Case Report: Schaaf-Yang Syndrome Milder Phenotype Due to Potential Pathogenic Novel Missense Variant as an Unusual Cause of Obesity in a Pediatric Patient

Introduction

Schaaf-Yang syndrome (SYS) is a rare imprinting disorder (prevalence < 1/1,000,000) which was described in 2013¹ and it is caused by almost always truncating or termination mutations in the paternally expressed MAGEL2 gene (chromosome 15q11.2–q13).²

The MAGEL2 gene (OMIM 605283) consists of a single exon and belongs to the MAGE protein family of RING E3 ubiquitin ligase regulators.^3–5 It encodes a ubiquitin ligase enhancer required for endosomal protein recycling^1,6 and plays an essential role in retrograde transport⁷ as well as endosomal trafficking.^8–10

MAGEL2 is thought to have evolved as a mammalian-specific regulator of hypothalamic neuroendocrine functions, crucial for maintaining physiological balance and behavior through hypothalamic signaling, thereby enabling adaptation to environmental changes.¹¹

Expression of the MAGEL2 gene occurs predominantly in the hypothalamus and pituitary between the 6th and 8th weeks of gestation.¹² This timing corresponds with neurogenesis and the formation of neuronal precursors.⁵

While overlapping phenotypically with PWS, SYS often presents distinct features such as arthrogryposis, autism spectrum disorder traits, and a wider range of endocrine abnormalities. Early-onset obesity, exacerbated by hypotonia and neurodevelopmental impairment, is a core manifestation.

Common endocrine manifestations include:

• Short stature: Reported in 50–60% of SYS patients, with a median height near the 22nd percentile. Recombinant growth hormone (rhGH) therapy may improve stature and muscle strength, although effects on weight are limited. As with PWS, careful monitoring for sleep apnea during rhGH therapy is essential.
• Hypogonadism: Frequently presents as micropenis, cryptorchidism, or delayed puberty. Unlike PWS, true hypogonadotropic hypogonadism is less common in SYS. Management may include orchiopexy and hormonal replacement therapy.
• Central hypothyroidism: Similar to PWS, an increased incidence is suspected. Diagnosis requires thorough endocrinological evaluation, including TSH and peripheral thyroid hormone levels. Levothyroxine therapy is indicated if diagnosed.^7–10
• Temperature dysregulation and episodes of hypothermia or hyperthermia are frequently reported in children with PWS and SYS, and accumulating evidence suggests underlying oxytocin pathway dysfunction.^1,2

Recombinant growth hormone (rhGH) is commonly used in Prader–Willi syndrome and increasingly in Schaaf–Yang syndrome to improve linear growth, body composition, and muscle strength.^1,2

Case Presentation

A male patient was born in 2014 via cesarean section at 34+3 weeks of gestation due to breech presentation. Birth weight was 1870 g and length 40 cm. The neonatal period was complicated by hypotonia, poor sucking reflex, and a hemodynamically significant patent ductus arteriosus (PDA), which was unresponsive to pharmacological closure and later required surgical ligation at 2.5 months of age. Other anomalies included a duplicated right renal pelvis and non-autoimmune congenital hypothyroidism, managed with levothyroxine until age 7. At age 3, the patient developed strabismus and global developmental delay. Ophthalmological evaluation revealed astigmatism and esotropia. Cognitive testing (SON-R) showed mild intellectual disability (IQ = 57), with developmental delay in both reasoning and perception scales. Initial genetic analysis excluded Prader–Willi syndrome, DiGeorge syndrome, and Bardet–Biedl syndrome. Conventional karyotyping revealed a normal male chromosomal complement (46, XY). Whole-genome sequencing performed at the age of nine identified a previously unreported heterozygous missense variant, MAGEL2(NM_019066.5):c.1265C>T (p.Pro422Leu, rs1484822926), thereby probably confirming the diagnosis of SYS. Genetic testing in the mother showed that the variant was absent and paternal genetic testing could the father was not in contact with the patient’s family. An overview of the genetic testing performed in individual family members is provided in Table 1.

Table 1 Summary of Genetic Testing

Obesity developed early: by age 3, weight was 24.7 kg (BMI 29.8) (Figure 1).

Figure 1 Trajectory of body mass index (BMI).

Despite -SPA based interventions (balneotherapy, supervised physical activity, dietary counseling, and lifestyle education as part of obesity management) and nutritional counseling, obesity persisted (BproMI 25.9 at age 4, waist circumference >97th percentile). Nutritional intervention was comprehensive, individualized, and family-centred. A key component was educating the entire family on the principles of healthy eating, dietary habits, and the promotion of an active lifestyle. Emphasis was placed on the gradual adjustment of energy intake, increasing the proportion of fresh vegetables, fruits, whole grains, and quality protein sources, while simultaneously reducing energy-dense, nutrient-poor foods (such as sweets, sugar-sweetened beverages).

Endocrine follow-up began at 6 months of age, when non-autoimmune mild hypothyroidism was detected (TSH 10.786 mIU/l [0.350–4.940], FT4 9.0 pmol/l [9.1–19.1], TGAB 3.3 kU/l [0.0–4.1], TPOAB <1.0 kU/l [0.0–5.6]). The boy needed a small dose of levothyroxine (25mcg per day) to achieve euthyroid state. This treatment was discontinued at 7 years of age without recurrence of the hypothyroidism. The patient was growing around 3rd percentile. His mid-parental height is 170 cm. Last endocrinological evaluation (June 2024) showed spontaneous pubertal onset at age 10 (Tanner stage G2, testicular volume 4–5 mL, LH 1.01 IU/l, FSH 3.4 IU/l), with stable thyroid function (TSH 4.2 mIU/L, fT4 10.8 pmol/L) without substitution treatment.

Rehabilitation interventions included proprioceptive neuromuscular facilitation (PNF) and dynamic neuromuscular stabilization (DNS), aiming to improve motor control and postural stability. Initially, gross motor limitations (eg, unstable gait) precluded increased physical activity. Through consistent physiotherapy and strong family engagement, the patient achieved functional mobility and joined a swimming club, participating in regular swim training and coordination exercises (eg, TRX, gym ball workouts).

Discussion

This case illustrates the multisystemic complexity of SYS. Early-onset obesity—already evident at 1 year of age—was a central challenge, worsened by hypotonia, feeding issues, and global developmental delay. Although major congenital cardiac defects are rare in SYS, this patient required early cardiac surgery for PDA. SYS leads to a complex phenotype, characterized by profound ID/DD, Autism spectrum disorder (ASD), respiratory dysfunction, feeding difficulties, digestive complications, skeletal abnormalities, sleep dysfunction, hypogonadism, and temperature instability. However, the severity of the SYS phenotype is highly variable, and may depend on the particular type and location of the mutation in MAGEL2.² MAGEL2 loss-of-function explains a broad range of symptoms in SYS and PWS, but incompletely accounts for the severity observed in SYS.¹³ MAGEL2, together with USP7 and TRIM27, activates the WASH (WASP and SCAR Homolog) complex through K63-linked ubiquitination, thereby controlling the formation of F-actin on endosomes. This process is essential for proper endosomal cargo sorting and transport.⁸ MAGEL2 is crucial for the proper regulation of secretory granules and neuropeptide production.¹⁰ Loss of MAGEL2 disrupts endosomal transport and causes misrouting of secretory granule proteins to lysosomal degradation. Consequently, the number of granules decreases, leading to reduced synthesis and release of neuropeptides. Impaired neuropeptide signaling may therefore contribute to the hormonal imbalances observed in PWS patients. In MAGEL2 knockout mice, symptoms include growth retardation, altered circadian regulation,¹³ and excessive weight gain.¹⁴ Similarly, rats with paternal truncation of MAGEL2 exhibit alterations in body composition, cardiac structure and function, respiration, and social behavior and anxiety—symptoms that resemble those seen in individuals affected by SYS. McCarthy described 78 patients with 39 different types of mutations in the MAGEL2 gene and identified a mutational hotspot within nucleotides c.1990–c.1996, where the highest density of pathogenic variants was observed.² The c.1996dupC mutation was associated with a more severe phenotype compared with other reported variants. Different mutations in MAGEL2 have been associated with distinct clinical presentations. Truncating mutations have been reported in patients with arthrogryposis multiplex congenita^15,16 as well as in those diagnosed with Opitz Trigonocephaly C syndrome.¹⁷

Molecular findings and variant interpretation of MAGEL2( NM_019066.5):c.1265C>T

The MAGEL2 gene is a paternally expressed, imprinted gene, and pathogenic variants have been associated with SYS and related phenotypes. In the study, we identified a previously undescribed missense variant, MAGEL2 (NM_019066.5):c.1265C>T, p.(Pro422Leu, rs1484822926). This variant was absent in the mother and is therefore presumed to be of paternal or de novo origin. Given paternal imprinting in this genomic region, both of these facts represent a strong argument for its potential pathogenicity.

The variant has not been reported in population and annotation databases, including gnomAD Exomes, gnomAD Genomes or ClinVar. It is located within a moderately phylogenetically conserved region (PhyloP = 1.9) corresponding to a disordered segment of the protein, situated outside the main MAGE homology domain that is crucial for MAGEL2’s molecular function. Nevertheless, intrinsically disordered regions may also play important regulatory roles, such as mediating post-translational modifications or serving as flexible linkers between structured domains.

According to the ACMG/AMP criteria, the variant meets the PS2 moderate criterion, as it is not inherited from the mother and is presumed to be of paternal or de novo origin. The PM2 supporting criterion is fulfilled because the variant is novel and absent from population databases. Computational evidence consistently predicts a deleterious effect, meeting the PP3 supporting criterion (DANN 0.93; PrimateAI 0.80; GenoCanyon 1.0). The PP4 supporting criterion is partially met, since the patient’s phenotype partially overlaps with the typical SYS spectrum, including hypotonia, developmental delay, and hypogonadism, though joint contractures and ASD are absent. No benign evidence or increased population frequency was identified, and thus the BS1–BP4 criteria are not met.

Based on the combination of these criteria (PS2 strong + PM2 supporting + PP3 supporting + PP4 supporting + PM6 moderate), the MAGEL2(NM_019066.5):c.1265C>T (p.Pro422Leu, rs1484822926) variant may be classified as likely pathogenic. Summary of the variant classification is shown in Table 2.

Table 2 The Variant Classification According to ACMG/AMP Guidelines (Richards et al, 201518)

Although this variant meets the criteria for likely pathogenic classification, it is supported only by moderate and supporting evidence per ACMG guidelines and should therefore be interpreted with caution.

The amino acid substitution of proline to leucine may locally alter the structure of this region and lead to partial functional impairment of the protein, due to a slight decrease in protein stability. This could result in weakened interactions with TRIM27 or USP7, although the overall complex formation is likely maintained.

Regarding the phenotype–genotype correlation, the relatively mild neurodevelopmental presentation in our patient and the absence of typical SYS features such as arthrogryposis and ASD may be related to the nature and localization of the identified missense variant. Truncating mutations within the established mutational hotspot (c.1990–c.1996) are generally associated with a severe SYS phenotype, whereas the p.Pro422Leu variant lies outside the critical MAGE homology domain, in a less conserved and likely disordered region of MAGEL2. This suggests that the variant may cause only partial functional impairment or a modest reduction in protein stability, which could be sufficient re major skeletal and social deficits. In contrast, the missense variant reported by Patak et al (2019) (p.Ala538Glu), located in a more functionally relevant region, was associated with the different phenotypic SYS spectrum (Table 3). Interestingly, early-onset obesity was the dominant clinical feature in our patient (BMI 30 at 1 year of age), which is less typical for SYS than for Prader–Willi syndrome. This observation raises the possibility that certain missense variants may preferentially disrupt hypothalamic pathways regulating energy balance while leaving other MAGEL2-dependent functions relatively intact.

Table 3 Comparison of Phenotypic Characteristics in Schaaf–Yang Syndrome

Conclusion

The first missense mutation in MAGEL2 associated with MAGEL2-related disorders was reported in a patient exhibiting an overall milder phenotype compared to truncating cases, although he presented with severe autism spectrum disorder, dysmorphic facial features, and developmental delay.¹⁹

We also compared the clinical manifestations of our patient with those reported by Patak, who described a patient harboring the missense variant MAGEL2:c.1613C>A (p.Ala538Glu) (Table 3). Both patients share several core features of Schaaf-Yang syndrome, including neonatal hypotonia, developmental delay, and signs of hypogonadism. However, they differ in the presence of autistic traits, dysmorphic features, and arthrogryposis multiplex congenita, which were observed in the patient reported by Patak et al but were absent in our case. Conversely, our patient exhibited obesity, which was not reported in the previously described case. These findings illustrate the variable expressivity and potentially distinct functional consequences of different MAGEL2 missense variants.¹⁹ Cells with mutant MAGEL2 display abnormal subcellular localization. MAGEL2 has been shown to participate in the regulation of transcription factors and chromatin remodeling, which may in turn affect gene transcriptional activity in the 15q11–q13 region. Furthermore, impaired interactions between mutant MAGEL2 and SMN, FMRP, KHSRP, and FUS proteins have been observed, leading to disruption of RNA stability and processing, including transcripts originating from the PWS region.²⁰ Endocrine abnormalities, including non-autoimmune hypothyroidism and short stature, are common in SYS and warrant proactive monitoring. Notably, spontaneous pubertal development occurred, albeit at the lower end of growth percentiles.²¹ In children with early-onset obesity and neurodevelopmental features not explained by common syndromes, testing for MAGEL2 mutations should be considered. Genetic confirmation facilitates prognosis and guides coordinated multidisciplinary care. Parents play a crucial role as behavioural models — their own lifestyle changes have a direct positive influence on the child’s motivation and long-term adherence. Intervention should be delivered by a multidisciplinary team (paediatrician, dietitian, psychologist, and, where appropriate, physiotherapist) and include regular follow-up.

In accordance with standard genetic counseling recommendations, parental testing would be warranted; however, the father is unavailable for genetic testing. Consequently, the observed mutation may be either paternally inherited or de novo in origin.

This case underscores the complexity of managing early-onset obesity in the context of a rare genetic disorder. It is suggested that the early use of whole genome sequencing, particularly in critical situations such as the early development of significant obesity in combination with other multi-organ involvement, could facilitate early diagnosis of rare conditions such as SYS. This could help save time and resources and contribute to improved clinical outcomes for patients. Multidisciplinary surveillance—particularly in endocrinology, rehabilitation, cardiology, and nutrition—is essential. Genetic testing for MAGEL2 mutations should be part of the diagnostic algorithm for children with severe hypotonia, obesity, and syndromic features. Currently, the patient attends regular swim training, participates in mainstream school without support needs, and successfully completed a 400m charity athletic event.

In case of planning future offspring, it is advisable to discuss the possibility of in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M) to prevent recurrence of the pathogenic variant.