Mutations in MAGEL2 and L1CAM are associated with congenital hypopituitarism and arthrogryposis.
Congenital hypopituitarism (CH) is rarely observed in combination with severe joint contractures (arthrogryposis). Schaaf-Yang syndrome (SHFYNG) phenotypically overlaps with Prader-Willi syndrome, with patients also manifesting arthrogryposis. L1 syndrome: a group of X-linked disorders including hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis.We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients.The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple SHFYNG patients, was identified in Patients 1-4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea and visual problems. Non-identical twins (Patients 2 and 3) had diabetes insipidus and macrocephaly, and Patient 4 presented with ACTH insufficiency. A hemizygous L1CAM variant, p.G452R, previously implicated in L1 syndrome patients, was identified in Patient 5, who presented with antenatal hydrocephalus.Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CS) 19, 20 and 23, and in Rathke’s pouch at CS20 and 23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon and hindbrain (CS19, 20, 23), but not in Rathke’s pouch.We report MAGEL2 and L1CAM mutations in four pedigrees with variable CH and arthrogryposis. Patients presenting early in life with this combined phenotype should be examined for features of SHFYNG and/or L1 syndrome. This study highlights the association of hypothalamo-pituitary disease with MAGEL2 and L1CAM mutations.