ESPE Abstracts (2014) 82 FC14.3

ESPE2014 Free Communications Puberty (6 abstracts)

Novel Genetic Variants in a Cohort of Paediatric and Adolescent Patients with Hypogonadotrophic Hypogonadism and Kallmann Syndrome

Louise Gregory a , Mark McCabe a , Rodrigo Bancalari b , Vaya Tziaferi a , Helen Spoudeas c & Mehul Dattani a,

aUCL Institute of Chils Health, London, UK; bPediatrics Department of Universidad Catolica de Chile, Santiago, Chile; cGreat Ormond Street Hospital for Children, London, UK

Background: Hypogonadotrophic hypogonadism (HH) is a complex developmental disorder characterized by a reduction in gonadotrophins (LH, FSH) released from the anterior pituitary. LH and FSH stimulate the ovaries or testes to release sex hormones that cause the onset of puberty, therefore delay in onset or complete absence of puberty is seen in the phenotype, often accompanied by short stature and genital abnormalities. When anosmia accompanies HH in the phenotype it is termed Kallmann syndrome (KS).

Objective and Hypotheses: We screened 63 HH/KS patients in our cohort for variants in KAL1, PROKR2, FGFR1 and FGF8.

Method: Using PCR and direct sequencing analysis.

Results: We identified four variants in KAL1 and FGFR1, two of which were novel. A hemizygous missense substitution, KAL1 c.257G>A, p.C86Y, was identified in a male KS patient. A heterozygous base pair deletion causing a frameshift, FGFR1 c.915delG, p.(Leu305LeufsX6), was identified in two siblings with KS: one male with cleft lip/palate, anosmia and short stature and one female with anosmia and microform cleft lip. The father is the heterozygous carrier, and is clinically unaffected. Two previously described variants, with unknown functional consequence, have also been identified in our cohort: a hemizygous early stop codon, KAL1 c.1267C>T, pR423X, in a KS patient and a heterozygous missense substitution, FGFR1 c.2059 G>A, p.G687R in a male HH patient. His mother had primary amenorrhoea and carries the variant. All four variants are located at highly conserved residues across multiple species and absent from any control databases.

Conclusion: We report two novel and two previously described variants in two different candidate genes in a cohort of HH/KS patients. The potential genetic cause remains unknown in 94% of this cohort, signifying the need for further investigation into genes involved in GnRH neuronal development and migration and potentially responsible for the pathogenicity. Studies are currently on-going.

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