Background Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.
Methods and results We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion.
Conclusions Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.
- growth hormone deficiency
- schaaf-yang syndrome
- chitayat-hall syndrome
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In 1990 Chitayat et al 1 reported siblings with distal arthrogryposis, hypopituitarism, intellectual disability and dysmorphisms. This condition is known as Chitayat-Hall syndrome or distal arthrogryposis with hypopituitarism including growth hormone (GH) deficiency, mental retardation and facial anomalies (OMIM #208080). A similar phenotype has been described in other patients, including one case with consanguineous parents. Autosomal recessive inheritance has been suggested based on the history of consanguinity and sibling recurrence.1–3 Here we report six patients with Chitayat-Hall syndrome from four families, including updated information on the female proband originally reported by Chitayat et al.1 All patients were found to have truncating sequence variants in the MAGEL2 gene, including the first reported disease-causing complex rearrangement involving MAGEL2. Patients with truncating variants in MAGEL2 have been described to have Schaaf-Yang syndrome (SHFYNG; OMIM #615547), a variable phenotype characterised by intellectual disability, early feeding difficulties followed by excessive weight gain in some patients, hypotonia, and contractures ranging in severity from distal arthrogryposis to severe arthrogryposis multiplex congenita.4–6 We demonstrate that Chitayat-Hall syndrome has the same aetiology as SHFYNG, and that GH deficiency is an important feature of this condition.
The cohort was recruited from centres across Canada. All patients initially received a clinical diagnosis of Chitayat-Hall syndrome from a medical geneticist, with the exception of patient 4-I, who did not have a clinical diagnosis but was noted to have similar features. Clinical features are summarised in table 1. Pedigrees are shown in figure 1 and patient photographs in figure 2. Full phenotype reports are found in the online supplementary clinical information. Here we provide detailed information regarding GH deficiency in this cohort. Consent to publish clinical information was obtained from all families.
Patient 1-I presented with poor growth velocity. She was treated with somatotropin until age 17. Her final height is on the 10th percentile. In addition to GH deficiency, she has central hypothyroidism and is treated with levothyroxine.1 She has not been formally investigated for hypogonadism, but has amenorrhoea.
At 4 months of age patient 2-I presented with rhythmic limb movements. At arrival to the emergency room, blood glucose was 2.2 mmol/L. She suffered recurrent hypoglycaemic episodes, with critical samples taken on three occasions and showing low GH levels: 1.04 μg/L, 0.8 μg/L and 2.45 μg/L with blood glucose concentrations of 1.3 mmol/L, 0.8 mmol/L and 2.3 mmol/L, respectively. She was started on somatotropin treatment at 0.17 mg/kg/week and the hypoglycaemic episodes decreased. She presented again at 11 months with a further episode of hypoglycaemia. Arginine stimulation testing confirmed GH deficiency with a peak GH level of 1.32 μg/L. Her somatotropin dose was adjusted to 0.18 mg/kg/week and her glycaemic control improved again. At age 2, a brain MRI revealed hypothalamic hypoplasia, with normal sella turcica. Her height increased from the 5th to the 25th percentile after treatment.
Her younger sister, patient 2-II, presented at 2 months with multiple hypoglycaemic episodes, including during an arginine stimulation test. GH was inappropriately low on multiple critical samples: 4.8 μg/L, 4.6 μg/L and 3.3 μg/L with blood glucose concentrations of 2.2 mmol/L, 2.8 mmol/L and 1.8 mmol/L, respectively. The rest of the endocrine and metabolic work-up was normal. She was treated with somatotropin at 0.23 mg/kg/week, since her hypoglycaemia was more severe. Subsequently the dose was reduced to 0.185 mg/kg/week. After treatment her height increased from below the 3rd to the 25th percentile. Brain MRI at age 6 showed hypersignal of the pituitary stalk and posterior pituitary.
Patient 3-II developed seizures at 12 months, thought to have been precipitated by hypoglycaemia (glucose 2.4 mmol/L). At 14 months of age her Insulin-like growth factor 1 (IGF-1) was 27 μg/L (reference value 49–342 μg/L). Arginine stimulation testing revealed GH deficiency (GH peak value 4.1 μg/L). Her blood glucose was monitored leading to a decision not to start somatotropin treatment. At 3 years of age she presented again with hypoglycaemic seizures. A critical sample showed an insulin level of 26 pmol/L, GH was low at 0.08 μg/L, beta-hydroxybutyrate was 0.020 mmol/L (normal, 0.02–0.29 mmol/L) and free fatty acids was 263 µmol/L (normal, 100–900 µmol/L) for a glucose of 1.7 mmol/L. However, a second critical sample showed a fully suppressed insulin of <7 pmol/L and GH of 0.2 μg/L, for a glucose of 2.5 mmol/L. Her blood glucose was monitored regularly and the hypoglycaemic episodes have improved over time. She has not been treated with somatotropin.
Following the diagnosis of GH deficiency in her younger sister, patient 3-I was investigated. Her IGF-1 was low at <25 μg/L at 3 years and 10 months and 28 μg/L at 6 years 1 month (reference value 49–342 μg/L). Arginine stimulation testing revealed a peak value of 2.7 μg/L. Her blood glucose was monitored, but the decision was made not to start somatotropin treatment. Brain MRI at 4 years showed a small pituitary gland.
Patient 4-I had hypoglycaemic episodes requiring hospitalisation at 6 months. GH deficiency was first suspected at 11 months and confirmed at 19 months. The GH measured during two hypoglycaemic episodes was low and a clonidine GH stimulation test showed a deficiency (GH peak value 4.42 μg/L). The arginine GH stimulation test was also abnormal (4.435 mg intravenously ×1: GH peak value 3.53 μg/L). She was successfully treated with somatotropin. With treatment her height increased from below the 3rd to the 10th percentile. Brain MRI done at 3 months and repeated at 3 years and 7 months revealed a thin pituitary stalk and slight dilation of the third ventricle, possibly secondary to hypothalamic atrophy.
Detailed results of GH stimulation testing can be found in online supplementary clinical information, tables 1–3.
For all families, genetic analysis was performed by either whole genome sequencing (WGS) or whole exome sequencing (WES) with pathogenic variants confirmed by Sanger sequencing. For family 1, WGS of the proband and her father was performed. WES was performed on samples from affected patients in family 2, and the probands in families 3 and 4 (online supplementary methods).
Analysis of WES and WGS data prioritised variants based on allele frequency, presence in databases of medically relevant variants including ClinVar7 and the Human Gene Mutation Database,8 predicted impact on coding sequence, phenotype in the OMIM database, zygosity, and mode of inheritance. In family 2, where both affected individuals were sequenced, shared variants were examined. In family 1 variants shared between the proband and her unaffected father were prioritised due to the paternal family history of similarly affected individuals (figure 1, online supplementary figure 5).
Since MAGEL2 is expressed exclusively from the paternal allele, only pathogenic variants located on the paternal allele will cause disease.9 To determine the parental origin of the c.2179_2180del variant identified in family 3, long-range PCR of MAGEL2 followed by Sanger sequencing was performed on genomic DNA after methylation-sensitive digestion, as described previously4 (online supplementary methods).
All affected individuals were found to carry truncating variants in MAGEL2. Patient 1-I was found to have a complex rearrangement interrupting the MAGEL2 gene, consisting of a 22 kb inversion and 3 kb deletion that removes the last 852 bp and the 3’ end of the gene (online supplementary figures 1–3). The variant was paternally inherited and segregation analysis for several additional family members was performed (figure 1). Siblings 2-I and 2-II have a nonsense variant (NM_019066; c.1762 C>T(p.Gln588Ter)) in MAGEL2. Parental samples were not available for testing. Patients 3-I and 3-II carry a frameshift variant (c.2179_2180del(p.Asp727Profs*6)) in MAGEL2. The variant was not present in parents or unaffected siblings, and was determined to be on the paternal allele (online supplementary figure 4). Patient 4-I has a previously reported frameshift insertion (c.1996dupC(p.Gln666Profs*47))6 in MAGEL2, inherited from her unaffected father.
Multiple features first reported in Chitayat-Hall syndrome overlap with those described in the majority of individuals with SHFYNG, including contractures, hypotonia, developmental delay/intellectual disability, feeding difficulties, dysmorphisms, small hands and feet, and tapering fingers.1 4–6 10–12 Our cohort also has other features reported in a minority of individuals, including scoliosis, gastro-oesophageal reflux, increased subcutaneous fat and prominent ridge over the metopic suture. While eye abnormalities are described, this is the first report of microcornea in patients with an MAGEL2-related disorder.6
The most common pathogenic sequence variant identified to date in MAGEL2, c.1996dupC(p.Gln666Profs*47), has been reported in 14 individuals from nine families diagnosed with SHFYNG.6 10 11 These individuals present with the features most commonly described in association with SHFYNG, including contractures, developmental delay/intellectual disability, dysmorphism, hypotonia and feeding difficulties. Short stature was reported in 6/14 cases. Our patient 4-I, with the c.1996dupC variant, has a very similar phenotype to the 14 reported patients, apart from her GH deficiency. Unfortunately, there is no information available regarding GH levels in these 14 individuals.
Deficiency of hormones produced by the anterior pituitary is a prominent feature of Chitayat-Hall syndrome. All patients reported here demonstrated biochemical abnormalities related to GH deficiency on more than one occasion, with either low IGF-1, low GH peak after arginine stimulation, low GH in the context of hypoglycaemia, or all of the above. One patient with SHFYNG has been previously reported to have GH deficiency, presenting with poor linear growth and treated from 2 years of age.4 However, short stature is common in these patients, and is likely caused by undiagnosed GH deficiency in some cases.4 6 11 Four patients in our study presented with hypoglycaemia, another manifestation of GH deficiency. Hypoglycaemic episodes have not been reported in the majority of patients with SHFYNG, although may go undiagnosed if not leading to convulsions or loss of consciousness.
The pathophysiology of GH deficiency in patients with MAGEL2 variants requires further investigation. MRI findings in our patients were not consistent, although it is notable that imaging for patients 2-I and 4-I demonstrated possible hypothalamic hypoplasia. Magel2 is expressed in both fetal and adult brain,9 13 and mouse studies have demonstrated robust expression in the fetal hypothalamus. In adult mice Magel2 is mainly expressed in the hypothalamus, including the arcuate nucleus where GH-releasing hormone (GHRH) is produced.14 15 There is evidence of GH deficiency related to hypothalamic dysfunction in the Magel2-null mouse. Tennese and Wevrick16 found low levels of IGF-1 in female Magel2-null mice compared with controls. The mice demonstrated a blunted response to hypothalamic stimulation of the GH pathway with ghrelin compared with wild-type littermates, while their response to GHRH was equivalent, indicating a possible hypothalamic origin for the deficiency.16
Family 1 carries a complex rearrangement and partial deletion. To our knowledge this is the first report of such a change causing an MAGEL2-related disorder. The first 2.9 kb of the coding and the 5’ region are apparently intact, and it is possible that a truncated protein product is produced. It has been suggested that frameshift and nonsense variants in MAGEL2 escape nonsense-mediated decay and have a neomorphic or dominant negative effect, explaining the milder phenotype seen in full gene deletions.6 17 18 Functional studies are required to investigate this possibility, but are difficult to pursue given that the expression of MAGEL2 in adult tissues is very limited.9 13 This case illustrates the benefits of WGS as a diagnostic test, as this complex variant would not have been detected using exome, microarray or targeted sequencing methodologies.
In family 3 we demonstrated that the variant identified in the two affected sisters was on the paternal allele. It was not detectable in paternal blood by Sanger sequencing. This does not rule out the possibility of low level mosaicism in blood or other tissues. This is the third reported case of apparent mosaicism in an unaffected father in MAGEL2-related disorder.10 11 In this situation, the recurrence risk could be up to 50%.
The phenotype of MAGEL2-related disorder continues to evolve, now including Chitayat-Hall syndrome. With the exception of the endocrinological findings we describe, our patients’ phenotypes are very similar to those observed in patients with SHFYNG, and one of our patients carries the most common recurrent variant c.1996dupC reported in SHFYNG. This suggests that SHFYNG and Chitayat-Hall syndromes are likely the same disorder. A systematic investigation of endocrinological abnormalities in patients with MAGEL2-related disorder is needed and GH deficiency should always be considered in the context of poor growth and/or hypoglycaemia.
We would like to thank the families who participated in this work. The authors also thank, the SickKids Centre for Genetic Medicine, the University of Toronto McLaughlin Centre, The Toronto Centre for Applied Genomics, and the GlaxoSmithKline-CIHR Chair in Genome Sciences at The Hospital for Sick Children and the University of Toronto (SWS), and the Fondation Jeanne et Jean-Louis Lévesque (JLM).
JLM and DC contributed equally.
Contributors CC, SM, FR, NA, RR, MM, SA, MJMN, CLD, RW, PM and DC performed clinical assessment and provided phenotypic information regarding the patients. FR, FDL, JG, FFH, CN, J-FS, JLM, RJ, DJS, CRM, SWS, JO and SW provided sequencing, data analysis, interpretation and validation of variants. RJ, VL and MMA performed phasing experiments for the variant in family 3. The manuscript was drafted by RJ, FR, DC and JLM. All authors provided critical revision of the article.
Funding The McLaughlin Centre, University of Toronto, Toronto, Canada, and Fondation Jeanne et Jean- Louis Lévesque (JLM). The Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Canada. FDL has a fellowship funded by FCT - Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010).
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Ethics approval The Hospital for Sick Children, Toronto, Canada, and Centre hospitalier universitaire Sainte-Justine.
Provenance and peer review Not commissioned; externally peer reviewed.