Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis.
Arthrogryposis
/ genetics
Child
Child, Preschool
Diencephalon
/ metabolism
Female
Genetic Diseases, X-Linked
/ genetics
Humans
Hypopituitarism
/ congenital
Hypothalamus
/ metabolism
Infant
Infant, Newborn
Male
Mutation
Neural Cell Adhesion Molecule L1
/ genetics
Pedigree
Phenotype
Proteins
/ genetics
Exome Sequencing
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
01 12 2019
01 12 2019
Historique:
received:
18
03
2019
accepted:
18
07
2019
pubmed:
11
9
2019
medline:
5
6
2020
entrez:
11
9
2019
Statut:
ppublish
Résumé
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. 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 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. 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. 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.
Identifiants
pubmed: 31504653
pii: 5537539
doi: 10.1210/jc.2019-00631
pmc: PMC6916815
doi:
Substances chimiques
L1CAM protein, human
0
MAGEL2 protein, human
0
Neural Cell Adhesion Molecule L1
0
Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5737-5750Subventions
Organisme : Medical Research Council
ID : MR/R006237/1
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-099-0002-RG-UCLIC
Pays : United Kingdom
Informations de copyright
Copyright © 2019 Endocrine Society.
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