Original Paper
HOR MONE
RE SE ARCH I N
PÆDIATRIC S
Horm Res Paediatr 2015;83:190–197
DOI: 10.1159/000369804
Received: September 5, 2014
Accepted: November 10, 2014
Published online: February 5, 2015
Liver Disease and Other Comorbidities in
Wolcott-Rallison Syndrome: Different Phenotype
and Variable Associations in a Large Cohort
Abdelhadi M. Habeb a, b Asma Deeb d Matthew Johnson e Mohammed Abdullah f
Majidah Abdulrasoul g Hussain Al-Awneh i Mohammed S.F. Al-Maghamsi b
Fathiya Al-Murshedi j Ramlah Al-Saif c Siham Al-Sinani k Dina Ramadan h
Hala Tfayli l Sarah E. Flanagan e Sian Ellard e
a
Paediatric Department, Prince Mohammed bin-Abdulaziz Hospital, b Endocrine and Diabetes Unit, Maternity and
Children Hospital, Madinah, and c Paediatric Department, Maternity and Children Hospital, Dammam, Saudi Arabia;
d
Paediatric Endocrinology Department, Mafraq Hospital, AbuDhabi, United Arab Emirates; e Institute of Biomedical
and Clinical Science, University of Exeter Medical School, Exeter, UK; f Paediatric Department, Khartoum University,
Khartoum, Sudan; g Paediatric Department, Kuwait University, and h Paediatric Department, Sabah Hospital, Kuwait;
i
Paediatric Endocrinology Division, Queen Rania Al Abdullah Hospital for Children, KHMC, RMS, Amman, Jordan;
j
Genetic and Developmental Medicine Clinic, and k Gastroenterology Unit, Department of Child Health, Sultan Qaboos
University Hospital, Muscat, Oman; l Department of Pediatrics and Adolescent Medicine, American University of Beirut
Medical Center, Beirut, Lebanon
Key Words
EIF2AK3 mutations · Hepatitis · Childhood diabetes ·
Liver transplantation · Skeletal dysplasia
Abstract
Background: Wolcott-Rallison syndrome (WRS) is caused by
recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has
been reported in 60% of patients. Aims: To describe a cohort
of WRS patients and discuss the pattern and management of
their liver disease. Methods: Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients. Results: Twenty-eight genetically confirmed patients
(67% male; mean age 4.6 years) were identified. 17 different
EIF2AK3 mutations were detected, of which 2 were novel.
The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented
before 25 months with diabetes with variation in the fre-
© 2015 S. Karger AG, Basel
1663–2818/15/0833–0190$0.00/0
E-Mail karger@karger.com
www.karger.com/hrp
This is an Open Access article licensed under the terms of
the Creative Commons Attribution 3.0 Unported license
(CC BY 3.0) (www.karger.com/OA-license-WT), applicable to the online version of the article only.
quency and severity of 10 other features. Liver disease, first
manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28).
22/24 had at least one episode of acute hepatic failure which
was the cause of death in all deceased patients (13/28). One
child was treated by liver transplantation and had no liver
disease and better diabetes control for the following 6 years.
Conclusions: Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.
© 2015 S. Karger AG, Basel
Introduction
Wolcott-Rallison syndrome (WRS) is a rare condition
that was initially described in 1972 in siblings with earlyonset diabetes mellitus and skeletal dysplasia (SD) [1].
Further reports extended the phenotype to recurrent hepAbdelhadi M. Habeb
Paediatric Department
Prince Mohammed bin-Abdulaziz Hospital, NGHA
PO Box 20873, Madinah (Saudi Arabia)
E-Mail amhabeb @ hotmail.com
atitis, renal dysfunction, failure to thrive, developmental
delay, neutropenia and hypothyroidism [2–7]. Most reported families with WRS originate from the Middle East
[8, 9], and the condition is the commonest cause of permanent neonatal diabetes mellitus (PNDM) in consanguineous pedigrees [4] and Arabs [10].
WRS is caused by recessive loss of function mutations
in the EIF2AK3 gene [11], and almost all reported cases
have identifiable mutations. The EIF2AK3 gene encodes
a protein called pancreatic PKR-like endoplasmic reticulum kinase (PERK), which plays a key role in detecting
and initiating the cellular response to endoplasmic reticulum stress. Failure of appropriate PERK response results
in accumulation of misfolded proteins, which leads to cell
damage and apoptosis [12, 13].
Liver disease was reported in some patients with WRS
since 1982 [2–7, 14]. The typical manifestation was intermittent hepatitis precipitated by stress and characterized
by raised liver transaminase, jaundice and hepatomegaly.
Acute fatal hepatic failure and chronic hepatic dysfunction were also reported [8]. The hepatic histology varied
from progressive fibrosis with mild steatosis and intrahepatic cholestasis [2] to preserved architecture with mild
lobular infiltration by lymphocytes and oedema of the
portal spaces [15]. The frequency of liver disease was 60%
in 35 WRS patients reviewed by Ozbek et al. [5] in 2009.
However, our clinical impression was that liver disease in
WRS is more frequent and has high mortality. The aim of
this study was to describe a new cohort of patients with
WRS and discuss the pattern and management of hepatic
dysfunction in this cohort.
Informed consent was signed by the parents, and DNA was
extracted from the whole blood using the standard methods. Patients were tested for mutations in the KCNJ11, ABCC8 INS and
EIF2AK3 genes by Sanger sequence analysis as previously described [4].
Results
In total, 32 patients were identified. Four patients were
excluded from the analysis (2 with incomplete follow-up
data and 2 because their physicians did not return the
questionnaire). 28 patients (20 families) from 8 Arab
countries were studied. Of these, 18 were not previously
described and 10 were initially reported by us in 2009 and
2011, but remained under follow-up by the same physicians since diagnosis. The genotypes and phenotypes of
studied patients are shown in table 1.
Clinical Characteristics
All patients were the product of consanguineous marriages; their mean age was 4.6 years (range: 10 months to
17.5 years) and 67% were male. There was a variation in
the phenotype between patients with the same mutations
including siblings. Diabetes was the presenting feature in
all subjects: 25/28 patients have PNDM (onset <6 months
old; mean age at diagnosis 7.6 weeks) and 3 presented at
14, 18 and 24 months old. 46.4% of patients were deceased
(13/28) at a mean age of 5.8 years, and all living subjects
were on insulin therapy. The longest survived patient in
the cohort was 17.5 years. Two patients have isolated
PNDM, and the rest showed at least one extra-pancreatic
feature (fig. 1).
Patients and Methods
The study was conducted according to the Declaration of
Helsinki.
We searched the database at the Exeter molecular genetics laboratory for genetically confirmed WRS cases referred from Arab
states until July 2014. Paediatricians in the region were contacted
to identify unreported WRS cases tested outside Exeter. A questionnaire on the details of the genotype and phenotype of WRS was
distributed to the referring physicians of unreported cases and they
were also requested to provide follow-up data of their reported
WRS cases. We excluded patients in whom clinical data were incomplete or if their clinicians did not return the questionnaire. We
defined liver disease as the presence of at least one episode of noninfective non-autoimmune hepatitis, unexplained jaundice, hepatomegaly, high liver transaminase, deranged liver function or
acute hepatic failure (AHF; INR of >1.5 and evidence of impaired
sensorium). The frequency of liver disease in WRS was expressed
as the percentage of patients with hepatic dysfunction of the total
number of the studied cohort.
Liver in WRS
Frequency and Pattern of Liver Disease
Twenty-four of 28 patients have liver disease, giving
a frequency rate of 85.7%. The mortality rate in patients
with liver disease was 54.1% (13/24), and AHF was the
cause of death in all deceased subjects. During followup of the 10 reported cases, 2 experienced their first
hepatitis episode and 3 died of AHF. The first presentation of liver disease in all 24 patients was acute nonautoimmune hepatitis triggered by viral illnesses and
characterized by high liver enzymes, jaundice and hepatomegaly. In 6 patients, the hepatitis episodes were associated with impaired renal function (table 1). Seven
patients had hepatitis at diagnosis, along with diabetes,
and the remaining 17 patients experienced their first
episode between 2 weeks and 2 years after the onset of
diabetes. In 3 children, the first hepatitis episode proHorm Res Paediatr 2015;83:190–197
DOI: 10.1159/000369804
191
192
Table 1. Demography, genotype and clinical characteristics of the 28 studied patients with WRS
Horm Res Paediatr 2015;83:190–197
DOI: 10.1159/000369804
Habeb et al.
Patient Country
of origin
Gender Age at diagnosis and
presenting features
EIF2AK3 mutation
Acute hepatitis – age
at 1st episode and
frequency
Acute hepatic failure –
age at onset, number,
and outcomes
Other features
Prognosis/comments
1.1
KSA
Male
Hyperglycaemia at 8
weeks
p.W430X (c.1290G>A)
1 episode at 8 months
No
No
Alive at 18 months old
2.1 [17] KSA
Male
DKA at 21 weeks
p.V349Sfs*3
(c.1044_1057del)
20 months; 8 episodes
(first after reporting)
1 fatal episode at 6 years
SD, SS, FTT and impaired Died at 6 years
RF during hepatitis
3.1 [4,
17]
KSA
Female
DKA and hepatitis at p.V349Sfs*3
8 weeks
(c.1044_1057del)
8 weeks; 20 episodes
2 episodes at 3 years and
1 fatal at 7.5 years
No
Died at 7.5 years (after
initial reporting)
3.2 [17] KSA
Female
DKA and hepatitis at p.V349Sfs*3
10 weeks
(c.1044_1057del)
10 weeks; 8 episodes
1 fatal episode at 2 years
SD, SS and impaired RF
during hepatitis
Died at 2 years
3.3 [17] KSA
Male
Hyperglycaemia at
6 weeks
p.V349Sfs*3
(c.1044_1057del)
2 years; once proceeded 1 fatal episode at 2 years
to acute hepatic failure
No
Died at 2 years
4.1 [17] KSA
Male
DKA at 8 weeks
p.V349Sfs*3
(c.1044_1057del)
18 months; 4 episodes
(first after reporting)
1 episode (after first
reporting)
No
Alive at 6 years
5.1a
KSA
Male
Hyperglycaemia at
2 years
p.W163X (c.491G>A)
2.4 years; once
proceeded to acute
hepatic failure
1 treated conservatively
Impaired RF during
hepatitis episode
Alive at 5 years
6.1a
KSA
Male
Hyperglycaemia at
1.5 years
p.N420Tfs*14
(c.1259del)
2.5 years; once
proceeded to hepatic
failure
1 fatal episode at 7 years
SD, SS and impaired
RF during hepatitis
Died at 7 years
7.1
Jordan
Male
DKA and hepatitis at p.G1010D
6 weeks
(c.3029G>A)
6 weeks; 4 episodes
1 fatal episode at
3.5 years
SD, SS, PH, ASD, DD
and epilepsy
Died at 3.5 years
8.1a
Kuwait
Male
Hyperglycaemia at
15 days
FS 523STOP
(delGAAA1639-42)
10 months; once
proceeded to acute
hepatic failure
1 fatal episode at
10.5 months
Impaired RF during
hepatitis episode
Died at 10.5 months
9.1
Iraq
Male
Hyperglycaemia at
7 weeks
p.W520X (c.1560G>A)
No
No
No
Alive at 14 months;
siblings died of WRS
10.1
Lebanon
Female
DKA at 11 weeks
p.R1064X (c.3190C>T)
11 months; 1 episode
recovered
spontaneously
No
Impaired RF during
hepatitis and deafness
Alive at 15 months;
siblings died of WRS
11.1
Oman
Male
Hyperglycaemia at
4 weeks
p.Y588X (c.1764T>G)
10 months; 6 episodes
2 episodes, 1 led to death
Neutropenia, SD, SS, FTT, Died at 6.5 years; had
liver biopsy for
DD and ADHD
persistent hepatomegaly
11.2
Oman
Female
DKA and hepatitis at p.Y588X (c.1764T>G)
6 weeks
6 weeks; 5 episodes
1 treated conservatively
Neutropenia and FTT
Alive at 5 years
12.1
UAE
Female
DKA at 6 weeks
8 weeks; 9 episodes
1 treated conservatively
Anaemia and RH
Alive at 10 months; had
liver biopsy
p.W430X (c.1290G>A)
Liver in WRS
Table 1. (continued)
Horm Res Paediatr 2015;83:190–197
DOI: 10.1159/000369804
Patient Country
of origin
Gender Age at diagnosis and
presenting features
EIF2AK3 mutation
Acute hepatitis – age
at 1st episode and
frequency
Acute hepatic failure –
age at onset, number,
and outcomes
Other features
Prognosis/comments
12.2
Female
DKA at 10 weeks
p.W430X (c.1290G>A)
11 weeks; 7 episodes
4 episodes treated
conservatively
SD, SS anaemia,
neutropenia,
squint and RH
Alive at 2.5 years; had
liver biopsy
12.3 [4] UAE
Male
DKA and hepatitis at p.W430X (c.1290G>A)
7 weeks
7 weeks; 7 further
episodes
1 fatal episode
SD, SS, anaemia,
neutropenia and RH
Died at 7 years
12.4 [4] UAE
Male
DKA and hepatitis at p.W430X (c.1290G>A)
6 weeks
6 weeks; >8 episodes
3 episodes, 1 resulted in
death
SD, SS, anaemia,
neutropenia and RH
Died at 4 years
12.5 [4] UAE
Male
DKA at 6 weeks
p.W430X (c.1290G>A)
8 weeks; once/3
months
6 episodes, 1 resulted in
death
SD, SS, anaemia,
neutropenia and RH
Died at 5 years
12.6
Female
Hyperglycaemia and
hepatitis at 7 weeks
p.W430X (c.1290G>A)
7 weeks; 6 episodes
4 episodes treated
conservatively
Pancytopenia, FTT and
RH
Alive at 2.4 years; had
liver biopsy
13.1 [4] UAE
Male
Hyperglycaemia at 14 p.I650T (c.1949T>C)
months
1 episode at 2 years;
none since transplant
1 episode led to
transplant
Anaemia, SD and SS
Alive at 8 years
14.1 [4] UAE
Male
DKA at 8 weeks
p.G956E (c.2867G>A)
10 weeks; >15 episodes 1 fatal episode (after
reporting)
SD, SS and anaemia
Died at 15 years (after
initial reporting)
15.1
UAE
Male
Hyperglycaemia at 8
weeks
p.E524X
(c.1567_1570del)
9 months; 3 episodes
1 episode treated
conservatively
SD and anaemia
Alive at 18 months
16.1
UAE
Female
DKA at 6 weeks
p.? (c.1427-?_2490+?del) 8 months; 2 episodes
1 fatal episode
No
Died at 2.9 years
17.1
Kuwait
Male
Hyperglycaemia at 2
months
p.S991N (c.2972G>A)
2 episodes treated
conservatively
DD, SD, SS and PH
Alive at 17.5 years
18.1
Sudan
Male
Hyperglycaemia, at 2 p.P269fs (c.802_803dup) No
months
No
DD and SD
Alive at 3.5 years
19.1
Sudan
Female
Hyperglycaemia at 2
months
p.Y989X (c.2967T>A)
No
No
No
Alive at 3 years; twin
brother healthy
20.1
Sudan
Male
Hyperglycaemia at 2
months
p.? (c.1647+2T>A)
No
No
FTT
Alive at 2 years
UAE
UAE
14 months; 2 episodes
All mutations listed are homozygous. KSA = Kingdom of Saudi Arabia; UAE = United Arab Emirates; DKA = diabetic ketoacidosis; FTT = failure to thrive; SS = short stature; RF = renal function; ADHD = attention deficit hyperactivity disorder; ASD = atrial septal defect; RH = recurrent hypoglycaemia; DD = developmental delay. All nucleotide and amino acid numbering refers to transcript AF110146.1, which contains 7 leucine residues in the microsatellite region of exon one. The c.1427-?_2490+?del and c.1647+2T>A mutations have been listed at
the protein level as p.?, which denotes that the protein has not been analyzed, although an effect is expected.
a These samples were tested outside Exeter.
193
100%
Diabetes
85.7%
Liver disease
50%
Skeletal dysplasia
42.8%
Short stature
32.1%
Anaemia
Neutropenia
21.4%
Renal impairment
21.4%
Recurrent hypoglycaemia
21.4%
17.8%
Failure to thrive
14.3%
Developmental delay
7.1%
Primary hypothyroidism
Fig. 1. Frequency of clinical features of
0
2
4
6
WRS in 28 Arab patients expressed as
number and percentage of the total patients
(features reported once are not included).
ceeded to fatal AHF; however, in the remaining 21 patients the episodes were intermittent, lasting for 3–20
days, with full recovery except in patient 11.1 who continued to have persistent hepatomegaly. The highest liver transaminase levels during the episodes varied between patients from 242 to 50,000 IU/l (mean 8,620).
22/24 patients experienced at least one episode of AHF.
Of these, 13 died, 8 recovered with conservative management and 1 child was treated by liver transplantation
(LT). This child (13.1) was diagnosed with diabetes at
14 months old and needed LT at 28 months to treat his
first AHF. The genetic diagnosis of WRS was subsequently confirmed. During a 6-year post-transplant follow-up, he maintained normal liver function without
hepatitis, and his average HbA1c was 7.8%. He remained
short due to marked hip and knee deformities; however,
his average growth velocity over the last 3 years was
6 cm/year (online suppl. fig. S1; for all online suppl.
material, see www.karger.com/doi/10.1159/000369804).
Liver biopsy was performed between hepatitis episodes
in 4 patients. In 12.1, 2 and 6, it was for a second opinion and in patient 11.1 for persistent hepatomegaly before the genetic testing was conducted. The histological
features were variable between the 4 patients including
markedly swollen hepatocytes with rarefied cytoplasm,
occasional necrotic hepatocytes, minimal fibrosis and
cholangiopathy.
194
Horm Res Paediatr 2015;83:190–197
DOI: 10.1159/000369804
8
10 12 14 16 18 20 22 24 26 28 30
Number of patients
Genotype
Genetic diagnosis was confirmed in all 28 patients
(table 1). 25 patients were tested in Exeter, while patients
6.1, 7.1, and 11.1 were tested elsewhere, and the results
were provided by their physicians. 17 different homozygous EIF2AK3 mutations were identified of which 2,
p.S991N and p.G1010D, were novel. Both mutations affect residues that are highly conserved across species, and
in silico analysis predicts that both substitutions are disease causing (Alamut Interactive Biosoftware, version
1.5, Rouen, France). The most frequent mutation,
p.V349Sfs*3 (c.1044_1057del), was detected in 3 families
followed by p.W430X (c.1290G>A) identified in 2 families (6 patients from an extended family; online suppl. fig.
S2). There was no genotype-phenotype correlation apart
from longer survival of 17.5 years associated with the p.
S991N mutation, and a delayed age at onset of 14 months
with the p.I650T mutation.
Discussion
We studied the genotype and phenotype of 28 patients
with WRS from 8 Arab countries. Two novel EIF2AK3 mutations and 18 new patients were described. This is the first
study to focus on liver disease in WRS, and it also provides
long-term data on the first child with WRS to undergo LT.
Habeb et al.
All patients presented with diabetes, and liver disease
was the commonest extra-pancreatic feature and the
cause of death in all deceased children. The frequency of
hepatic disease in our cohort was 85% compared to 60%
reported by Ozbek et al. [5]. The most likely explanation
for the higher frequency of liver disease in our cohort is
the availability of long-term follow-up data on some of
our patients. Of the 10 reported patients in this series, 2
experienced their first hepatitis episode after the initial
report and 3 died of AHF during follow-up. Of note, our
patients without liver disease were younger than 3.5 years.
Considering the disease course in this cohort, we suspect
that all of them might eventually develop liver disease.
Children with WRS typically present in the first few
months of life with diabetes, and it is recommended that
any child of consanguineous parents presenting with diabetes within the first 6 months of life should be tested
for EIF2AK3 mutations [4]. All our patients presented
with diabetes; however, 3 of them were diagnosed at 14,
18 and 24 months, making a total number of 4 WRS
cases with delayed onset reported to date [3]. We suggest
that WRS should be considered in children of consanguineous families diagnosed with diabetes within the
first 2 years of life. Of the 4 mutations detected in patients with delayed presentation, the p.N656K and
p.I650T missense mutations were only reported in these
patients and appear to be associated with delayed onset
of WRS. Both were located close to each other on the
first kinase domain of PERK protein residue, and the
p.N656K mutation was shown to have a residual kinase
activity, which may explain the delayed onset in that patient [3]. However, the other 2 mutations (p.W164X and
p.N42Tfs*14) were reported in other patients with early-onset WRS [3, 4, 16]. The mean survival age in our
cohort was 5.8 years, which is similar to the figure reported by Ozbek et al. [5]. However, a mild course and
prolonged survival of 32 and 35 years was reported in 2
patients with the missense mutations p.F593 and p.L646,
respectively [3, 4, 14]. Interestingly, our longest surviving patient of 17.5 years has mild liver disease and was
homozygous for a novel missense mutation (p.S991N).
It is possible that these 3 missense mutations are associated with residual kinase activity of the PERK protein
resulting in a mild phenotype and prolonged survival;
however, functional studies are required to clarify this
hypothesis.
In agreement with previous reports [3, 4, 16, 17], we
found a variation in the phenotype between patients
with the same mutation. The exact cause of this phenomenon is still unclear; however, it seems likely that
other genetic and environmental factors influence the
tissue response to the mutant PERK protein. Primary
hypothyroidism (PH) has been recently reported in 3
patients with WRS [4, 18, 19]. We add 2 further patients
(7.1 and 17.1) with PH, supporting the suggestion that
PH is a new feature of this syndrome. Recurrent hypoglycaemia was occasionally described in WRS [20, 21],
and studies in Perk knockout mice suggested a role of
impaired hepatic gluconeogenesis [22]. Despite the high
frequency of liver disease in our cohort, symptomatic
hypoglycaemia was only documented in 6 patients with
liver disease from a family with a p.W430X mutation.
The only child with this mutation without recurrent hypoglycaemia was from a different family and experienced just one episode of hepatitis. It is possible that the
p.W430X mutation is linked to recurrent hypoglycaemia in patients with frequent hepatitis, or the family has
another predisposing factor for hypoglycaemia. SD is an
essential criteria of WRS; however, its frequency in our
cohort was lower than previously described [2, 5]. It is
possible that some of our patients were still too young to
develop it or have no regular skeletal survey to detect
subtle skeletal changes.
All our patients with liver disease presented with
non-autoimmune hepatitis triggered by viral illnesses,
and most of them recovered completely from the initial
episodes. However, in 3 children the first hepatitis attack
proceeded to fatal AHF. This indicates that the course of
WRS-related hepatitis is unpredictable and that every
episode should be considered as potentially fatal. WRSrelated hepatitis usually manifest after the onset of diabetes; however, Engelmann et al. [23] described a child
with WRS in whom the first hepatitis episode developed
a few months before diabetes, and 25% of our patients
had hepatitis at initial diagnosis along with diabetes. The
exact mechanism of liver dysfunction in WRS is unknown; however, the fact that the episodes are triggered
by viral illness and other stresses suggest the inability of
liver cells to deal with endoplasmic reticulum stress due
to EIF2AK3 mutations. We noticed a variation in the age
at onset, frequency, and prognosis of hepatitis between
patients. The fact that this variation was documented in
7 children with the p.W430X mutation and 5 patients
with the p. V349Sfs*3 suggests that the severity of liver
disease is not related to the specific mutation. In this series, the prognosis of acute liver failure was not related
to the age, gender or the number of hepatitis episodes
(results not shown). However, the retrospective nature
of our study limited our ability to define the role of other clinical or laboratory variables in the prognosis of
Liver in WRS
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DOI: 10.1159/000369804
195
liver disease in WRS. The histological findings in our 4
patients who had liver biopsy were also variable even
between children with the same mutation. Although liver biopsy may be useful in understanding the mechanism of liver disease, given the availability of genetic
testing, we feel that its clinical value in WRS is very limited.
The management of liver disease in WRS is a challenge as the mortality is high and the course is unpredictable. Our practice is to ensure that families recognize the symptoms of hepatitis, and we request parents
to bring the child to hospital for possible admission if
he/she develops flu-like illness or other stress. We prefer
early assessment in a tertiary care liver unit, so a care
plan is prepared to avoid any delay in starting the management of AHF. Confirming the genetic diagnosis,
particularly in patients with first hepatitis episodes or
atypical features, would avoid the need for invasive tests
such as liver biopsy. LT has been successfully used in
some children with hereditary disorders [24]; however,
to the best of our knowledge, its use in WRS has been
limited to 2 children: the first one was our patient 11.1,
and the second was a 6-year-old girl described in a recent media report [25]. Our patient had the transplantation at 2.4 years of age following his first AHF, and the
diagnosis of WRS was not confirmed at that time. The
LT saved his life and appeared to cure the liver disease.
The improvement of his diabetes control is unlikely to
be directly related to the LT, but may be reflecting a better lifestyle with no recurrent hepatitis. His SD led to
severe hip and knee deformities, explaining his short
stature; however, his recent growth was comparable to
other children with liver transplant [26]. Our experience with this child suggests that LT would be a successful therapy for WRS patients; however, more data are
needed to make it a standard treatment for WRS. As
WRS affects other organs such as pancreatic β-cell and
kidneys, combined organ transplant may be an option
for these patients. Clearly, the decision of transplantation should take into account the neurocognitive function of the child as some WRS patients have significant
neurodevelopmental delay.
In conclusion, WRS should be considered in children
of consanguineous families diagnosed with diabetes within the first 2 years of life. In this condition, liver disease is
more common than previously reported, has unpredictable course and carries high mortality. The first experience of LT in WRS is encouraging.
Acknowledgement
This study was partially funded by Wellcome trust. S.E. is a senior Wellcome trust investigator.
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