open access

Vol 62, No 3 (2011)
Original papers
Published online: 2011-06-29
Submitted: 2013-02-15
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Large deletion in the KAL1 gene in two related patients with hypogonadotropic hypogonadism: diagnostic usefulness of cytogenetic and molecular methods

Anna Krzymińska, Maciej Hilczer, Wanda Hawuła, Anna Ulańska, Lucjusz Jakubowski
Endokrynologia Polska 2011;62(3):224-229.

open access

Vol 62, No 3 (2011)
Original papers
Published online: 2011-06-29
Submitted: 2013-02-15

Abstract

Background: Kallmann syndrome type 1 (KS1) is a heterogeneous disorder where hypogonadotropic hypogonadism (HH) associated with an impaired sense of smell is observed. The aim of this study was to investigate the usefulness of the multiplex ligation-dependent probe amplification (MLPA) technique for differential diagnosis in comparison with molecular cytogenetics — fluorescence in situ hybridisation (FISH) or traditional PCR analysis and propose a diagnostic approach for patients with KS.
Material and methods: Karyotype and PCR analysis in two related patients and other family members were performed, followed by MLPA dosage sensitive analysis.
Results: In the proband and his maternal uncle, the PCR allowed the detection of a large deletion within the KAL1 gene, from exon 4 to 14 (c.469-?_6314+?del). The deletion was also diagnosed in three female carriers in the presented family. These results were proved by the MLPA technique. Moreover, we traced the presence of the region located downstream and upstream to the KAL1 gene on Xq22.32. However, FISH analysis failed to reveal any deletion in the critical region for KS. Simultaneously, we report difficulties connected with the PCR technique based on the primers for KAL1 amplification presented in the literature. We designed primers that are specific to the X chromosome and bypass pseudogene KALY amplification.
Conclusions: FISH analysis is a convenient screening technique, but in the presented family it failed to detect the deletion. Therefore, in the face of a distinctive manifestation of KS, a subsequent molecular assay should be introduced. The MLPA is a useful technique for differential diagnosis in patients with HH combined with smell impairment. (Pol J Endocrinol 2011; 62 (3): 224–229)

Abstract

Background: Kallmann syndrome type 1 (KS1) is a heterogeneous disorder where hypogonadotropic hypogonadism (HH) associated with an impaired sense of smell is observed. The aim of this study was to investigate the usefulness of the multiplex ligation-dependent probe amplification (MLPA) technique for differential diagnosis in comparison with molecular cytogenetics — fluorescence in situ hybridisation (FISH) or traditional PCR analysis and propose a diagnostic approach for patients with KS.
Material and methods: Karyotype and PCR analysis in two related patients and other family members were performed, followed by MLPA dosage sensitive analysis.
Results: In the proband and his maternal uncle, the PCR allowed the detection of a large deletion within the KAL1 gene, from exon 4 to 14 (c.469-?_6314+?del). The deletion was also diagnosed in three female carriers in the presented family. These results were proved by the MLPA technique. Moreover, we traced the presence of the region located downstream and upstream to the KAL1 gene on Xq22.32. However, FISH analysis failed to reveal any deletion in the critical region for KS. Simultaneously, we report difficulties connected with the PCR technique based on the primers for KAL1 amplification presented in the literature. We designed primers that are specific to the X chromosome and bypass pseudogene KALY amplification.
Conclusions: FISH analysis is a convenient screening technique, but in the presented family it failed to detect the deletion. Therefore, in the face of a distinctive manifestation of KS, a subsequent molecular assay should be introduced. The MLPA is a useful technique for differential diagnosis in patients with HH combined with smell impairment. (Pol J Endocrinol 2011; 62 (3): 224–229)
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Keywords

hypogonadotropic hypogonadism (HH); Kallmann syndrome (KS); KAL1 gene mutation; FISH; MLPA

About this article
Title

Large deletion in the KAL1 gene in two related patients with hypogonadotropic hypogonadism: diagnostic usefulness of cytogenetic and molecular methods

Journal

Endokrynologia Polska

Issue

Vol 62, No 3 (2011)

Pages

224-229

Published online

2011-06-29

Bibliographic record

Endokrynologia Polska 2011;62(3):224-229.

Keywords

hypogonadotropic hypogonadism (HH)
Kallmann syndrome (KS)
KAL1 gene mutation
FISH
MLPA

Authors

Anna Krzymińska
Maciej Hilczer
Wanda Hawuła
Anna Ulańska
Lucjusz Jakubowski

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