ESPE Abstracts (2021) 94 FC8.2

1Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.;2Centre for Craniofacial and Regenerative Biology, King’s College London, Guy’s Hospital Tower Wing, London, United Kingdom.;3Department of Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom.;4Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.;5Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.;6Department of Paediatrics, Mater Dei Hospital, Msida, Malta.;7Adult Endocrinology Service, Mater Dei Hospital, Msida, Malta.;8Centre for Craniofacial and Regenerative Biology, King’s College London, London, United Kingdom.;9Laboratory for Molecular and Developmental Biology, Institute for Protein Research, Osaka University, Osaka, Japan.;10The Francis Crick Institute, London, United Kingdom.;11MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom

Three patients from two unrelated families in Malta; one consanguineous (siblings: Patient 1, male and Patient 2, female) and one non-consanguineous (Patient 3, male), manifested hypogonadotropic hypogonadism with delayed puberty, intellectual disability, scoliosis, and ataxia with cerebellar hypoplasia on MRI. GnRH tests revealed low peak LH and FSH concentrations in the patients: Patient 1; LH 2.3 IU/L, FSH 4.4 IU/L (14.3y), Patient 2; LH 3.6 IU/L, FSH 6.4 IU/L (12.5y), Patient 3; LH 0.9IU/L, FSH of 3.1 IU/L (13y). 3 day hCG tests revealed a peak testosterone of 2.2 nmol/l in Patient 1, and a sub-optimal peak testosterone of 2.3 nmol/l in Patient 3, with the latter having an excellent peak of 30.7 nmol/l after 3 weeks of hCG. Patients were treated with testosterone or oestradiol respectively. Bilateral orchidopexies were performed in both males, and all patients required corrective surgery for scoliosis. They presented with either generalised hypotonia with hyporeflexia (Patients 1 and 2) or hypertonia with hyperreflexia (Patient 3). Whole exome sequencing revealed a novel homozygous 13bp deletion (c.398-3_407delCAGGGGAGGAGCG) in PRDM13 in the three patients, inherited from their heterozygous parents. PRDM13 (PR Domain containing 13) is a putative chromatin modifier and transcriptional regulator that functions downstream of the transcription factor PTF1A. Human and mouse expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum. Mice homozygous for a Prdm13 mutant allele manifested with cerebellar hypoplasia, however male gonadal development appeared unaffected in these mutants. As PTF1A has been linked to early GABAergic neuronal cell fate regulation in the spinal cord, we examined GABAergic neuron progenitor development in the hypothalamus and cerebellum. Results showed a significant reduction in Kisspeptin neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Microarray analysis of the patients and an unrelated heterozygous Maltese carrier of the 13bp deletion, shared an identical 0.2Mb region of homozygosity encompassing PRDM13, suggesting a common haplotype within the Maltese population. Our studies identify Prdm13/PRDM13 as a critical regulator of GABAergic cell fate during neurodevelopment, providing a mechanistic explanation for the co-occurrence of hypogonadotropic hypogonadism and cerebellar hypoplasia in this recessive syndrome. Therefore, patients with a combination of these phenotypes should be screened for PRDM13 mutations. To our knowledge, this is the first evidence linking disrupted regulation of Kiss1 neurons to congenital hypogonadotropic hypogonadism in humans.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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