American Journal of Medical Genetics 139A:52–53 (2005)

Research LetterKallmann Syndrome in a 47,XXX PatientE.P.M. Corssmit,1* S.B. Seminara,2 N. Pitteloud,2 and E. Fliers1

1Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam,Amsterdam, The Netherlands2Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts

To the Editor:

In this report, we describe a patient with Kallmann synd-rome (KS), chronic psychosis, and a 47,XXX genotype. Nomutation in the KAL or FGFR1 genes was found. This uniquecase suggests that additional genes on the X chromosome maybe involved in KS.

Patient is a 41-year-old woman, who was referred to us withthe question whether her primary amenorrhoea could be link-ed to the recently found 47,XXX karyotype. From youth on,she suffered from social and learning problems. From age17 onwards, she had been examined in different gynecologicoutpatient clinics because of primary amenorrhoea. Extensivegynecologic examination, including a laparoscopy, showed noabnormalities except for a low 24-hr urinary LH excretion(serum concentrations not measured). At the age of 30 years,treatment was started with oral contraceptives resulting inmonthly withdrawal bleedings and enhanced breast develop-ment. At the age of 32 years, she presented at the neurologyclinic because of episodes of oppressive headaches. Becauseherhistory also showed anosmia, diagnosed by an ENT physicianat the age of 5 years (presumed congenital), an MRI scan wasperformed and showed no abnormalities. In the same year, shehad her first episode of psychotic decompensation. A psychia-trist made a diagnosis of chronic psychosis, and startedneuroleptic medication (pimozide 2 mg/day). Because of hersomewhat underfeminized appearance (small hips, smallbreasts) in combination with the history of primary amenor-rhoea, her family doctor performed akaryotype at the age of 41,which showeda47,XXXpattern (101 extra cellswere analyzed:96 cells showed a 47,XXX pattern, 4 a 46,XX pattern, and1 a 48,XXXX pattern; no Y chromosome was found). Thepatientwas referred touswith thequestionwhether the above-mentioned combination of abnormalities could be due to aspecific endocrinologic syndrome. Besides a low libido, therewere no neuroendocrine complaints. The family history wasnegative for hypo/anosmia and delayed puberty.

On physical examination, she had a normal posture (height1.72 m, weight 82 kg) and no dysmorphic signs. Laboratoryexamination showed central hypogonadism (LH <1 U/L(reference value (follicular phase): 5–25 U/L), FSH 2.5 U/L

(reference value: 1–10 U/L), 17b estradiol <0.04 nmol/L(reference value follicular phase: 0.04–0.73 nmol/L, lutealphase: 0.22–0.95 nmol/L), progesterone <1.0 nmol/L (refer-encevalue follicular phase:<1.0–3.0nmol/L, luteal phase: 12–60 nmol/L)). Serum TSH, freeT4, cortisol, ACTH, and IgF1were normal, as well as kidney function. The combination ofanosmia, central hypogonadism, and a delayed puberty led usto the diagnosis of Kallmann syndrome in a patient with a47,XXX genotype. MRI scanning of the brain showed noabnormalities of the pituitary or hypothalamus, and noagenesis of the olfactory bulb. After obtaining additionalwritten informed consent for genetic studies, whole bloodsamples were obtained from the proband and DNA wasextracted. Genomic screening revealed no mutation in thecoding sequence of the KAL- or FGFR1 gene. On abdominalultrasound, both kidneys were present. A dexascan showedosteoporosis of the lumbar spine and osteopenia of the leftfemurneck (T-score�2.88and�2.09, respectively). Treatmentwas started with calcium and vitamin D supplementation andoral contraceptives were restarted.

There is considerable clinical and genetic heterogeneityin patients with idiopathic hypogonadotropic hypogonadism(IHH). Within and between families, the clinical spectrum canvary between KS with anosmia or hyposmia, normosmic IHH(nIHH), and isolated anosmia [Oliveira et al., 2001]. A numberof mutations have been discovered in IHH. These includedefects in the KAL gene (X-linked KS), FGFR1 gene (KS),GnRH receptor gene (nIHH),GPR54 gene (nIHH), andDAX-1gene (combination of IHH and congenital adrenal hypoplasia).Currently, however, mutations are identified in only 20–25%of the cases [Oliveira et al., 2001].

We report on the first patient with the coexistence ofKallmann syndrome and a 47,XXX karyotype. Since in most47,XXX patients the additional X chromosome is of maternalorigin, we speculated that meiotic non-disjunction could haveoccurred leading to two copies of a KAL mutation. However,genetic analysis showed no abnormalities in the KAL gene,althoughmutations in the non-coding regions of theKAL genecannot be excluded at thismoment. Telvi et al. [1996] describedthree sibs with a partial duplication of distal Xp associatedwith IHH. Interestingly, in this report the male proband wasaffected whereas the two sisters carrying the same duplicationwere not. In contrast to the male, the duplicate X chromosomeappeared to be inactive in his sisters in the majority of cellsexamined, supporting the hypothesis that the male phenotypemight be caused by the presence of two active copies of gene(s)located at Xp. No patients with the anosmic form of IHH anddistal Xp duplication have been reported to date. InC. elegans,both loss and overexpression of the KAL1 homolog areassociated with the same phenotype, pointing to dose sensi-tivity of theKAL1 gene [Rugarly et al., 2002]. Dode et al. [2003]described four families with loss-of-function mutations in theFGFR1 gene associated with autosomal dominant Kallmannsyndrome (so-called KAL2). Dominant gain-of-function andloss-of-function mutations in FGFR1 are associated with

E.P.M. Corssmit’s present address is Department of Endocri-nology, Leiden University Medical Center, Albinusdreef 2,Postbus 9600, 2300 RC Leiden, The Netherlands.

*Correspondence to: E.P.M. Corssmit, M.D., Ph.D., Depart-ment of Endocrinology C4R, Leiden University Medical Center,Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands.E-mail: E.P.M.Corssmit@lumc.nl

Received 21 April 2005; Accepted 27 August 2005

DOI 10.1002/ajmg.a.30996

� 2005 Wiley-Liss, Inc.

different developmental disorders: premature fusion of skullbone sutures (craniosynostosis) and failed morphogenesis ofthe olfactory bulbs (Kallmann syndrome), respectively. Theauthors suggest that the KAL1 gene product, anosmin-1, isinvolved in FGF signaling and propose that the genderdifference in anosmin-1 dosage (because KAL1 partiallyescapes X inactivation) explains the higher prevalence of thedisease in males. In our patient, mutational analysis ofthe FGFR gene revealed no abnormalities. This still leavesopen the possibility that in our patient, the extra X-chromo-some creates a milieu in which there is too much anosminleading to a KAL phenotype in a 47,XXX karyotype. Alter-natively, an unknown mutation on the X chromosome or anautosomal mutation might be present. In our patient, muta-tional analysis for a GNRHR or GPR54 mutation was notperformed since these mutations have not been found inpatients with hyposmia/anosmia so far.

The incidence of the 47,XXX karyotype is approximately 1/1,000 to 1/2,000 female births [Linden et al., 1996]. The onlyconsistent physical characteristic is tall stature (above the80th centile) by adolescence. Sexual development, puberty,and fertility are normal. IQ scores are usually 10–15 pointsbelow that of siblings.

In conclusion, we describe the first patient with the co-occurrence ofKSand a 47,XXXgenotype. The absence of aKALor FGFR1 mutation in this patient raises the possibility ofadditional genes on the X chromosome that might be involved

in the pathogenesis of KS or, alternatively,KAL-1 gene dosagerelated effects.

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