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Schaaf-Yang syndrome (SYS), first identified in 2013, is a rare genetic disorder affecting multiple systems. SYS is caused by mutations in the MAGEL2 gene, which is located in the Prader-Willi syndrome (PWS) region of chromosome 15. SYS is caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with PWS in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence.

Many clinical features of SYS are similar to PWS, including hypotonia (poor muscle tone), feeding difficulties in infants, developmental delay/intellectual disability, behavioral problems, poor bone health and endocrine abnormalities. However, additional features are more common in SYS than in PWS, such as contractures (rigidity of joints), autism and severe intellectual disability.

The full spectrum of SYS features remain to be defined, and the natural history of the disorder is incompletely characterized. Further, while cellular studies have identified a role for the MAGEL2 protein in “recycling” functions in the cell, the normal function of this protein is not well understood, and it’s not yet clear how disruption of its function leads to the characteristics of SYS. Finally, optimal standards of care have yet to be established for individuals with SYS, and novel therapeutic interventions have yet to be advanced.

History

SYS was described in 2013 by Cristian Schaaf, assistant professor of molecular and human genetics at Baylor Medical College and member of the faculty at the Jan and Dan Duncan Neurological Research Institute at the Hospital Children of Texas, and by his colleague Yaping Yang, associate professor of Molecular and Human Genetics at the Baylor College of Medicine.

Both documented the case of a child who had a very similar clinical PWS subsequently Schaaf did sequencing of exome full where a change of a single molecular basis or identified point mutation in the gene MAGEL2. This produced great surprise in Schaaf, since, in PWS, the missing section of said chromosome is much larger. When observing more similar cases, it was concluded that in the first year of life, the diagnosis was suggestive of PWS; but when growing up it was distinguished from this syndrome giving rise to a variant of this, which was later named as SYS. [ 1 ]

Epidemiology

According to information provided by Schaaf, there are currently knowledge of about 100 cases worldwide with SYS.

Schaaf argues that the low incidence of cases could be due to:

The syndrome was recently described by what is widely unknown in the medical community. Currently the syndrome is diagnosed by complete exome sequencing; a technology that is not available in many places and is often not covered by insurers worldwide. The gene is very difficult to sequence, since it is very rich in gene code (GC). It is common that de novo inheritance is not taken into account in exome sequencing, because it is not on the list of identification genes. This would lead to the failure of detection of cases whose etiology is de novo, because this type of mutation of the MAGEL2 gene that can be inherited by an unaffected parent would be leaked. [ 2 ]

Etiology

Autosomal dominant alteration consisting of a point mutation of the MAGEL2 gene of chromosome 15q11.2. [ 3 ] Each individual receives a paternal and maternal copy of the gene, the MAGEL2 gene is a maternally printed gene, which means that the copy received from the mother is inactive, which explains why SYS is expressed only if the alteration occurs in the paternal allele, whether autosomal dominant or de novo. [ 4 ]

SYS, caused by a point mutation, consists of a minor anomaly in contrast to its variant PWS, since in this syndrome the affected region is within a 6Mb genomic locus in the long arm of chromosome 15 whose main molecular causes are:

The elimination of paternal section 15q11-q13 present in 65% to 75% of cases Uniparental disomy maternal present in 20% to 30% of cases 2 [ 5 ]

Clinical picture

The clinical picture of SYS is very similar to that of PWS in the first year of life and as the patient grows, it differentiates.

During the neonatal stage is where the greatest number of similarities with PWS such as hypotonia, hypogonadism, developmental delay, difficulty feeding, intellectual disability, and sleep apnea occur. The main differences between both syndromes are joint contractures, which can only affect interphalangeal or reach a fetal akinesia with severe arthrogryposis and the highest prevalence of autistic disorder in the PWS is 27% and in contrast the six individuals with SYS old enough to be evaluated were all diagnosed with autistic disorder. They may be short. At the genital level, hypogonadism, cryptorchidism and microfalosomy can be observed. At the ocular level, strabismus , exotropia and myopia can be observed. On a psychological level, patients can develop impulsive, compulsive, stubborn, manipulative behaviors and may have a tendency to self-mutilation. At the facial level they can present facial dimorphism, characterized by alterations in the positions of the ears, alteration of the nasal structures, frontal protuberance, prognathism with square chin, bushy eyebrows and small nose. At the limb level they can present small hands and feet with sharp fingers, clinodactyly, brachydactyly and thumbs in adduction which are corrected by surgery. At bone level a loss of bone density is manifested. [ 6 ]

Diagnostics

The diagnosis is made by complete sequencing of the exome or the MAGEL2 gene. [ 4 ]

Recommended tests

Sleep apnea test Lab tests: Glucose tolerance IGF-1 / IGF-BP3 FSH and LH TSH and T4 Total cholesterol Triglycerides HDL LDL Uric acid X-ray to evaluate scoliosis DEXA examination of both hips and lower spine to evaluate bone density [ 4 ]

Treatment

According to Schaaf, the key to treatment is an early intervention and aimed primarily at the treatment of symptoms, most children require extensive medical attention in the first years of life, such as feeding tubes, gastrostomy, respiratory support and tracheostomies. The physical therapy helps reduce contractures which generally are not treated with medication, because the cause is the lack of movement rather than a rheumatologic process.

In the words of Schaaf "It is currently being investigated whether treatment with growth hormone would make sense. Recombinant growth hormone has been a staple in the treatment of PWS for many years. This not only helps us with longitudinal growth, but also (and perhaps more importantly) helps us with muscle strength and endurance, in addition this hormone changes the body composition of adipose tissue to lean muscle mass."

As cases of SYS begin to surface in the adult population with the rise of genetic whole exome studies, Growth hormone therapy for adults diagnosed with SYS will address and treat abnormal body composition with increased fat mass (especially central adiposity), decreased lean muscle mass, extracellular fluid volume, diminished muscle strength, physical energy and stamina, lack of motivation, lethargy, lability (changes in mood), depression, and impairment of cognitive functions.

See also

Chromosome 15 Chromosomal aberration Prader-Willi syndrome Genetic mutation Autosomal dominant Genomic medicine Adult Growth Hormone Deficiency

References

"A matter of health — Naming disorders brings order to nomenclature". From the Labs (in American English). April 15, 2015. Retrieved on November 22, 2017. Aten, Emmelien; Fountain, Michael D .; Haeringen, Arie van; Schaaf, Christian P .; Santen, Gijs WE (2016/11). "Imprinting: the Achilles heel of trio-based exome sequencing . " Genetics in Medicine (English) 18 (11): 1163-1164. ISSN 1530-0366. doi : 10.1038 / gim. 2016.128 . Retrieved on November 22, 2017. Tollefsbol, Trygve (July 10, 2017). Handbook of Epigenetics: The New Molecular and Medical Genetics (English). Academic Press ISBN 9780128054772. Retrieved on November 22, 2017. Makar, AB; McMartin, KE; Palese, M .; Tephly, TR (June 1975). «Formate assay in body fluids: application in methanol poisoning». Biochemical Medicine 13 (2): 117-126. ISSN 0006-2944. PMID 1. Retrieved on November 22, 2017. Fountain, Michael D .; Schaaf, Christian P. (January 13, 2016). "Prader-Willi Syndrome and Schaaf-Yang Syndrome: Neurodevelopmental Diseases Intersecting at the MAGEL2 Gene". Diseases (in English) 4 (1): 2. doi : 10.3390 / diseases4010002. Retrieved on November 22, 2017. Fountain, Michael D .; Aten, Emmelien; Cho, Megan T .; Juusola, Jane; Walkiewicz, Magdalena A .; Ray, Joseph W .; Xia, Fan; Yang, Yaping et al. (May 19, 2016). «The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families». Genetics in Medicine (English) 19 (1): 45-52. ISSN 1530-0366. doi : 10.1038 / gim. 2016.53 . Retrieved on November 22, 2017.

Bibliography

Tollefsbol, T. (2017). Handbook of Epigenetics. [SL]: Elsevier Academic Press. Firth, H. (2017). Oxford Desk Reference. [SL]: Oxford Univ. Press.

External links

«Schaaf-Yang Syndrome - Foundation for Prader-Willi Research». www.fpwr.org (in English).

WdData: Q48789662

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