ESPE Abstracts (2018) 89 FC9.3

aGenetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, UK; bDivision de Pediatria, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile

Background: Congenital hypopituitarism (CH), involving deficiencies in one or more anterior pituitary hormones, is rarely observed in combination with severe joint contractures, termed arthrogryposis. Schaaf-Yang syndrome (SHFYNG), which has phenotypic overlap with Prader-Willi syndrome, may be associated with arthrogryposis. L1 syndrome, a group of X-linked disorders including hydrocephalus and spasticity of the lower limbs, may also present with generalized contractures in rare cases. In this study, we investigated the molecular basis in five patients with CH and arthrogryposis.

Methods: Whole exome sequencing (WES) was performed in five individuals with CH and arthrogryposis (Patients 1-5). Patients 1 and 2 had growth hormone deficiency (GHD), Patient 1 also had dysmorphic features, developmental delay and mild optic nerve hypoplasia, and Patient 2 had hydrocephalus. Patients 3 and 4 were non-identical twins with diabetes insipidus, GHD, dysmorphism, macrocephaly, micrognathia, and optic nerve hypoplasia. Patient 5 had multiple pituitary hormone deficiency including GH and ACTH insufficiency and hyperprolactinaemia, with dysmorphic features. Hypothalamo-pituitary expression of implicated genes (MAGEL2 and L1CAM) was studied by in situ hybridization of human embryonic tissue (Carnegie stages (CS) 16, 19, 20 and 23).

Results: A de novo heterozygous (c.1996dupC, p.Q666fs*47) mutation in the maternally imprinted MAGEL2 gene was identified in four patients from three unrelated pedigrees (Patients 1, 3, 4 and 5). Mutations in MAGEL2 are associated with Shaaf-Yang (SHFYNG) syndrome, a disorder characterised by hypotonia, feeding difficulties during infancy, global developmental delay/intellectual disability and sleep apnoea, often associated with arthrogryposis. The mutation reported in our patients had previously been described in a patient with SHFYNG, but with no reported endocrinopathy. A hemizygous L1CAM variant (c.1354G>A, p.G452R) known to be pathogenic in patients with L1 syndrome, was identified in Patient 2. In situ hybridization revealed that MAGEL2 was expressed in the developing hypothalamus and ventral diencephalon at CS19, 20 and 23, and in Rathke’s pouch at CS20 and 23. L1CAM was expressed in the developing hypothalamus and trigeminal ganglia at CS19, 20 and 23, but not in Rathke’s pouch at any stage.

Conclusions: We report mutations in MAGEL2 and L1CAM in four unrelated pedigrees with variable hypopituitarism and arthrogryposis. The association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations respectively is extremely rare. Our expression analysis supports a role for these genes in hypothalamo-pituitary development and function. Our data suggest that patients with SHFYNG and L1 syndromes should be screened for hypothalamo-pituitary abnormalities.

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