypothyroidism. Having diabetes for 1 year and 6 months, hypertension and hypothyroidism, his main purpose to visit my clinic was to control of blood sugar and to have free communication to clear certain disease-related doubts.

Medical history: Does not have any relevant and significant history, except that he does not have children.

Social: He is non-alcoholic, a non-smoker and is an agriculture worker residing at a rural setup.

Family: Both parents are diabetic and they are under my care. There is no past history of infective disease, jaundice, malaria, etc. He consulted with medical conditions: hypertension and hypothyroidism.
[s2If !is_user_logged_in()]…

[/s2If][s2If is_user_logged_in()]


As per the records, his BP: 130/80, BG: FPG: 114mg/dl and PPG: 185mg/dl, O/E-CVS, RS, NAD, Abdomen-soft and Kidney Profile: Urine: alb3+, Blood urea : 137mg, Creatinine : 1.8mg, Na: 137, K: 4.1 and Cal: 9.6.

In the next visit, his Hb: 9.2G, RBS: 227mg, Creatinine: 2.2mg, Urine: protein: 4+, Pus cells: 10-15 hpf, RBC: 4-7 hpf and so advised olmesatan 20mg. Plan of treatment was in the line of renal failure.

On 25/4/12 lab tests: Hb: 7.6G, Platelets: 9000/cumm, ESR: 40mm/1hr, BT: 4.3mts, CT: 5.3mts, PT240(13.5) inr 1.7, APTT46(28)

His Hb was drastically reduced, which has been recorded as above. The further investigation plan in view of the falling of Hb and in search of hematological disorder included bone marrow aspiration, followed by marrow biopsy. In the intervening period, a trial of B12 injections, presuming as megaloblastic anemia.

Differential Diagnosis

  • Anemia
  • Cytopenia: Comprehensive and holistic approach is needed in a case of complex nature
  • Klinefelter’s Syndrome: Due to varying clinical features, this syndrome may be underdiagnosed. Only about 1 out of 4 adult males with Klinefelter’s Syndrome are diagnosed, and 60% of referred KS patients are not known to have the condition. [1] Unsuspected, undiagnosed KS requires a thorough cytologenic evaluation.

Basing on Bone marrow biopsy

  • Gross-measuring 1.5cms


  • Normal bony trabeculae
  • Intervening marrow – 70% cellularity – erythroid series are increased with megaloblastic change
  • Myeloid series
  • Megakaryocytes
  • Impression – Possibilities – 1 – megaloblastic anemia

Basing on the above Bone marrow report, the hematologist and clinician doubted megaloblastic anemia, so an injection of B12 was given for certain time.

  • WBC-5000/cumm, RBC-2.23mill, platelets
  • P/s – Anemia, abnormal distribution of platelets, thrombocytopenia

On 4/5/12- further change in counts-like:

  • Platelet count: 50,000/cumm (1.5-4.5 lakhs)
  • Change in haemoglobin from 9.2 to (25/4/12) 7.6 to -7.0G (4/5/12)(13-17G dl)
  • Total count: 6,900/cumm

With the genetic abnormality and rapid falling of Hb with Cytopenia, it was concluded that he is having MDS.


LENALIDOMIDE 10mg 21 days – an immunomodulator (Thalidomide derivative) has been prescribed by the multi-specialty hospital, which was regularly followed up in my clinic.

Outcome and Follow Up

It was not encouraging once he was diagnosed with cancer. The patient went into depression, and the family did too. As a family physician, I was able to council the patient regarding the illness and helped in maintaining the euglycemia in a way to improve the quality of life.


Historically, the myelodysplastic syndromes (MDS) were previously called oligoblastic leukaemia, refractory anaemia, smouldering acute leukaemia and preleukemia. A review of selected cases and papers follows.

Agnogenic myeloid metaplasia associated with Klinefelter syndrome: a case report.
Kumar S et al. found that germ cell tumors and breast cancer were more prevalent in patients with KS, but did not find a definite link to leukemia or other hematologic malignant diseases. [2]

Unsuspected Klinefelter syndrome diagnosed during oncologic evaluation: a case series.
This series of cases covers the “medical, genetic, and psychosocial implications of the Klinefelter diagnosis,” in a review of 5 patients. [3]

Extra X Chromosome in Mosaic Klinefelter Syndrome Is Associated with a Hematologic Malignancy
The association between mosaic KS and hematologic malignancies is discussed, along with the use of FISH to differentiate mosaic and non-mosaic KS. [1]

Hematologic malignancies and Klinefelter syndrome. A chance association?
Keung et al. present a retrospective study on KS patients and a review of literature. [4]

The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism.
Bojesen et al. report that metabolic syndrome is much more prevalent in patients with KS, particularly through increased fat and decreased muscle mass. [5]

Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition
This study compares body composition and other factors in patients with KS and normal men, with the possibility of treatment with testosterone, but also notes that there is a lack of studies on this treatment. [6]

A similar case was reported in a Japanese journal as “Blooms syndrome” with multiple malignancies. [7] It is appropriate to name it as “variant of Blooms syndrome” as it involves multiple endocrines. This case is presented for its complexity and varied symptoms. Family physicians are cautioned to analyze the symptom complex and help to improve the quality of life of these unfortunate patients, with a team approach.

Myelodysplasia (MDS) Clinical Issues
Many times, the presentation is variable clinically and biologically. The prognostic outcome also varies from person to person. The disease progress slowly, and sometimes it may take months or years.

Sometimes it is missed in the clinician’s observation, in diagnosing at the earliest stage. Careful assessment is needed in elderly patients for correct diagnosis, and the co-morbidities should not mislead the clinician.

A Second Case: MDS Refractory Anaemia 50/F

  • In another similar case, a 50-year-old woman in New Rajarajeswari Peta Vijayawada gave a history of initially having (2006) DM, hypertension for c/o weakness/breathlessness/edema. She was referred to NRI Medical College Hospital, wherein she underwent BATTERY OF TESTS and had a transfusion every 4 days for 4 months. She was later diagnosed at Hyderabad laboratory as having defective functioning bone marrow with refractory anemia and MDS. She is on regular medication at the Urban Health centre where I was working. Regular follow up was done for anaemia, DM and hypertension.

MDS in a Nutshell

  • End result
  • Transformation to AML (acute myeloid leukemia) in one third of cases
  • Goals of treatment
  • Prevent and/or treat complications
  • Attempt to cure MDS, if possible
  • Maintain the highest possible quality of life
  • Prolong survival
  • MDS are now considered the most common forms of leukaemia, and in some cases, they deserve immediate intervention.

Key Point

The main points of this case are:

  • A rare combination of DM, hypertension, Hypothyroidism, Klinefelter’s with MDS presented
  • Keep in mind the complexity of the problem – team work is important
  • Prompt referral to a hematologist or oncologist is VITAL
  • Supportive care is stressed
  • MDS are more prevalent than previously realized and are mainly a disease of older adults
  • Suspect and investigate any patient with unexplained cytopenia

Keep In mind certain rare conditions:

  • Male / 30 / agricultural worker / no significant history / no consanguineous family / non-smoker / non-alcoholic presented with hypogonadism / Klinefelter’s association (clinically)
  • Came for consultation for DM: Under control
  • MDS (recent diagnosis)
    • Lenalidomide was introduced (this drug has had a recent warning of secondary cancers developing, including acute leukemia or Hodgkin lymphoma) [8]
    • DM’s relationship with other cancers – pre-cancerous MDS is discussed
    • DM’s insulin resistance with other endocrine involvement resulting in MDS

About The Author

RamaRaoDr. Valluri Ramarao MBBS, DNB (FAM-MED) DCP, MSc (psychology) is an experienced family physician for nearly 50 years, with a special interest in diabetes and primary care. Dr. Ramarao is currently practicing as a family physician and diabetologist at the Vijayawada Akshadha Diabetes and Family Clinic. With passion and enthusiasm for cost-effective healthcare with the most ethical practice, and concentrating on poor and middle class, he is extending medical support for the poor in UHC (Urban Health Centre), Giripuram, Municipal Corporation in Vijayawada.

References (click to show/hide)

  1. Jang Mi-Ae, Chul Won Jung. Extra X Chromosome in Mosaic Klinefelter Syndrome Is Associated with a Hematologic Malignancy. Ann Lab Med. Jul 2013; 33(4): 297–299.
  2. Kumar S, Menke DM, Dewald GW, Colon-Otero G. Agnogenic myeloid metaplasia associated with Klinefelter syndrome: a case report. Ann Hematol. 2002 Apr;81(4):215-8. Epub 2002 Mar 7.
  3. Eberl MM, Baer MR, Mahoney MC, Sait SN, Block AW, Farrell CD. Unsuspected Klinefelter syndrome diagnosed during oncologic evaluation: a case series. J Am Board Fam Pract. 2005 Mar-Apr;18(2):132-9.
  4. Keung YK, Buss D, Chauvenet A, Pettenati M. Hematologic malignancies and Klinefelter syndrome. A chance association? Cancer Genet Cytogenet. 2002 Nov;139(1):9-13.
  5. Bojesen A, Kristensen K, Birkebaek NH, Fedder J, Mosekilde L, Bennett P, Laurberg P, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH. The metabolic syndrome is frequent in Klinefelter’s syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care. 2006 Jul; 29(7):1591-8.
  6. Bojesen A, Host C, Gravholt CH. Klinefelter’s syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod. 2010 Jun;16(6):396-401. Epub 2010 Mar 15.
  7. Iwahara Y, Ishii K, Watanabe S, Taguchi H, Hara H, Miyoshi I. Bloom’s syndrome complicated by myelodysplastic syndrome and multiple neoplasia. Intern Med. 1993 May;32(5):399-402.
  8. Guide to Cancer Drugs: Lenalidomide.

Further Reading:

  • Bennett JM et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982; 51:189.PMID 6952920.
  • Block M, Jacobson LO and Bethard WF. Preleukemic acute human leukemia. JAMA.1953; 152:1018-28. PMID 13052490.
  • Harris NL et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. J Clin Oncol.1999; 17:3835-49. PMID 10577857.
  • Foucar K. Bone Marrow Pathology. 2nd Edition, ASCP Press. c 2001
  • Greenberg, Peter L. (editor) “Myelodysplastic Syndromes: Clinical and Biological Advances” Cambridge University Press, New York 2006 ISBN-13:978-0521496681 ISBN-10:0521496683


Log in or register for free to continue reading
Register Now For Free Already Registered? Log In
This entry was posted in Case Studies and tagged . Volume: .

Post a Comment

You must be logged in to post a comment.