Schaaf–Yang syndrome

Schaaf–Yang syndrome (SYS) is a rare genetic disorder that is caused by a heterozygous mutation in a paternal-expressed gene MAGEL2.^[2] Main signs of this disorder are: intellectual disability/developmental delay, autism spectrum disorder, hypogonadism, hypotonia in infancy with feeding problems, and distal arthrogryposis.^[3] Facial features are: short noses, dense eyebrows, and protruding jaw.^[4]

Schaaf–Yang syndrome
Other names	Prader–Willi-like syndrome (PWLS), Chitayat–Hall syndrome[1]
Person showing facial features of SYS, such as: Trigonocephaly and tooth malposition. Also limb contractures can be seen.
Specialty	Neurology, Medical genetics, Endocrinology

Signs and symptoms

Symptoms of this disease are:^[5]

Very frequent

• Facial shape abnormality
• Undescended testis
• Feeding problems
• Hypotonia
• Flexion contracture
• Delay of Neurodevelopment

Frequent

• Visceral obesity
• Temper tantrums
• Eye problems
• Lack of pubertal development
• Unusual behaviour
• Autistic behaviour
• Chronic constipation
• External genital hypoplasia
• Borderline/Mild Intellectual disability
• Kyphosis
• Scoliosis
• Sleep apnea
• Squint eye
• Temperature regulation problems
• Failure to thrive
• Gastroesophageal reflux disease
• Hypogonadism
• Enlargment of сerebral ventricles

Occasional

• Almond-shaped eyes
• Atrial septal defect
• Hypothyroidism
• Central sleep apnea
• Downturned corners of mouth
• Thin nasal bridge
• Thin upper lip
• Seizure
• Abnormal dryness of the mouth
• Type II diabetes

Cause

The cause of this disease are mutation in a gene MAGEL2 which is located on chromosome 15 (15q11.2) and that gene is expressed from paternal chromosome 15 and methylated on maternal chromosome 15.^[6][7] The MAGEL2 is a part of regulatory complex MUST, which consist of MAGEL2-USP7-TRIM27.^[8][9] This complex regulates WASH complex which function is to promotes endosomal actin polymerization.^[10] 50% of people with SYS inherited mutation from their father and remainder are de novo mutation (which means that mutation is new and none of the parents have it).^[7][11]

MAGEL2-regulated WASH complex is important for the regulated secretion in the hypothalamus.^[12] MAGEL2 mutation causes decreased secretion of hormones, such as: oxytocin, AVP, somatostatin, thyrotropin-releasing hormone, growth hormone, and luteinizing hormone.^[13][14] Loss of that protein also showed neuronal activity loss in the hypothalamus and hippocampus of mice by disruptions of neuronal activity and changes in the synaptic excitation/inhibition balance through AMPA receptor trafficking defects.^[15][16]

Diagnosis

SYS can be suspected by symptoms and subsequently can be diagnosed by genetic testing.^[17]

Treatment

SYS doesn't have a cure.^[7] Although symptomatic management is available, It might be effective but it still doesn't alleviate overall impact of SYS, which leaves caregivers unsatisfied.^[18]

Prognosis

Life expectancy of person with SYS can be reduced due to fatal complication.^[7] Survival into adulthood is possible and oldest patient with SYS is 36 years olds (at the time of article's publication).^[19]

History

The first mention of SYS-like symptoms was described by Chitayat et al. (1990).^[20] Although the name was coined by Christian P Schaaf and Yaping Yang, who described SYS in details in 2013.^[21]

Prevalence

The prevalence of SYS is < 1/1,000,000.^[22][19] Currently, it is estimated that about 250 people are diagnosed with SYS.^[23]