Two siblings with Schaaf-Yang syndrome treated with growth hormone

Abstract.

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder with overlapping features with Prader-Willi syndrome (PWS). We report two Japanese siblings with SYS harboring a rare MAGEL2 variant (NM_019066.5:c.1621C>T, p.(Q541*)). Both patients had GH deficiency and received GH therapy. The older sibling presented with neonatal hypotonia, joint contractures, and severe autism, while the younger sibling showed milder features but developed obesity and behavioral problems. GH therapy led to only modest improvement in their growth. The limited effect may have been related to the late initiation of treatment, marked non-adherence to therapy, and GH doses. This report highlights the phenotypic variability of SYS and demonstrates difficulties and potential issues of GH treatment as well as clinical response to GH treatment in this rare disorder.

Highlights

● We report siblings with Schaaf-Yang syndrome caused by a MAGEL2 variant.

● Schaaf-Yang syndrome resembles Prader-Willi syndrome but is a distinct disorder.

● GH therapy showed limited effect in our reported cases.

Introduction

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares several clinical features with Prader-Willi syndrome (PWS) (1,2,3). Common manifestations of SYS include neonatal hypotonia with feeding difficulties, joint contractures, developmental delay or intellectual disability, and autism spectrum disorder, and some degree of hypothalamic dysfunction, such as short stature, hypogonadotropic hypogonadism, temperature instability, and sleep disturbance. Although SYS and PWS are distinct disorders, both are caused by genetic variants in the 15q11-q13 region and have overlapping pathophysiological features.

Here, we report Japanese siblings with SYS due to a rare MAGEL2 variant (NM_019066.5: c.1621C>T, p.(Q541*)). Both presented GH deficiency and received GH treatment. Patients with SYS are often treated with GH, either because of their phenotypic similarity to PWS or based on a formal diagnosis of GH deficiency (4, 5). However, at present, in Japan and many other countries, GH therapy for SYS is not permitted solely on the basis of phenotypic similarity to PWS.

Given the rarity of SYS and the limited information on genotype-phenotype associations and treatment outcomes (6, 7), documenting their clinical course may provide valuable insights into this disorder.

Case Presentation

Patient 1 and 2 were siblings from non-consanguineous healthy parents (Fig. 1). Although the older brother (Patient 1) had been followed for developmental growth and development since infancy, he was lost to follow up since the age of 8. When he was 12 yr old and the younger brother (Patient 2) was 8 yr old, they presented to us for the evaluation of short stature and sleep disturbance.

Fig. 1.

Pedigree of the family. The father was a carrier of the MAGEL2 variant, which was identified in both brothers but not in their younger sister. The father was asymptomatic.

Ethical approval and informed consent

This study was conducted in accordance with the Declaration of Helsinki. Whole-exome sequencing (WES) was performed as part of a multicenter research project entitled “Comprehensive analysis and biomarker exploration for the diagnosis of hereditary diseases” (approval number: G1233-18), which is led by Kyoto University Hospital. Our institution participated as a collaborating research center under a centralized ethical review system. The study protocol was approved by the Ethics Committee of Kyoto University Hospital. Written informed consent for participation in the study and for genetic analyses was obtained from the parents of the patients. In addition, written informed consent for publication, including the use of clinical information and the patient’s photographs, was obtained from the patients’ guardian.

Patient 1

He was born at 37 wk gestation with a birth weight of 2550 g. He was born with birth asphyxia of unknown cause and was admitted to the neonatal intensive care unit (NICU) for one month treated with oxygen and tube feeding for feeding problem due to hypotonia. There was apparent delay in growth and development from infancy, with rolling over at 7 mo of age, independent sitting at 1.5 yr, and independent walking at 2.5 yr of age. Developmental testing at age 6 showed developmental quotient (DQ) 15. At the time of his first visit at the age of 12, he was short, with a height of 109 cm (–5.3SD) and a weight of 20 kg (–4.6SD). SD scores for height and weight were calculated according to the Japanese growth standards (8). He had dysmorphic face, strabismus, contractures of elbow and shoulder joints, tapered fingers, and kyphoscoliosis (Figs. 2A–D). Although he was able to walk unaided, he was unable to run or jump. He could not speak meaningful language. He exhibited continuous motor restlessness and had self-injurious behavior such as skin picking. His autism was severe level 3 with severe developmental delay. He was not obese and had no overeating behavior.

Fig. 2.

Photograph of Patient 1 at 12 yr of age. A. Standing position showing shoulder and elbow contractures and valgus positioning of the lower limbs with unstable posture. B. Facial appearance. C. Lateral view demonstrating kyphosis. D. Hands showing tapering fingers.

Patient 2

He was born at 40 wk gestation, weighing 2929 g, without asphyxia. During the neonatal period, there were no pathological symptoms such as hypotonia, respiratory distress or feeding difficulties. Developmental delays became apparent in infancy, with head control at 5 mo, sitting at 9 mo, and independent walking at 2 yr of age. He was more athletic than Patient 1. He was able to run and jump. At the time of the initial visit at the age of 8, he was short with 110 cm tall (–3.1SD), but he was obese, with a body weight of 27kg (+0.2SD) and a body mass index (BMI) of 22.3, which was above the 95th percentile for age and sex. He had been obese with overeating since the age of 2 yr. He also had a dysmorphic face and strabismus, and facial features were similar to those of Patient 1. There were no joint contractures, no kyphoscoliosis. He was able to communicate using simple language. There were behavioral problems, including odd shouting, yelling, joking, hitting, and throwing things. He was easily anxious and irritable. He showed no self-injurious behavior. He was diagnosed with autism spectrum disorder at the age of 4, level 2, with moderate psychomotor developmental delay (Developmental Screening DQ of 55).

Both of Patient 1 and Patient 2 exhibited abnormal sleep patterns and circadian rhythms, had insomnia with difficulty falling asleep, and often woke up and were active in the middle of the night. They had a 4-yr-old sister. She was born at 39 wk gestation with a birth weight of 2664 g. Until the age of 3, no developmental delays were noted. When she was 3 yr-old, a delay in speech was identified, and at the age of 4, she was diagnosed with autism spectrum disorder. Her physical growth was age-appropriate. She was not obese, had no joint contractures or skeletal abnormalities. She was not receiving any treatment.

Diagnostic assessment

Genetic testing: Whole-exome sequencing (WES) using the DNBSEQ-G400 platform (MGI Tech) was performed in Patient 1 and his parents (trio analysis) at the age of 16, following a comparative genomic hybridization (CGH) array at 14 yr that showed no abnormalities. Methods for WES data analysis and variant filtering are provided in the Supplementary Information.

WES identified a MAGEL2 variant, NM_019066.5:c.1621C>T, p.(Gln541*), previously reported as a cause of Schaaf-Yang syndrome (SYS) (6), in Patient 1 and his father. No additional variants considered causative for the patients’ phenotype were identified by WES. Subsequently, targeted Sanger sequencing for MAGEL2 was performed in Patient 2 and their younger sister, confirming the same variant in Patient 2 but not in the sister. The father was asymptomatic despite carrying the variant. SYS is an autosomal dominant disorder caused by a paternally expressed gene, and maternally inherited variants do not result in clinical manifestations. Therefore, the father most likely inherited the variant from his mother.

Pituitary function tests: Patient 1 was diagnosed as GH deficiency (GHD) at another hospital at the age of 8 yr in an examination of his extreme growth retardation but remained untreated. At the age of 12, a pituitary function test was performed at our hospital, including re-evaluation of GH secretion. The peak values of GH stimulation test were as follows: peak value 20.2 ng/mL, 2.13 ng/mL, and 2.25 ng/mL for the GHRP-2 test, arginine test, and insulin tolerance test, respectively. An adequate hypoglycemic stimulus was achieved during the insulin tolerance test, with a nadir blood glucose level of 32 mg/dL at 30 min. Baseline IGF-1 level was 56 ng/mL which was –2.2SD for his age. The results were consistent with mild GHD due to hypothalamic dysfunction. He was prepubertal with serum testosterone level of 0.037 ng/mL, but the luteinizing hormone-releasing hormone (LHRH) test showed a peak luteinizing hormone (LH) value of 12.1 mIU/mL, and a peak follicle- stimulating hormone (FSH) value of 2.1 mIU/mL, suggesting imminent pubertal onset. Puberty had started soon after the test and pubertal maturation was considered complete, as he reached adult height by 17 yr of age and fully developed secondary sexual characteristics. Adrenal and thyroid dysfunctions were not evident.

Patient 2 underwent GH stimulation tests at the age of 8 yr. The peak values were 4.56 ng/mL and 2.28 ng/mL in the arginine test and clonidine test, respectively. Baseline IGF-1 level was 54 ng/mL (–2.1SD), consistent with moderate GHD. At that time, he was prepubertal, LH < 0.1 mIU/mL, FSH 2.9 mIU/mL, testosterone 0.08 ng/mL, and his thyroid function was within the normal range.

GH treatment

The growth curves of the two patients are shown in Fig. 3. GH treatment for Patient 1 was started at 12 yr and 5 mo and ended at 14 yr and 1 mo (treatment duration was 1 yr and 8 mo) (Fig. 3A). The schedule was once-daily somatropin (0.175 mg/kg/wk) subcutaneous injection. After one year of treatment, poor adherence was noticeable. At 14 yr and 1 mo, his mother decided that GH therapy could not be continued. Furthermore, at that time, we observed worsening scoliosis (Cobb angle 13.8° > 28.1°) and worsening torticollis. The growth rate in the first year of GH treatment was +4.6 cm/yr, which was higher than the growth rate in the year before (+2.0 cm/yr). In the second year of treatment, when adherence was poor, the increase in height was +3.1 cm/yr. No progression of puberty was evident during this period. No significant bone age acceleration was observed.

Fig. 3.

Growth Curves of Patient 1 (A) and Patient 2 (B). The periods of GH therapy are indicated by gray bars. Bone ages are marked with triangles (▲) and connected to the corresponding heights with dotted lines. No significant advancement in bone age was observed during GH treatment.

Patient 2 started GH treatment at age 9 yr and 3 mo, receiving daily somatropin (0.175 mg/kg/wk) subcutaneous injection (Fig. 3B). The dose was calculated as standard body weight × 1.2 because of obesity. Less than a year after initiation, he became non-adherent. In the first and second years of treatment, the growth velocities were +5.3 cm/yr and +5.4 cm/yr, respectively, which were higher than the pre-treatment growth rate (4.2 cm/yr). At the age of 11, he was injecting himself but sometimes pretended to inject himself. After the age of 13, GH treatment became difficult to continue due to changes in the family environment and worsening psychiatric symptoms, and was terminated.

Outcome and follow-up

Their parents were busy raising autistic children, and hospital visits were irregular. It was difficult to implement regular oral and injectable medications without interruption. GH treatment had little effect on the siblings’ short stature. As age increased, management of psychiatric symptoms associated with autism became the mainstay of treatment.

Patient 1 reached adult height at the age of 18 yr. His height, body weight, and BMI were 133.1 cm, 30.7 kg, and 17.6, respectively (approximately the average height and weight of a 9-yr-old Japanese boy). Self-injurious behavior has lessened with age. As for Patient 2, his antisocial behavior became more serious with age. He is currently in psychiatric inpatient treatment and a life under probation at a medical facility.

Discussion

The siblings were followed by pediatric neurologists and pediatric endocrinologists from an early age and were seen by a genetics expert, but a diagnosis was not reached. The use of WES led to the diagnosis of SYS. In our sibling cases, there were some phenotypic variations. Patient 1 exhibited more severe symptoms, with feeding and breathing problems in the neonatal period, joint contractures and kyphoscoliosis, and severe intellectual disability and severe autism, all of which are characteristic of SYS. Patient 2 lacked some of the hallmark features of SYS, such as neonatal symptoms and joint contractures, but he did exhibit other symptoms including autism, intellectual disability, and hypotonia. His prominent features were overeating, obesity, and problematic behavior, which were more reminiscent of PWS than SYS.

Although SYS and PWS have overlapping clinical features, they are considered distinct disorders (2, 9,10,11,12). In 2024, Heimdörfer et al. (13) provided the first experimental demonstration of a direct molecular link between SYS and PWS, showing that truncated variants of MAGEL2 reduce the expression of genes within the PWS locus. Therefore, it is not surprising that individuals diagnosed with SYS may exhibit prominent features typically associated with PWS. Given that a younger sister in this family has autism without the MAGEL2 variant, it is plausible that additional genetic or environmental factors may be contributing to the phenotypic variability seen among the siblings.

Endocrine abnormalities are frequently observed in SYS (2, 3, 12). Most cases involve pituitary hormone deficiencies secondary to hypothalamic dysfunction. MAGEL2 is highly expressed in the hypothalamus and is thought to play an important role in protein trafficking and recycling, thereby affecting the production of secretory granules (2). In our cases, both patients had GH deficiency, while no abnormalities were detected in the production of thyroid-stimulating hormone, adrenocorticotropic hormone or antidiuretic hormone.

GH treatment has been reported to be effective in individuals with SYS (4, 5). Beyond improving height, GH treatment has been perceived as beneficial in increasing muscle strength and endurance. Furthermore, many parents reported improvements in cognitive function, social interaction, and motor development following GH treatment (4). Similar to the effects observed in PWS, it has been suggested that earlier initiation of GH therapy in SYS may lead to more pronounced improvements. In our two cases, GH therapy appeared to be partially effective; however, the overall benefit was limited. Improvements in muscle strength, cognition, or motor development were not observed beyond a slight increase in height. Moreover, treatment continuation was challenging from the outset, resulting in a short duration of therapy. It is possible that earlier initiation and a longer treatment period might have yielded more significant effects. In our cases, treatment was initiated after a diagnosis of GH deficiency, and using a dose of 0.175 mg rhGH/kg/wk. In previous report (4), the GH dosage administered was comparable to that used in PWS, at approximately 0.24 mg rhGH/kg/wk. Considering the close phenotypic overlap between SYS and PWS, the use of a PWS-equivalent dose (0.24 mg rhGH/kg/wk) might potentially result in greater therapeutic benefits.

Among the symptoms that plagued the care givers were sleep disturbances and problematic behavior during the night, and even with medication, it was difficult to ensure a sufficiently long night’s sleep and regulate circadian rhythms. Continued multidisciplinary approach is important to provide better care for these patients.

Conclusion

We reported Japanese siblings with SYS caused by a rare MAGEL2 variant (NM_019066.5: c.1621C>T, p.(Q541*)). The siblings showed marked phenotypic variability, with overlapping features of both SYS and PWS. GH therapy was only partially effective, suggesting that factors such as timing of initiation, dosing strategy, and treatment adherence may influence outcomes. This report provides important insights for future considerations in the clinical management of SYS, including the potential role of GH treatment.

Supplementary information

Whole-exome sequencing data were analyzed using an in-house bioinformatic pipeline. Variants were filtered based on standard quality control criteria, population allele frequency (<0.01), and predicted functional impact. Family-based (trio) analysis was performed under de novo, autosomal recessive, and X-linked inheritance models. Variant interpretation was performed based on the results using in silico prediction tools, reference databese information(ClinVar), and consistency with the patients’ clinical features.

Conflict of interests

K.N. received research funding from AstraZeneca, which is unrelated to the content of this work. The other authors declare that they have no conflicts of interest.