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Nigerian J Paediatrics 2017 vol 44 issue 1

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7Alagille syndrome in an eleven year old Nigerian child A case report
Niger J Paediatr 2017; 44 (1): 35 - 38
CASE REPORT
Ahmed P
Alagille syndrome in an eleven
Wey YO
Uno MG
year old Nigerian child – A case
report
DOI:http://dx.doi.org/10.4314/njp.v44i1.7
Accepted: 8th November 2016
Abstract : Background
Alagille
head, flat nasal bridge, prognathia
syndrome (AGS) is a rare cause of
and genetic report of no mutation
Ahmed P
(
)
prolonged jaundice.
It has an
in JAG 1 gene, karyotype 46XX.
Wey YO, Uno MG
autosomal dominant inheritance
At the time of current hospital ad-
Department of Paediatrics,
National Hospital Abuja, Nigeria
pattern expressed variably, with a
mission she was in addition small
Email: ahmedpatience@yahoo.com
reported incidence of 1:100,000
for age, had hepatosplenomegy,
live births in the United States.
ascities and talked irrationally.
The objective is to highlight the
Chest radiograph showed multiple
clinical features and diagnostic
butterfly vertebrae; Echocardio-
challenges to this rare cause of
graph aortic and pulmonary steno-
cholestatic jaundice.
sis; Liver aminotransferase were
Case Report: T.O, Female 11
marked elevated. Brain MRI
years, had a history of recurrent
showed multiple chronic infarcts.
episodes of yellowness of the
She was diagnosed with Allagille
eyes, first noticed soon after birth,
syndrome presenting in hepatic
associated with pale stools, dark
failure with encephalopathy.
urine, and body itching. From age
Conclusion: Allagille syndrome
three she was noticed to have pro-
should be considered early in older
gressive loss of sight, recurrent
children with persistent cholestatic
body swellings and irrational
jaundice.
talks. She was diagnosed to have
a cardiac murmur at age six, when
Key words: Allagille, syndrome,
diagnosis of ALS was made due
cholestatic, jaundice, hepatic en-
to features of, recurrent jaundice
cephalopathy and congenital heart
and perculiar facies of broad fore-
disease.
Introduction
(JAG1) gene; with less than one percent of cases result-
ing in a mutation in the notch-2 ( NOTCH2) gene as the
cause.
7,8,9
Alagille syndrome is a complex hereditary disorder that
The JAG1 gene provides instructions for mak-
is associated with cardiac, hepatic, skeletal, ocular, renal
ing a protein called Jagged-1, which is involved in an
and facial abnormalities first reported by Alagille et al.
important pathway by which cells can signal to each
in 1969. Peculiar facie, chronic cholestasis, posterior
1
other. The Jagged-1 protein is inserted into the mem-
embryotoxon, butterfly like vertebral arch and peripheral
branes of certain cells, connected with other proteins
pulmonary artery stenosis are the main features that
called Notch receptors, which are bound to the mem-
characterize syndromic paucity of interlobular bile
branes of adjacent cells. These proteins fit together like
duct.
2,3,4
Common facial features
include broadened
a lock and it’s key. When a connection is made between
forehead, pointed chin, and elongated nose with bulbous
the Jagged-1 and Notch proteins, it launches a series of
tip, which may not be obvious during infancy but may
signaling reactions (Notch signaling) that affects cell
functions.
8,9
become more apparent as the child ages. The ocular ab-
Notch signaling controls how certain types
normalities
5
of posterior embryotoxon, an opaque ring
of cells develop in a growing embryo, especially cells
present in the cornea, were seen in about 75percent of
destined to be part of the heart, liver, eyes, ears, and
patients reported in one large series conducted by Emer-
spinal column. The Jagged-1 protein continues to play a
ick et al. Other ophthalmologic findings reported in-
6
role throughout life in the development of new blood
clude retinitis pigmentosa, pupillary abnormalities, and
cells. The NOTCH2 gene provides instructions for mak-
anomalies of the optic disc.
ing a protein called Notch2, a member of the Notch fam-
ily of receptors. The lack of Notch signaling causes er-
Alagille syndrome is an autosomal dominant disorder
rors in development that result in missing or narrowed
with variable expression. Mild-to-moderate mental retar-
bile ducts in the liver, heart defects, distinctive facial
dation may also be present. Most cases of Alagille syn-
features, and changes in other parts of the body. People
drome are caused by a mutation in the JAGGED1
with JAG1 gene mutations may have one or more of
36
these problems. The syndrome has been mapped to the
longed bleeding was noticed from puncture site, with
chromosome 20 (20p12-jagged-1 locus) JAG1.
8, 9
A mi-
epistaxis while on admission. She had a history of poor
nority (6-7percent) of patients have complete deletion of
growth when compared to her other sibs. She was found
JAG1 , and approximately 15-50percent of mutations are
to be small for age, ill looking and deeply icteric
spontaneous.
10,11
In the United State, reported incidence
(greenish tinge), with sparse fluffy hair, broad forehead,
rate is approximately one case in every 100,000 live
flat nasal bridge and prognathia (fig 1 and 2). She had
births. Alagille syndrome is the fourth leading indica-
12
poor oral hygiene with a cross bite dentition. She was,
tion for liver transplant.
13
The first reported case in
pale, acyanosed, afebrile, with digital clubbing of grade
Nigeria was by Akinyinka et al in 1998.
14
3 and bilateral pitting edema up to the knees. She had
The objective of this case report is therefore to highlight
neck retraction, thin long limbs, broad wrist and elbow
the clinical features and diagnostic challenges of this
joint with rachitic rosary, genu valgum. She was drowsy
rare cause of cholestatic jaundice.
with irrational talks had neck stiffness and increased
muscle tone. Eye examination showed bilateral optic
Case Report
atrophy. Her precordium was hyperactive with a palpa-
ble thrill; normal first and second heart sounds with a
T.O, a female presented at age of 11 years with a history
grade 4 pansystolic murmur loudest at the left upper
of recurrent yellowness of the eyes since birth, progres-
sternal border radiating to the axilla and root of the neck.
sive loss of sight and recurrent body swelling of over
Her abdomen was distended with prominent abdominal
5years, reversal of sleep and irrational talk of a month
veins, tense generalized vague tenderness with moderate
duration.
ascites. The diagnosis was Alagille syndrome with he-
Jaundice was noticed on the first day of life and this was
patic failure and encephalopathy.
present most days with only few days jaundice free in
between episodes. It progressively deepened with asso-
Her chest radiograph revealed multiple butterfly verte-
ciated passage of pale stools and dark urine. There was
brae (fig 3) and brain magnetic resonance imaging
associated body itching and generalized whitish body
(MRI) multiple chronic infarcts involving the right pa-
rash in early childhood. At about age 3, she was noticed
rietal lobe and the basal ganglia (fig 4). Laboratory in-
to have been bumping into objects from gradual loss of
vestigations revealed deranged liver function test with
sight. This led to her withdrawal from formal school to a
an 8-fold increase aspartate aminotransferase (AST), a 2
school for the blind. She had a fall about this time and
-fold rise alanine aminotransferase (ALT) and Gamma
sustained a fracture of her left femur and was subse-
glutamyltranspeptidase (GGT), a 9-fold rise Alkaline
quently home schooled. The body swelling involved the
phosphatase (AP); prolonged prothrombin time (PT) and
lower limbs and abdomen mainly. She was seen at vari-
partial thromboplastin time (PTT), and abnormal inter-
ous hospitals and treated for the yellow eyes and body
national normalization ration (INR); decreased serum
swellings with several medications that included urosor-
proteins and albumin. Viral serology markers; namely
dil 750mg twice daily to reduce itching. She was re-
hepatitis B surface antigen (HBsAg) or anti-HBV core
viewed by an ophthalmologist for her poor vision and
(anti-HBC) for hepatitis B infection and Hepatitis C
treated for the pathological fracture by the orthopedic
virus (HCV), anti- HCV for hepatitis C infection and
surgeon. Because of heart murmurs she was diagnosed
HIV screening were negative. Others were hypokalemia,
to have ventricular septal defect (VSD) at 8months and
hypocalcemia, hypophosphatemia, and thrombocyto-
at 6years with aortic and pulmonary stenosis following
penia. She had intravenous unasyn, oral neomycin and
echocardiography evaluation and had surgery in India.
lactulose and other supportive care. Parents were coun-
With the combinations of clinical features of cholestatic
seled on need for liver transplant. By the second week of
jaundice, visual impairment, cardiac lesions and genetic
admission patient deteriorated and became comatose and
testing, she was diagnosed to have Allagille syndrome at
was bleeding from the nose and puncture sites and died
the age of 6years old. Her karyotype was 46XX, and
subsequently.
genetic analysis showed no mutation in JAG 1 gene.
Fig 1: Showing fluffy
Her pregnancy and delivery was supervised and mother
hair, deep jaundice, flat
well except for a history of polyhydramnios in the 3
rd
nasal bridge, broad nose
trimester. Birth weight was 2.4kg and immunization was
completed according to the National programme of im-
munization guideline. She had delay in walking until
2years old and eruption of teeth. She is the second of
four children in a monogamous non-consanguineous
marriage; other children alive and well. Father is a
49years old lawyer; mother is a 39years old caterer with
Fig 2: Showing broad
forehead and nose, with
tertiary level of education with no family history of a
flat nasal bridge, widely
similar illness.
spaced eyes
She presented to our health centre at age 11years with
deepening jaundice, increasing body swelling, reversal
of sleep and irrational talk of one month duration. Pro-
37
Fig 3: Showing multiple
consultations. Another report showed that affected chil-
butterfly vertebrae
dren were evaluated when younger than 6months for
either neonatal jaundice (70percent), or cardiac murmurs
and symptoms (17percent).
12
The case report had sub optimal growth with smallness
for age, fluffy hair changes and body swelling with low
proteins and albumin levels as features of chronic liver
disease. Sub optimal growth has been documented
12
as
a consequence of Alagille syndrome. The history of fall
and fractures could have been associated with presence
of rickets with other skeletal abnormalities. This case
Fig 4: Showing multi-
report had rickety rosary chest and ribs cage, hypoplasti-
ple cerebral infarcts
cenemal teeth, butterfly hemivertebrae and low serum
calcium and phosphate. Vitamin D levels could not be
determined. Emerick et al in a large series of patients
6
with Alagille syndrome reported the presence of butter-
fly hemivertebrae in half of the patients analyzed. Visual
loss from optic atrophy seen in this case has been re-
ported as part of a posterior embryotoxon, which was
observed in more than 75percent of patients in one large
series conducted by Emerick et al.
6
Treatment is usually supportive and some would require
liver transplant. As at 2010 ALGS has been reported as
Discussion
fourth most common cause of liver transplantation in
children. The case report died as a young adolescent
7
The case report was diagnosed Alagille syndrome
(ALGS) with hepatic failure and encephalopathy, an
after 15days on admission. The presence of significant
autosomal dominant multi-system disorder affecting
co- morbidities, that include cardiac malformation, cho-
several body systems based on clinical presentation. The
lestatic liver disease and vascular brain lesions seen in
case report did not have JAG1 mutation, hence the pos-
this case have been reported as some of the leading
causes of morbidity in patients with ALGS.
10,12
sibility of Notch 2 mutation. However, the typical clini-
cally consistent features of the syndrome has mutationin
JAG1 in up to 94percent of cases, with a small 2percent
A 20years predicted life expectancy in 75percent for all
having a mutation in NOTCH2. Some reports have
8,9
ALGS patients, 80percent for those not requiring liver
shown thatover half of individuals with mutations in the
transplantation, and 60percent for those who required
liver transplantation was reported by Emerick, et al .
6
gene did not inherit it from either parent, and thus have a
de novo mutation.
8,9,15
The case report lived up to young adolescent age before
death with the several morbidities. She did not have the
This case report had the constellation of five main
benefit of transplantation. Of the 41 cases in the Korean
symptoms consistent with ALGS,
2,3,4
namely chronic
report,eight patients died after a median period of 2.67
cholestasis characterized by the paucity of intrahepatic
years (range, 0.33-15 years) and those with combined
bile ducts, congenital cardiac anomaly involving pulmo-
severe liver and heart disease had the poorest survival
( P <0.001).
16
nary stenosis, butterfly-like vertebral abnormalities, ocu-
lar changes of posterior embryotoxon, and peculiar fa-
ALGS could be differentiated from other rare conditions
cial abnormalities (broad forehead, deep-set and widely
that present as cholestatic liver disease from its syn-
spaced eyes, small pointed chin, and saddle or straight
drome clinical features, laboratory tests and imaging
nose). The case report was diagnosed at about 6years of
studies.
age after several hospital visitations. The diversity of
symptoms and lack of routine genetic analysis may have
contributed to the delay diagnosis. In the case reported
by Akinyinka et al,
14
the characteristics facial features
Conclusion
suggestive of Alagille syndrome and the clinical and
echocardiological evidence of pulmonary stenosis were
Alagille syndrome is a rare syndrome, presenting as
first observed when the child was 58months. Because of
cholestatic liver disease, with peculiar features. Multid-
the diverse clinical features, diagnosis may be delayed
isciplinary approach in management is required and sur-
until established by age 4-5, which may explain why our
vival depends on severity of associated morbidities and
case report was diagnosed at age 6 after several hospital
available transplant facilities care.
38
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