A Novel Mutation of MAGEL2 in a Patient with Schaaf-Yang Syndrome and Hypopituitarism

Hidalgo-Santos, Antonio David; DeMingo-Alemany, Maria Del Carmen; Moreno-Macián, Francisca; Roselló, Mónica; Orellana, Carmen; Martı́nez, Francisco; Caro-Llopis, Alfonso; León-Cariñena, Sara; Tomás‐Vila, Miguel

doi:10.5812/ijem.67329

Cited by 11 publications

(11 citation statements)

References 17 publications

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“…Interestingly, in a recent paper, Patak et al produced a review of their cases and a systematic review and found no clinical or genetic differences between SYS and Chitayat-Hall syndrome [14]. In addition, arthrogryposis, which is not found in PWS, was confirmed in all patients as previously reported [3,[5][6][7][8][9][10]. Many of the intellectual disabilities confirmed in this cohort were severe.…”

Section: Discussionsupporting

confidence: 48%

“…Paternal deletions of this region result in Prader-Willi syndrome (PWS, OMIM #176270) [1,2]. It was recently reported that truncating variants in MAGEL2, one of the paternally expressed genes located in this region, caused Schaaf-Yang syndrome (SYS, OMIM #615547) [3][4][5][6][7][8][9][10]. SYS patients present with several symptoms typical of PWS, such as developmental delay, neonatal hypotonia, poor suck that requires special feeding techniques, and excessive weight gain.…”

Section: Introductionmentioning

confidence: 99%

“…SYS patients present with several symptoms typical of PWS, such as developmental delay, neonatal hypotonia, poor suck that requires special feeding techniques, and excessive weight gain. However, they also experience symptoms not typically seen in PWS, including arthrogryposis and autism spectrum disorder (ASD) [3][4][5][6][7][8][9][10]. Truncating variants in MAGEL2 cause severe arthrogryposis with reduced fetal movement resulting in perinatal death [11].…”

Section: Introductionmentioning

confidence: 99%

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Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Negishi

Ieda

Hori

et al. 2019

Orphanet J Rare Dis

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Background: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. Results: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. Conclusions: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Negishi

Ieda

Hori

et al. 2019

Orphanet J Rare Dis

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“…Literature review yielded 23 articles and 1 Letter to the Editor pertaining to these syndromes, which are summarized in the Preferred Reporting Items for Systematic Reviews (PRISMA) diagram (Figure ) . We include a simplified summary of the patients' symptoms (Table ) and further summaries of all CHS and SYS patients to date (Table S1 in Appendix S1).…”

Section: Resultsmentioning

confidence: 99%

“…Literature review yielded 23 articles and 1 Letter to the Editor pertaining to these syndromes, which are summarized in the Preferred Reporting Items for Systematic Reviews (PRISMA) diagram ( Figure 2). 4,[7][8][9]14,15,[17][18][19][20][21][22][29][30][31][32][33][34][35][36][37][38] We include a simplified summary of the patients' symptoms (Table 1) and further summaries of all CHS and SYS patients to date (Table S1 in Appendix S1). In addition, tissue-specific symptomatic breakdowns for CHS, SYS and PWS are also included (Table S2 in Appendix S1).…”

Section: Literature Reviewmentioning

confidence: 99%

MAGEL2‐related disorders: A study and case series

et al. 2019

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Pathogenic MAGEL2 variants result in the phenotypes of Chitayat‐Hall syndrome (CHS), Schaaf‐Yang syndrome (SYS) and Prader‐Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype‐phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2‐related disorders.

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Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man

Bando

Brinkmeier

Castinetti

et al. 2022

Human Molecular Genetics

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Congenital hypopituitarism is a genetically heterogeneous condition that is part of a spectrum disorder that can include holoprosencephaly. Heterozygous mutations in SIX3 cause variable holoprosencephaly in humans and mice. We identified two children with neonatal hypopituitarism and thin pituitary stalk who were doubly heterozygous for rare, likely deleterious variants in the transcription factors SIX3 and POU1F1. We used genetically engineered mice to understand the disease pathophysiology. Pou1f1 loss of function heterozygotes are unaffected; Six3 heterozygotes have pituitary gland dysmorphology and incompletely ossified palate; and the Six3+/−; Pou1f1+/dw double; heterozygote mice have a pronounced phenotype, including pituitary growth through the palate. The interaction of Pou1f1 and Six3 in mice supports the possibility of digenic pituitary disease in children. Disruption of Six3 expression in the oral ectoderm completely ablated anterior pituitary development, and deletion of Six3 in the neural ectoderm blocked development of the pituitary stalk and both anterior and posterior pituitary lobes. Six3 is required in both oral and neural ectodermal tissues for activation of signaling pathways and transcription factors necessary for pituitary cell fate. These studies clarify the mechanism of SIX3 action in pituitary development and provide support for a digenic basis for hypopituitarism.

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A Novel Mutation of MAGEL2 in a Patient with Schaaf-Yang Syndrome and Hypopituitarism

Cited by 11 publications

References 17 publications

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

MAGEL2‐related disorders: A study and case series

Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man

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