Mutations in MAGEL2 and L1CAM Are Associated With Congenital Hypopituitarism and Arthrogryposis

Abstract

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.

A retrospective analysis of growth hormone therapy in children with Schaaf–Yang syndrome

“…The MAGEL2 gene encodes for a regulator protein of E3 ubiquitin ligase and affects retromer endosomal protein recycling 8 . It is highly expressed in the central nervous system, especially within the hypothalamus 9,10 . This has led to endocrinological assessments of individuals with SYS, indicating that similarly to PWS, growth hormone (GH) deficiency is a feature of SYS 11 …”

“…8 It is highly expressed in the central nervous system, especially within the hypothalamus. 9,10 This has led to endocrinological assessments of individuals with SYS, indicating that similarly to PWS, growth hormone (GH) deficiency is a feature of SYS. 11 For PWS, recombinant-human growth hormone (rhGH) therapy has been FDA-approved since 2000.…”

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

“…The contribution of individual PWS cluster genes to the clinical phenotype has been intensively studied, employing detailed genetic analysis and murine models of individual gene deletions (recently reviewed in [ 168 , 169 ]). There is some evidence that loss of the Magel2 function causes pituitary gland hypoplasia and GHD; patients with MAGEL2 deletions can display congenital hypopituitarism [ 39 ] and Magel2 knock-out mice are growth retarded with sex-specific defects in GH secretion. However, these mice also display considerable impairments to hypothalamic development that may impact on both the GH and the gonadotrophin axes [ 170 , 171 , 172 ].…”

“…Loss of function mutations in one such gene, melanoma antigen, family L, member 2 ( MAGEL2 ), cause Shaaf–Yang syndrome, which has considerable phenotypic overlap with PWS in infancy [ 38 ]. Notably, the loss of MAGEL2 function appears to cause at least some of the endocrine abnormalities of PWS, since patients with mutations in this gene display panhypopituitarism associated with a hypoplastic anterior pituitary gland [ 39 ]. Finally, acromegaly is associated with impaired expression of the guanine nucleotide-binding protein ( GNAS ).…”

“…Hypogonadism is an important clinical feature of PWS (reviewed in [ 32 ]). Loss of MAGEL2 function probably contributes to this pathophysiology, since loss-of-function mutations can cause hypopituitarism and gonadotrophin deficiency [ 39 ]. A second gene in the PWS cluster, makorin ring-finger protein 3 ( MKRN3 ), may also contribute to this phenotype, since the paternal inheritance of inactivating mutations causes CPP [ 40 ].…”