Kallmann syndrome in a patient with Weiss-Kruszka syndrome and a de novo deletion in 9q31.2

in European Journal of Endocrinology
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  • 1 A Iivonen, Department of Physiology, University of Helsinki, Helsinki, Finland
  • 2 J Kärkinen, New Children’s Hospital, Pediatric Research Center, Helsinki University Central Hospital, Helsinki, Finland
  • 3 V Yellapragada, Department of Physiology, University of Helsinki, Helsinki, Finland
  • 4 V Sidoroff, Department of Pediatrics, North Karelia Central Hospital, Joensuu, Finland
  • 5 H Almusa, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  • 6 K Vaaralahti, Department of Physiology, University of Helsinki, Helsinki, Finland
  • 7 T Raivio, Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland

Correspondence: Taneli Raivio, Email: taneli.raivio@helsinki.fi

Abstract

Patients with deletions in chromosome 9q31.2 may exhibit delayed puberty, craniofacial phenotype including cleft lip/palate, and olfactory bulb hypoplasia. We report a patient with congenital HH with anosmia (Kallmann syndrome, KS) and a de novo 2.38 Mb heterozygous deletion in 9q31.2.

The deletion breakpoints (determined with whole genome linked-read sequencing) were in the FKTN gene (9:108,331,353) and in a non-coding area (9:110,707,332) (hg19). The deletion encompassed six protein-coding genes (FKTN, ZNF462, TAL2, TMEM38B, RAD23B, and KLF4). ZNF462 haploinsufficiency was consistent with patient’s Weiss-Kruszka syndrome (craniofacial phenotype, developmental delay, and sensorineural hearing loss), but did not explain his KS. In further analyses, he did not carry rare sequence variants in 32 known KS genes in whole exome sequencing and displayed no aberrant splicing of 15 KS genes that were expressed in peripheral blood leukocyte transcriptome. The deletion was 1.8 Mb upstream of a KS candidate gene locus (PALM2AKAP2), but did not suppress its expression.

In conclusion, this is the first report of a patient with Weiss-Kruszka syndrome and KS. We suggest that patients carrying a microdeletion in 9q31.2 should be evaluated for the presence of KS and KS-related features.

 

     European Society of Endocrinology

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