Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2 -related disorders

Abstract

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.

Full text

316 JoblingR, etal. J Med Genet 2018;55:316–321. doi:10.1136/jmedgenet-2017-105222
SHORT REPORT
Chitayat-Hall and Schaaf-Yang syndromes:
a common aetiology: expanding the phenotype of
MAGEL2-relateddisorders
Rebekah Jobling,1,2 Dimitri James Stavropoulos,1,3 Christian R Marshall,1,4
Cheryl Cytrynbaum,2 Michelle M Axford,1 Vanessa Londero,1 Sharon Moalem,5
Jennifer Orr,1 Francis Rossignol,6,7 Fatima Daniela Lopes,6,8,9 Julie Gauthier,6
Nathalie Alos,6,7 Rosemarie Rupps,10 Margaret McKinnon,10 Shelin Adam,10
Malgorzata J M Nowaczyk,11 Susan Walker,4,12 Stephen W Scherer,4,12,13
Christina Nassif,6,7 Fadi F Hamdan,6,7 Cheri L Deal,6,7 Jean-François Soucy,6,7
Rosanna Weksberg,2 Patrick Macleod,14 Jacques L Michaud,6,7 David Chitayat2,15
Phenotypes
To cite: JoblingR,
StavropoulosDJ, MarshallCR,
etal. J Med Genet
2018;55:316–321.
►Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
jmedgenet- 2017- 105222).
For numbered affiliations see
end of article.
Correspondence to
Dr David Chitayat, Division
of Clinical Genetics and
Metabolism, Department of
Pediatrics, The Hospital for Sick
Children, Toronto, ON M5G
1X8, Canada; David. Chitayat@
sinaihealthsystem. ca
JLM and DC contributed equally.
Received 16 December 2017
Revised 2 March 2018
Accepted 11 March 2018
Published Online First
29March2018
ABSTRACT
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.
INTRODUCTION
In 1990 Chitayat et al1 reported siblings with
distal arthrogryposis, hypopituitarism, intellec-
tual disability and dysmorphisms. This condition
is known as Chitayat-Hall syndrome or distal
arthrogryposis with hypopituitarism including
growth hormone (GH) deficiency, mental retar-
dation 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 fami-
lies, 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 arthrogryp-
osis 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.
CLINICAL REPORTS
The cohort was recruited from centres across
Canada. All patients initially received a clin-
ical 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 supple-
mentary 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 addi-
tion to GH deficiency, she has central hypothy-
roidism 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 emer-
gency 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, respec-
tively. She was started on somatotropin treat-
ment at 0.17 mg/kg/week and the hypoglycaemic
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Phenotypes
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 crit-
ical 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-hy-
droxybutyrate 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 moni-
tored regularly and the hypoglycaemic episodes have improved
over time. She has not been treated with somatotropin.
Table 1 Clinical features of patients with Chitayat-Hall syndrome
Patient 1-I 2-I 2-II 3-I 3-II 4-I
Literature*
(affected
(n)/with
information
available (n))
Variant Partial deletion/
inversion
c.1762 C>T
(p.Gln588Ter)
c.1762 C>T
(p.Gln588Ter)
c.2179_2180del
(p.Asp727Profs*6)
c.2179_2180del
(p.Asp727Profs*6)
c.1996dupC
(p.Gln666Profs*47)
Age at last assessment
(years)
35 13 11 10 8 6
Short stature + + + + + + 14/22
Increased
subcutaneous fat
Noted in infancy,
current BMI 19.4
NR NR + + + 9/20
Developmental delay/
intellectual disability
+ (moderate) + + + (severe) + (severe) + (severe) 22/22
Eye abnormalities − + (nystagmus,
microcornea,
glaucoma)
+ (nystagmus,
microcornea)
− − + (myopia, hyperopia,
exotropia)
16/20†
Dysmorphisms + + + + + + 25/30
Heart defect − + (patent foramen
ovale)
− +(atrial septal defect) − − NR
Feeding problems + − − + + + 22/24
Gastro-oesophageal
reflux
+ − − + + + 8/14
Contractures + + + + + + 25/30
Scoliosis/kyphosis + + + + + + 9/19
Hypoglycaemic
episodes
− + + + + + 3/3‡
Growth hormone
deficiency
+ + + + + + 1/1§
Hypothyroidism + − − − − − NR
Hypotonia + + + + + + 15/15
MRI abnormalities MRI not
performed
Early myelination
delay,
hypothalamic
hypoplasia
Hypersignal of
pituitary stalk
Frontal volume loss and
decreased pituitary size
MRI not performed Thin pituitary stalk,
dilatation of third
ventricle possibly due to
hypothalamic atrophy,
ventriculomegaly
Previous normal
genetic testing
Karyotype,
array genomic
hybridisation
Karyotype, fragile
X,
Array genomic
hybridisation,
fragile X
Karyotype, array
genomic hybridisation
Array genomic
hybridisation
Karyotype, array genomic
hybridisation
NR indicates that this information was not reported.
*Refs 4–6, 10–12.
†Esotropia, myopia and strabismus.
‡Hyperinsulinaemic hypoglycaemia10 and recurrent hypoglycaemia of unknown origin.11
§Ref4.
BMI, body mass index.
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318 JoblingR, etal. J Med Genet 2018;55:316–321. doi:10.1136/jmedgenet-2017-105222
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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 hospitalisa-
tion 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 stimula-
tion test showed a deficiency (GH peak value 4.42 μg/L). The
arginine GH stimulation test was also abnormal (4.435 mg intra-
venously ×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.
METHODS
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 vari-
ants including ClinVar7 and the Human Gene Mutation Data-
base,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).
SEQUENCING RESULTS
All affected individuals were found to carry truncating variants
in MAGEL2. Patient 1-I was found to have a complex rear-
rangement 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
Figure 1 Pedigrees and MAGEL2 variants identified in patients with Chitayat-Hall syndrome. Filled black squares and circles indicate clinically affected
individuals, black dots indicate carriers, V indicates that the familial variant was found in an individual,+indicates the reference sequence and NT indicates
that the individual was not tested.
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Phenotypes
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 inser-
tion (c.1996dupC(p.Gln666Profs*47))6 in MAGEL2, inherited
from her unaffected father.
DISCUSSION
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 subcu-
taneous fat and prominent ridge over the metopic suture. While
eye abnormalities are described, this is the first report of micro-
cornea 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, dysmor-
phism, 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 infor-
mation 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 hypotha-
lamic hypoplasia. Magel2 is expressed in both fetal and adult
brain,9 13 and mouse studies have demonstrated robust expres-
sion in the fetal hypothalamus. In adult mice Magel2 is mainly
Figure 2 Features of affected patients. (A) Patient I-1—myopathic faces with droopy eyelids and open mouth. (B,C) Patients 2-I and 2-II, respectively—
both sisters had minor facial dysmorphism with a high forehead, a flat forehead in patient 2-I (B) and frontal bossing in patient 2-II (C) with a ridge over
the metopic suture, deep set eyes, depressed nasal bridge with a broad nasal root and tip, and a ‘square’ chin with a horizontal groove over the chin. In
patient 2-II (C) note thelow-set ears with the right ear being lower than the left. (D) Patient 3-I—high forehead with a ridge over the metopic suture,
hypoplastic supraorbital ridges, deep set eyes, a broad nasal root and tip and a long philtrum, full cheeks, thin upper lip and retrognathia with a square
chin and a horizontal groove over the chin. (E) Hand of patient 3-II—‘Puffy’ hand with proximally inserted thumb, tapering fingers and camptodactyly with
absent distal flexion creases. (F) Patient 3-II—deep set eyes, a broad nasal root and tip, long philtrum, thin upper lip, retrognathia, a ‘square’ chin with a
horizontal groove over the chin and low-set ears. (G) Patient 4-I—ridge over the metopic suture, deep set eyes, a broad nasal root and tip, thin upper lip,
retrognathia with a square chin, a horizontal groove over the chin and low-set ears. (H) Hand of patient 4-I—adducted thumb with the second and fifth
fingers overlapping the third and fourth.
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Phenotypes
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 dysfunc-
tion 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 hypo-
thalamic 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 neomor-
phic or dominant negative effect, explaining the milder pheno-
type 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 mosa-
icism 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 excep-
tion 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 endocrinolog-
ical 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.
Author affiliations
1Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital
for Sick Children, Toronto, Ontario, Canada
2Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital
for Sick Children, Toronto, Ontario, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada
4The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario,
Canada
5Regenoron, New York City, New York, USA
6CHU Sainte-Justine, Montréal, Quebec, Canada
7Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
8Life and Health Sciences Research Institute (ICVS), School of Medicine, University of
Minho, Braga, Portugal
9ICVS/3B’s - PT Government Associate Laboratory, Guimarães, Portugal
10Department of Medical Genetics, University of British Columbia, Vancouver, British
Columbia, Canada
11Division of Clinical Pathology, McMaster University, Hamilton, Ontario, Canada
12Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto,
Ontario, Canada
13Department of Molecular Genetics and McLaughlin Centre, University of Toronto,
Toronto, Ontario, Canada
14The Centre for Biomedical Research, University of Victoria, Victoria, British
Columbia, Canada
15The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics
and Gynecology, Mount Sinai Hospital, New York City, New York, USA
Acknowledgements 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).
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.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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