CONTEXT: 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 that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. OBJECTIVE: We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. PATIENTS: The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. RESULTS: Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. CONCLUSION: 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.
CONTEXT: 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 that include hydrocephalus and lower limb spasticity, also rarely presents with arthrogryposis. OBJECTIVE: We investigated the molecular basis underlying the combination of CH and arthrogryposis in five patients. PATIENTS: The heterozygous p.Q666fs*47 mutation in the maternally imprinted MAGEL2 gene, previously described in multiple patients with SHFYNG, was identified in patients 1 to 4, all of whom manifested growth hormone deficiency and variable SHFYNG features, including dysmorphism, developmental delay, sleep apnea, and visual problems. Nonidentical twins (patients 2 and 3) had diabetes insipidus and macrocephaly, and patient 4 presented with ACTH insufficiency. The hemizygous L1CAM variant p.G452R, previously implicated in patients with L1 syndrome, was identified in patient 5, who presented with antenatal hydrocephalus. RESULTS: Human embryonic expression analysis revealed MAGEL2 transcripts in the developing hypothalamus and ventral diencephalon at Carnegie stages (CSs) 19, 20, and 23 and in the Rathke pouch at CS20 and CS23. L1CAM was expressed in the developing hypothalamus, ventral diencephalon, and hindbrain (CS19, CS20, CS23), but not in the Rathke pouch. CONCLUSION: 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.
Authors: Jacques L Michaud; David Chitayat; Rebekah Jobling; Dimitri James Stavropoulos; Christian R Marshall; Cheryl Cytrynbaum; Michelle M Axford; Vanessa Londero; Sharon Moalem; Jennifer Orr; Francis Rossignol; Fatima Daniela Lopes; Julie Gauthier; Nathalie Alos; Rosemarie Rupps; Margaret McKinnon; Shelin Adam; Malgorzata J M Nowaczyk; Susan Walker; Stephen W Scherer; Christina Nassif; Fadi F Hamdan; Cheri L Deal; Jean-François Soucy; Rosanna Weksberg; Patrick Macleod Journal: J Med Genet Date: 2018-03-29 Impact factor: 6.318
Authors: S Lee; S Kozlov; L Hernandez; S J Chamberlain; C I Brannan; C L Stewart; R Wevrick Journal: Hum Mol Genet Date: 2000-07-22 Impact factor: 6.150
Authors: E De Angelis; J MacFarlane; J S Du; G Yeo; R Hicks; F G Rathjen; S Kenwrick; T Brümmendorf Journal: EMBO J Date: 1999-09-01 Impact factor: 11.598
Authors: Sarah E Soden; Carol J Saunders; Laurel K Willig; Emily G Farrow; Laurie D Smith; Josh E Petrikin; Jean-Baptiste LePichon; Neil A Miller; Isabelle Thiffault; Darrell L Dinwiddie; Greyson Twist; Aaron Noll; Bryce A Heese; Lee Zellmer; Andrea M Atherton; Ahmed T Abdelmoity; Nicole Safina; Sarah S Nyp; Britton Zuccarelli; Ingrid A Larson; Ann Modrcin; Suzanne Herd; Mitchell Creed; Zhaohui Ye; Xuan Yuan; Robert A Brodsky; Stephen F Kingsmore Journal: Sci Transl Med Date: 2014-12-03 Impact factor: 17.956
Authors: M Jouet; A Rosenthal; G Armstrong; J MacFarlane; R Stevenson; J Paterson; A Metzenberg; V Ionasescu; K Temple; S Kenwrick Journal: Nat Genet Date: 1994-07 Impact factor: 38.330