A number sign (#) is used with this entry because of evidence that Schaaf-Yang syndrome (SHFYNG) is caused by heterozygous mutation in the MAGEL2 gene (605283) on chromosome 15q11.

SHFYNG syndrome is an autosomal dominant multisystem disorder characterized by delayed psychomotor development, impaired intellectual development, hypotonia, and behavioral abnormalities. Additional features include contractures, feeding difficulties, and variable dysmorphic facial features. The severity of the disorder is highly variable: some patients may die in utero with fetal akinesia, whereas others can live with moderate disability. Some patients may have central endocrine abnormalities, such as growth hormone deficiency or hypothyroidism. Individuals are affected only if the mutation occurs on the paternal allele, since MAGEL2 is a maternally imprinted gene. Some of the features overlap with those observed in Prader-Will syndrome (PWS; 176270) (summary by Fountain et al., 2017; Jobling et al., 2018).

Chitayat et al. (1990) described a brother and sister with distal arthrogryposis manifest as camptodactyly of fingers and hammertoes, hypopituitarism, severe mental retardation, and facial anomalies, including a 'boxy' head, square face, small tipped nose, chubby cheeks, and micrognathia. The brother died unexpectedly at age 3 months of undetermined cause. The sister showed abnormality in the secretion of growth hormone and responded to growth hormone therapy.

Rao et al. (2013) reported a 3-year-old girl, born to first-cousin Somali parents, who had distal arthrogryposis, developmental delay, and evidence of anterior pituitary dysfunction. Other than 4 previous miscarriages in the current relationship, the family history was unremarkable. Fetal movements were reduced, and generalized hypotonia was noted after birth. She was microcephalic and had metopic suture synostosis. She had an oval face with frontal bossing, full cheeks, small nose with depressed nasal bridge, left microphthalmia, and retinal coloboma. She also had congenital stridor with a grade I laryngeal cleft, vocal cord palsy on the left, and partial vocal cord palsy on the right. Other distinctive features included progressive aminoaciduria, hypokalemia, and an abnormal skeletal survey that showed incomplete thoracic vertebrae. Brain MRI showed slightly delayed myelination, immature hemispheric white matter development, and some reduction in cortical folding. Rao et al. (2013) stated that their patient had features consistent with those in the sibs reported by Chitayat et al. (1990) and that their report extended the clinical phenotype of the disorder, which they called 'Chitayat-Hall syndrome.'

Schaaf et al. (2013) reported 4 unrelated boys with features resembling Prader-Willi syndrome (PWS; 176270). Clinical features that met the major criteria for PWS included neonatal hypotonia with poor suck, feeding problems in infancy, hyperphagia with excessive weight gain before age 6 years, developmental delay, and hypogonadism. Some patients had dysmorphic facial features, such as large mouth, coarse features, almond-shaped palpebral fissures, and bitemporal narrowing. More variable features in these patients that met the PWS minor criteria included short stature, small hands, narrow hands, eye abnormalities, speech defects, skin picking, and sleep apnea. Two patients had temper tantrums or violent outbursts. All had autism spectrum disorder. Two patients had contractures of the proximal and distal interphalangeal joints. Other variable features included constipation, micropenis, and cryptorchidism. One patient had seizures.

Soden et al. (2014) reported 2 sisters, born of unrelated Caucasian parents, with a neurodevelopmental disorder resembling Prader-Willi syndrome. The neonatal course in both patients was complicated by hyperinsulinemic hypoglycemia, poor feeding, respiratory difficulties, and hypotonia. Dysmorphic features included ptosis, exotropia, high palate, smooth philtrum, low muscle mass, short upper arms with decreased elbow extension, and increased central body fat. One patient had seizures. Both girls had global developmental delay and autistic features.

Fountain et al. (2017) reported 18 patients with SHFYNG ascertained on the basis of genetic studies from several different research groups or laboratories. There were 3 families with more than 1 affected individual, including a family with 11 affected who were not all tested molecularly. Combining the phenotypes with previously reported patients yielded a variable yet consistent picture of the clinical course. The patients had hypotonia and delayed psychomotor development ranging from sitting and speaking a few months later than normal to being unable to walk or speak in the late teens. On average, the patients sat independently at 19 months, walked at 39 months, and spoke their first word at 56 months. The level of impaired intellectual development ranged from mild to severe, and 4 patients had a formal diagnosis of autism, although 6 additional patients had symptoms of autism. Several patients had abnormal behavior described as impulsive, compulsive, stubborn, and manipulative, as well as habitual skin picking or automutilation. Two patients had seizures. Dysmorphic features were also common, including abnormal philtrum, ear position, nasal structure, and palpebral fissure length, as well as frontal bossing, prognathism, bushy eyebrows, esotropia, and strabismus. Joint contractures were present in almost all patients, and ranged from only the interphalangeal joints to lethal fetal akinesia with severe arthrogryposis (in patients 5 and 6, who were sibs). Abnormalities of the hands included tapering fingers, clinodactyly, camptodactyly, brachydactyly, and adducted thumbs. Other skeletal features included small hands, small feet, short stature, and scoliosis or kyphosis. Other features included sleep apnea and other sleep abnormalities, feeding difficulties requiring special techniques, and hypogonadism; cryptorchidism and/or micropenis was present in 8 of 11 male patients, and at least one 20-year-old female patient had hypogonadotropic hypogonadism.

Urreizti et al. (2017) reported a 19-year-old Spanish woman (patient 7) who presented at birth with contractures, hypotonia, and respiratory depression. She had premature fusion of the metopic sutures, resulting in trigonocephaly. Severe developmental delay was noted, with walking achieved at age 11 years, severely impaired intellectual development, lack of speech acquisition, and feeding difficulties with poor overall growth. She also had sleep disturbances, temperature instability, excessive salivation and sweating, and sleep apnea with episodic hyperventilation. Dysmorphic features included strabismus, short nose, anteverted nares, macrostomia, thick palatal and alveolar ridges, malpositioned teeth, widely spaced nipples, hypogonadism, asymmetric thorax, and marked lordosis. She was diagnosed clinically with Opitz syndrome C (211750) before genetic analysis confirmed SHFYNG.

Jobling et al. (2018) reported 5 patients from 3 unrelated families, including the affected sister originally reported by Chitayat et al. (1990), who were diagnosed clinically with Chitayat-Hall syndrome, but were found to carry heterozygous loss-of-function mutations in the MAGEL2 gene on the paternal allele. A sixth patient with a similar phenotype was also identified. These molecular findings provided evidence that Schaaf-Yang syndrome and Chitayat-Hall syndrome can be classified as a single disease entity. The patients reported by Jobling et al. (2018) ranged from 6 to 13 years of age, except for the patient reported by Chitayat et al. (1990), who was 35. All patients, except the 35-year-old, presented in infancy with hypoglycemic episodes associated with growth hormone (GH) deficiency and insulin-like growth factor I (IGF1; 147440) deficiency, when measured; some patients had hypoglycemic seizures. All had short stature, contractures, scoliosis, hypotonia, global developmental delay, and dysmorphic features. Dysmorphic features included myopathic facies, droopy eyelids, high forehead, prominent ridge over the metopic suture, deep-set eyes, depressed nasal bridge, broad nasal root, long philtrum, low-set ears, thin upper lip, retrognathia, and horizontal groove over the chin. Four had feeding difficulties associated with gastroesophageal reflux. Some had eye anomalies, including nystagmus, microcornea, myopia, hyperopia, and exotropia. Brain imaging was abnormal in all 4 patients who were studied: 3 had pituitary hypoplasia, 2 had hypothalamic hypoplasia, 2 had cortical atrophy, and 1 had delayed myelination. The 35-year-old also had central hypothyroidism and amenorrhea; brain imaging was not performed. Jobling et al. (2018) emphasized that GH deficiency is an important finding in patients with MAGEL2 mutations.

McCarthy et al. (2018) reported the clinical features of 9 patients from 7 unrelated families with SHFYNG confirmed by genetic analysis, with a focus on the hormonal, metabolic, and skeletal manifestations of the disorder. The patients, who ranged in age from 5 to 17 years, had short stature (-1 to -4.6 SD); 2 were on growth hormone treatment. Extensive laboratory studies showed that most had abnormally low IGF1, 3 had impaired glucose tolerance, all had increased ghrelin (GHRL; 605353), a few had abnormal lipid panel results, and 5 had decreased luteinizing hormone (see LHB, 152780). All patients had normal free T4, and all 4 male patients had normal serum testosterone levels. Radiographic studies showed scoliosis in 3 patients, and decreased bone mineral density in those who underwent DEXA scan. McCarthy et al. (2018) postulated that the elevated ghrelin levels may be an adaptive response to early feeding problems, since patients generally do not show hyperphagia. The authors noted some overlap with PWS.

Hidalgo-Santos et al. (2018) reported a 6-year-old girl with SHFYNG confirmed by genetic analysis. In infancy, she had axial hypotonia, peripheral spasticity, and poor feeding associated with gastric volvulus. She had global developmental delay with poor language development, signs of autism, and short stature. Dysmorphic facial features, including round face, broad forehead, micrognathia, and strabismus. She also had hypotonia with delayed walking, tapering slender fingers, and equinovarus feet. EMG showed a myopathic pattern with continuous myotonia. Laboratory testing showed signs of central hypothyroidism, hyperprolactinemia, and GH deficiency; she also had increased ACTH with normal cortisol levels. The authors emphasized that correct diagnosis of the disorder is important to identify possible associated abnormalities of the endocrine system.

Patak et al. (2019) reported 5 unrelated patients with SHFYNG identified through whole-exome sequencing and collected through collaborative efforts. The patients presented in the neonatal period with hypotonia, poor spontaneous movements, poor suck and feeding difficulties, sometimes requiring tube feeding, and respiratory insufficiency, sometimes requiring mechanical ventilation. They had variable dysmorphic features, such as prominent forehead, bitemporal narrowing, hypertelorism, downslanting palpebral fissures, epicanthal folds, deep-set eyes, prominent nasal bridge, micrognathia, short or deep philtrum, thick lips, low-set ears, and cleft palate. Most also had distal skeletal anomalies, such as tapering fingers, camptodactyly, poorly developed palmar creases, and clubfoot. The patients showed global developmental delay, delayed or absent walking, poor or absent speech, and behavioral abnormalities, such as autistic features, anxiety, hyperactivity, and aggressive behavior. Brain imaging in 3 patients showed dysplasia or hypoplasia of the corpus callosum, generalized brain atrophy, and/or delayed myelination, although 2 patients had normal brain imaging. More variable features included hypoplastic external genitalia, cryptorchidism, knee contractures, scoliosis, sleep apnea, and short stature. Two patients had tracheomalacia or velopharyngeal insufficiency, and 2 had hypoglycemia. One patient had thyroid-stimulating hormone (TSH; see 188540) and GH deficiency associated with a small hypophysis on brain imaging.

McCarthy et al. (2018) described 78 patients with Schaaf-Yang syndrome, including 43 previously reported patients. The average age of the cohort was 8.1 years, with males and females equally affected. The most commonly observed phenotype was intellectual disability and developmental delay, seen in 100%, and ranged from mild to profound impairment. Feeding problems requiring special feeding techniques, neonatal hypotonia, and joint contractures were present in over 85% of the cohort. Among those who have undergone formal evaluation, 78% were diagnosed with autism spectrum disorder. About a third of patients had experienced seizures, either focal, generalized, or of unknown onset. Digestive issues were frequent, with 39 of 55 patients (71%) with chronic constipation and 34 of 60 (57%) with gastroesophageal reflux. Short stature was seen in 56%, joint contractures in 88%, scoliosis in 57% and exaggerated kyphosis in 32%. Among the patients who had undergone sleep studies, 76% had central and/or obstructive sleep apnea. Two-thirds (67%) experienced temperature instability, either as excessive sensitivity to the cold or as excessive sweating.

Bayat et al. (2018) reported a 14-month-old boy, born to nonconsanguineous Moroccan parents, with clinical and molecular genetic findings consistent with Schaaf-Yang syndrome. Clinical features consisted of developmental delay/intellectual disability, hypotonia, feeding difficulties, and congenital joint contractures. He had several family members with findings consistent with the Schaaf-Yang phenotype in a pedigree that was compatible with a maternally imprinted, paternally expressed disorder; these family members were not available for genetic testing. In the first 10 days after birth, the patient required continuous positive airway pressure due to breathing difficulties. He also had feeding difficulties requiring a feeding tube that was replaced with a gastrostomy tube at the age of 3 months. Beginning at about 3 months of age, he developed episodes of abdominal discomfort and distention, increased gastric retention, and decreased defecation frequency, occurring every other week. These findings continued even after a laparotomy with repair of a minor duodenal web and intestinal malrotation and led to a diagnosis of chronic intestinal pseudoobstruction syndrome (CIPS), for which the patient required intermittent enteral supplementation. The authors proposed that CIPS may be a complication of Schaaf-Yang syndrome.

Clinical Variability

Mejlachowicz et al. (2015) reported a family in which 3 fetuses, offspring of unrelated parents, died in utero with a severe form of SHFYNG manifest clinically as arthrogryposis multiplex congenita (AMC). Prenatal ultrasound and pathologic examination showed polyhydramnios, decreased fetal movements, clubfoot, joint contractures, and camptodactyly. Additional features included hypertelorism, short palpebral fissures, microretrognathia, and short neck. Morphologic examination of the brain, spinal cord, and neuromuscular junction did not reveal any specific defect. An unrelated child presented with a similar disorder. She had microretrognathia, short neck, clubfeet, camptodactyly, and severe hypotonia with respiratory insufficiency, resulting in death at 2 days of age. Pathologic examination of other organs, including the brain and spinal cord, was normal.

Two of the patients reported by Fountain et al. (2017) were fetal sibs (patients 5 and 6) with SHFYNG manifest as AMC resulting in termination of the pregnancies. The patients had fetal akinesia, overlapping digits, rocker-bottom feet, retromicrognathia, and gnathopalatoschisis. One had multiple pterygia and talipes equinovarus.

The transmission pattern of SHFYNG in the families reported by Fountain et al. (2017) was consistent with autosomal dominant inheritance with the mutation present on the paternal allele, since the MAGEL2 gene is maternally imprinted and expressed only by the paternal allele. Unlike classical autosomal dominant disorders, the SHFYNG phenotype can skip several generations as long as the mutation resides on the maternal (imprinted) chromosome. However, the chance that the offspring of male individuals carrying a deleterious MAGEL2 mutation will be clinically affected is 50%.

Buiting et al. (2014) reported a 3-year-old boy with a paternally inherited deletion of approximately 3.9 Mb that included MAGEL2, but not the SNRPN (182279)/SNORD116 (605436) locus. Apart from delayed motor skills, the boy was asymptomatic. Buiting et al. (2014) stated that this was the second individual with a MAGEL2 deletion who certainly did not have Prader-Willi syndrome; the first individual was also described by this group (Kanber et al., 2009). The authors concluded that it is important to distinguish between point mutations and whole gene deletions, and that because the effect of the genes in the PWS chromosomal region may be epistatic rather than additive, the role of MAGEL2 in Prader-Willi syndrome remained unclear.

In 4 unrelated boys with a syndrome resembling Prader-Willi syndrome, Schaaf et al. (2013) identified 4 different de novo heterozygous truncating mutations in the MAGEL2 gene (605283.0001-605283.0004). All mutations occurred on the paternal allele. Because the maternal allele is not normally expressed, the findings were consistent with a loss of MAGEL2 function. The mutation in the first patient was found by clinical whole-exome sequencing. Based on these results, a research database of 1,248 whole-exome sequencing cases were reviewed, and the 3 remaining cases were identified.

In 2 sisters with Schaaf-Yang syndrome, Soden et al. (2014) identified a heterozygous truncating mutation in the MAGEL2 gene (c.1996dupC; 605283.0005). The mutation was found by whole-genome sequencing and apparently resulted from gonadal mosaicism; the mutation was missed by initial whole-exome sequencing. The patients were part of a larger cohort of 100 families with neurodevelopmental disorders who underwent whole-exome or whole-genome sequencing.

In 18 patients with SHFYNG, Fountain et al. (2017) identified heterozygous truncating mutations in the MAGEL2 gene (see, e.g., 605283.0005-605283.0006, 605283.0008-605283.0009). The patients were ascertained based on genotype from whole-exome or direct Sanger sequencing through multiple research-based centers or laboratories. All mutations, which were confirmed by Sanger sequencing, resulted in a truncated protein. All patients tested carried the mutation on the paternal allele, consistent with maternal imprinting of the MAGEL2 gene. In 3 families, the mutation segregated with the disorder: unaffected fathers inherited the mutation from an unaffected mother. Fountain et al. (2017) speculated that the mutations could result in a dominant-negative effect. The phenotype was highly variable, ranging from relatively mild contractures to fetal akinesia, AMC, and early death. Nucleotides c.1990-1996 of MAGEL2 include a sequence of 7 cytosines that represent a mutational hotspot: 11 individuals from 7 families had a c.1996dupC mutation (605283.0005), and 2 from the same family had a c.1996delC mutation (605283.0006). Functional studies of the variants and studies of patient cells were not performed.

Jobling et al. (2018) reported 5 patients from 3 unrelated families who were diagnosed clinically with Chitayat-Hall syndrome but were found to carry heterozygous loss-of-function mutations in the MAGEL2 gene on the paternal allele (see, e.g., 605283.0005). One of the patients was the affected sister originally reported by Chitayat et al. (1990), who was heterozygous for a complex rearrangement and partial deletion of MAGEL2.

In 5 unrelated patients with SHFYNG, Patak et al. (2019) identified heterozygous mutations in the MAGEL2 gene. The mutations were found by whole-exome sequencing and the patients were ascertained through collaborative efforts. Four patients carried frameshift or nonsense mutations, including c.1996delC, and 1 (patient 2) carried a missense variant (A538E; 605283.0010). The mutations, all of which occurred on the paternal allele, occurred de novo in 4 patients and resulted from low levels mosaicism in an unaffected father in the fifth. Functional studies of the variants and studies of patient cells were not performed.

Among 78 patients with Schaaf-Yang syndrome reported by McCarthy et al. (2018), 42 had MAGEL2 mutations within a mutation hotspot region where there are 7 cytosines at nucleotides 1990-1996. The most common mutation was c.1996dupC (605283.0005), which was found in 35 patients. The most severe phenotype occurred in patients with the c.1996delC mutation (605283.0006), which was found in 5 patients.

In a patient with Schaaf-Yang syndrome and chronic intestinal pseudoobstruction, Bayat et al. (2018) performed MAGEL2 gene sequencing and identified heterozygosity for the c.1996dupC mutation.

In 3 fetuses, born of unrelated parents, with Schaaf-Yang syndrome manifest as AMC and death in utero, Mejlachowicz et al. (2015) identified a heterozygous truncating mutation in the MAGEL2 gene (c.1996delC; 605283.0006). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father who inherited it from his unaffected mother. Direct Sanger sequencing of the MAGEL2 gene in 84 additional cases of AMC and/or decreased fetal motility identified another patient with a de novo heterozygous truncating mutation (c.2118delT; 605283.0007) that occurred on the paternal allele.

Fountain et al. (2017) identified the same heterozygous c.1996delC mutation in 2 sib fetuses (patients 5 and 6) with SHFYNG manifest as AMC, resulting in termination of the pregnancies.

Bischof et al. (2007) found that Magel2-null mice showed features similar to those of Prader-Willi syndrome (PWS; 176270) in humans. There was reduced embryonic viability associated with loss of Magel2. Magel2-null mice showed neonatal growth retardation, excessive weight gain after weaning, and increased adiposity with altered metabolism, including increased fasting insulin and elevated cholesterol, in adulthood. Mutant mice also showed abnormalities in the circadian pattern of feeding behavior. The findings implicated loss of the Magel2 gene in hypothalamic dysfunction.

Schaller et al. (2010) reported that a Magel2-deficient mouse strain with 50% neonatal mortality had an altered onset of suckling activity and subsequent impaired feeding, suggesting a role of MAGEL2 in the suckling deficit seen in newborns with PWS. The hypothalamus of Magel2 mutant neonates showed a significant reduction in oxytocin (OT; 167050). Furthermore, injection of a specific oxytocin receptor antagonist in wildtype neonates recapitulated the feeding deficiency seen in Magel2 mutants, and a single injection of oxytocin, 3 to 5 hours after birth, rescued the phenotype of Magel2 mutant pups, allowing all of them to survive. The authors proposed that oxytocin supplementation might constitute a promising treatment for feeding difficulties in PWS neonates and potentially in other newborns with impaired feeding onset.