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    Clinical and biological parameters in 166 boys, adolescents and adults withnonmosaic Klinefelter syndrome: a Copenhagen experienceLise Aksglde (, Niels E Skakkebk, Kristian Almstrup, Anders JuulUniversity Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark

    KeywordsGrowth, Klinefelter syndrome, Reproduction

    CorrespondenceLise Aksglde, Department of Growth and Repro-duction, Rigshospitalet, Section 5064, Blegdamsvej9, DK-2100 Copenhagen , Denmark.Tel: +45 3545 5085 |Fax: +45 3545 6054 |Email:

    Received22 November 2010; revised 5 February 2011;accepted 24 February 2011.


    ABSTRACTAim: Klinefelter syndrome (KS) is the most frequent sex chromosome disorder inmales, but the phenotype varies greatly and is therefore highly under-diagnosed. We aimed

    at describing the phenotypic characteristics throughout life from clinical follow-up of our

    large cohort of patients with KS.Methods: A retrospective observational study of 166 males with nonmosaic 47,XXYKS aged 0.380.3 years. Data on phenotype, growth, body composition, bone mineral

    density, sex hormones, lipids, glycosylated haemoglobin (HbA1C) and prostate-specific

    antigen were recorded. In addition, histological examination of testicular biopsies from 29

    patients was performed.Results: Patients with Klinefelter were taller already in childhood. All patients hadsmaller testicular volume and elevated luteinizing hormone (LH) and follicle-stimulating

    hormone levels in adulthood. Cryptorchidism was reported in 14%, gynaecomastia in

    44%, and 36% required speech therapy or educational support. The abnormal biochemi-

    cal parameters became evident after onset of puberty and correlated with histological find-

    ings of a gradual deterioration of seminiferous tubules and massive Leydig cell hyperplasia

    in adults.Conclusion: Our patients presented with a wide spectrum of the classical Klinefeltersymptoms. In adulthood, two features were consistently present in every patient: small tes-

    tes and high LH testosterone ratio, often despite normal testosterone levels. Such bio-chemical parameters combined with small testes should lead to a suspicion of KS.

    INTRODUCTIONKlinefelter syndrome (KS) is the most frequent sex chromo-some disorder in the male affecting 1:660 newborn boys (1).The majority of affected males carry an additional X chro-mosome, 47,XXY, while the remaining have higher-gradeaneuploidies (e.g. 48,XXXY) or mosaic forms. The rareKlinefelter variant, the SRY-positive 46,XX-male, occurswith a prevalence of one in 20 00025 000 males (2).

    Adolescent and adult patients with KS are characterizedby the constellation of tall stature with eunuchoid body pro-portions, small, firm testes and androgen deficiency,whereas no specific clinical or physical hallmarks have beenidentified at birth or during infancy and childhood.

    However, the adult phenotype varies greatly, and the symp-toms of KS are not exclusive, and possibly therefore, thesyndrome is highly under-diagnosed. In Denmark,

  • aged 080.3 years were followed in our endocrine outpa-tient clinic during the years 19902010. The distribution ofpatients according to karyotype and reason for diagnosis isshown in Table 1. Only patients with nonmosaic 47,XXYKS (n = 166) were included in this retrospective, observa-tional study.

    Chromosome analysis was performed on peripheral bloodlymphocytes in each case, and a prenatal karyotype was con-firmed on a postnatal blood sample. Karyotypes were estab-lished on 30 metaphases from each patient. All XX-maleswere SRY-positive (detected by polymerase chain reaction).

    Clinical examinationAll patients were followed regularly from the time of diag-nosis. If possible, the child was seen at the age of 3 monthsduring the infantile mini-puberty, and thereafter the chil-dren were seen yearly until the time of expected puberty.From the age of 912 years, the clinical visits were more fre-quent with quarterly clinical and biochemical evaluation. Inadulthood, patients were seen at yearly visits.

    The clinical examination included height, weight andpubertal staging according to Tanner at every visit duringchildhood and adolescence, and at the first visit in adult-hood. Testicular volume was estimated by Praders orchi-dometer. If the sizes of the two testes were not identical, thelarger was chosen to determine testicular volume. Onset ofpuberty was defined as a testicular volume 4 mL.

    Dual energy X-ray absorptiometry (DEXA) scansAs part of clinical practice, many patients underwent regu-lar DEXA scans. Whole body scans were performed in chil-dren and adolescents using a Hologic 1000 W scanner(Hologic, Inc., Waltham, MA, USA) as previously described(3), but not presented here. In adults, bone mineral density(BMD) at the level of the hip and spine was evaluated byDEXA scans (XR-46; Norland Medical Systems, Inc., FortAtkinson, WI, USA, or Lunar Prodegy GE Medical Systems,Madison, WI, USA).

    Laboratory analysisNonfasting blood samples were drawn from an antecubitalvein, clotted and centrifuged. Serum follicle-stimulating hor-mone (FSH) and luteinizing hormone (LH) were measuredby time-resolved immunofluorometric assays (Delfia; Perk-inElmer, Boston, MA, USA) with detection limits of 0.05and 0.06 IU L for FSH and LH, respectively. Intra- and in-terassay Coefficient of variation (CVs) were

  • haematoxylin and eosin (H&E), periodic acid-Schiff (PAS),Masson Trichrom and martiusscarletblue (MSB). Testicu-lar histology was evaluated by three independent trainedobservers (NES, KA, AJ). Only nonmosaic 47,XXY karyo-types was evaluated here.

    Normal pubertal and childhood samples were obtainedfrom archives of testicular tissue from boys who were trea-ted for ALL and therefore were routinely screened for lym-phoblastic infiltration (6). Foetal samples were obtainedfrom archives of testicular tissue from spontaneous abor-tions miscarriages and adult samples from archives of tes-ticular tissue from men in infertility workup but withnormal spermatogenesis.

    EthicsAll Klinefelter subjects and their parents (when the patientwas A mutation in the fibroblast growth factor receptor3 (FGFR3) gene) was excluded from the analysis because ofan atypical presentation with motile sperms in the ejaculateand reproductive hormones within the normal range as pre-viously described (7).

    PhenotypeGrowthThe majority of patients exhibited accelerated growthalready from early childhood (Fig. 1A,B). This phenomenon

    was present both in pre- and postnatally diagnosed patients(Fig. 1A,B). Mean height in patients older than 20 yearswas 184.7 cm (Fig. 1A). Final height (measured after theage of 18 years) tended to be higher in patients who wereinitiated on testosterone therapy after the age of 18 years(n = 65) [184.3 cm (range 168.4 to 207.0)] as comparedwith patients treated with testosterone from the time ofpuberty (T started 15 years) (n = 17) [median height181.2 cm (range 173.7 to 201.0)], although the differencewas not statistically significant (p = 0.27) (Table 3). Medianages at initiation of testosterone substitution in the two sub-groups were 29.7 years (range 18.957.3) and 13.3 years(range 10.915.0), respectively. Part of the data on heightand weight have previously been published (8,9).

    Body compositionBMI was within the normal reference range of healthymales in the majority of patients irrespective of age and irre-spective of time of diagnosis (pre- or postnatally)(Fig. 1C,D). Accordingly, and as previously published, thechildren and adolescent patients had a normal BMI despitean unfavourable muscle fat ratio (increased body fat % anddecreased muscle fat mass as measured by whole bodyDEXA scan) (3).

    Table 2 Registered co-morbidities in non-mosaic 47,XXY

    Diagnosis N


    Cleft palate 1

    Cryptorchidism (unilateral) 9

    Cryptorchidism (bilateral) 12

    Fragile X syndrome 1

    Acondroplasia 1


    Precocious puberty 1

    Cushings syndrome 1

    Type II diabetes 2


    Neurosfibromatosis 1

    Mentally retarded 2

    Epilepsy 2


    Scoliosis 1

    Femural fracture 1


    Lung cancer 1

    Acute Lymphblastic Leukemia 1

    Malignant melanoma 1


    Leydig cell tumor 1


    HIV 1

    Psychiatric disorders

    Depression (medically treated) 8

    Psychosis 2

    Anxiety (medically treated) 2

    Asperger syndrome 2

    Autism 1

    Attention Deficit Hyperactivity Disorder (medically treated) 2

    Aksglde et al. Klinefelter syndrome throughout life

    2011 The Author(s)/Acta Pdiatrica 2011 Foundation Acta Pdiatrica 2011 100, pp. 793806 795

  • Bone mineral densityBone mineral density was decreased, although the majorityof patients (age at first DEXA scan 14.954.3 years, n = 59)had a BMD within the normal range at the level of the hipand spine (Fig. 2A,D). Thus, 44% presented with osteopeniaand even 5% had frank osteoporosis. In general, the patientswere more severely affected at the level of the spine [meanT-score )0.76 (range )3.6 to +4.1)] compared to the hip[mean T-score )0.24 (range )2.8 to +4.8)]. T-score at thelevel of the spine was significantly lower than the expectedvalue of zero (p < 0.0001), whereas T-score at the level ofthe hip did not differ from expected (p = 0.24). In theuntreated patients, femoral T-score correlated significantlywith serum testosterone and with serum E2 (r = 0.54,p = 0.03 and r = 0.62, p = 0.01, respectively) (Fig. 2B,C).Lumbar T-score correlated significantly with serum testos-terone, but not with E2 (r = 0.66, p = 0.005 and r = 0.36,p = 0.17, respectively) (Fig. 2E,F). There was no correla