Arch Dis Child 2001;85:415–420
415
ARC syndrome: an expanding range of phenotypes
K M Eastham, P J McKiernan, D V Milford, P Ramani, J Wyllie, W van’t HoV,
S A Lynch, A A M Morris
Department of
Paediatrics, James
Cook University
Hospital, Marton
Road, Middlesbrough,
Cleveland TS4 3BW,
UK
K M Eastham
Department of
Neonatology, James
Cook University
Hospital
J Wyllie
Liver Unit, Children’s
Hospital NHS Trust,
Birmingham B4 6NH,
UK
P J McKiernan
Department of
Nephrology, Children’s
Hospital NHS Trust,
Birmingham
D V Milford
Department of
Histopathology,
Children’s Hospital
NHS Trust,
Birmingham
P Ramani
Nephro-Urology Unit,
Institute of Child
Health, University
College London
Medical School,
London, UK
W van’t HoV
Department of Human
Genetics, 19
Claremont Place,
Newcastle upon Tyne
NE2 4AA, UK
S A Lynch
Department of
Metabolic Medicine,
Great Ormond Street
Hospital, London
WC1N 3JH, UK
A A M Morris
Correspondence to:
Dr Morris
morria1@gosh.nhs.uk
Accepted 20 August 2001
Abstract
Aim—To describe the clinical phenotype
in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis.
Methods—The medical records for six
patients with ARC syndrome were reviewed, presenting over 10 years to three
paediatric referral centres.
Results—All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient,
who presented with nephrogenic diabetes
insipidus. Although all patients had severe
cholestasis, serum ã glutamyltransferase
values were normal. Many of our patients
showed dysmorphic features or ichthyosis.
All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films
revealed abnormally large platelets.
Conclusions—ARC syndrome exhibits notable clinical variability and may not be as
rare as previously thought. The association of Fanconi syndrome, ichthyosis,
dysmorphism, jaundice, and diarrhoea
has previously been reported as a separate
syndrome: our observations indicate that
it is part of the ARC spectrum.
(Arch Dis Child 2001;85:415–420)
Keywords: arthrogryposis; renal tubular acidosis;
Fanconi syndrome, cholestasis
ARC syndrome refers to an association between
arthrogryposis, renal tubular dysfunction, and
cholestasis. Eleven pedigrees have been reported
since the association was first described in
1973.1–8 Autosomal recessive inheritance is suggested by the frequency of parental consanguinity and recurrence in siblings.
As more patients with ARC syndrome have
been identified, it has become apparent that
there is notable clinical variability, even within
the same family. AVected siblings with and
without arthrogryposis have been reported.8
Renal tubular dysfunction ranges from isolated
renal tubular acidosis to complete Fanconi
syndrome, and hepatic histology shows variable combinations of cholestasis, intrahepatic
biliary hypoplasia, giant cell hepatitis, lipofuscin deposition, and fibrosis, ultimately progressing to cirrhosis. Additional features have
been reported in some patients, including failure to thrive, nephrogenic diabetes insipidus,
neurogenic muscular atrophy (which appears
to be responsible for the arthrogryposis),
cerebral malformations, and nerve deafness.8
Most patients die by the age of 7 months, but
www.archdischild.com
those surviving longer have shown severe
developmental delay.8
We report a further six patients, from five
pedigrees. Additional clinical features in our
patients included dysmorphism, ichthyosis,
diarrhoea, recurrent febrile illnesses, and abnormal platelets. Similar features have been
reported by Deal et al in patients from four
consanguineous families9; we suspect that these
patients also had ARC syndrome.
Methods
We have reviewed all cases of ARC syndrome
referred to three paediatric centres in the UK,
over a 10 year period from April 1990. Clinical
features and results of investigations were
obtained from the medical records, and histology was reviewed.
Case reports
PATIENT 1
This girl was the first child of healthy, first
cousin, Pakistani parents. There is a complex
family history of intermarriage and three cousins
died as neonates of unknown aetiology. Pregnancy was complicated by oligohydramnios.
The baby had a birth weight of 3.23 kg, and was
noted to have a sloping forehead, small anterior
fontanelle, a high arched palate, a low set posteriorly rotated left ear, and redundant skin folds
in the neck. There was generalised hypotonia
and multiple contractures, including talipes calcaneovalgus, flexion contractures of the knees,
dislocated hips, radial deviation of the wrists,
and camptodactyly of the fingers (fig 1). Muscle
bulk of deltoid and triceps was notably reduced.
Within 72 hours, she developed renal tubular
acidosis and cholestatic jaundice. Diarrhoea,
recurrent sepsis, and failure to thrive ensued
despite treatment with sodium bicarbonate,
phenobarbitone, vitamin K, and a formula milk
high in medium chain triglycerides. The baby
died of pneumonia at 11 weeks of age.
Permission for autopsy was refused.
PATIENT 2
This female sibling of case 1 was born at term
with a birth weight of 2.99 kg. Antenatal scans
had shown oligohydramnios, reduced fetal
movements, and arthrogryposis. At birth, she
was noted to have upward slanting eyes, an alar
appearance to the mouth, a high arched palate,
and redundant posterior skin folds in the neck.
The baby was hypotonic with contractures
similar to her sister. She developed hyperchloraemic metabolic acidosis and jaundice on day 3
and was treated symptomatically. She died at
home at the age of 5 days. A liver biopsy specimen was obtained postmortem.
416
Eastham, McKiernan, Milford, Ramani, Wyllie, van’t HoV, et al
complicated by recurrent infections, including
bronchiolitis caused by respiratory syncytial
virus, and acute on chronic renal failure. He
died at 5 months of age.
PATIENT 5
Figure 1
Infant with ARC syndrome.
PATIENT 3
This boy was the third child of first cousin
Pakistani parents. His two siblings are healthy.
Antenatal scans showed hydronephrosis and
bilateral talipes equinovarus. He was delivered
by caesarean section for a footling breech presentation, with a birth weight of 3.37 kg.
Bilateral femoral fractures were identified
following delivery. He had a beaked nose, small
anterior fontanelle, lax skin, low set thumbs,
and cryptorchidism. Multiple contractures of
the lower limbs were present, including talipes
equinovarus, flexion contractures of the knees,
and dislocated hips. A skeletal survey showed
slender long bones and ribs. He developed
cholestatic jaundice and renal tubular defects,
including acidosis, by 10 days of age and was
treated with sodium bicarbonate, phosphate,
and potassium chloride supplementation. Subsequently, he had diarrhoea, recurrent fever,
and failed to thrive. Despite normal coagulation studies and platelet numbers, a liver biopsy
at seven weeks led to a haemoperitoneum,
which required laparotomy for evacuation. He
died at 3 months of age.
This girl, the second child of healthy first
cousin Pakistani parents, was born at term with
a birth weight of 2.84 kg. Reduced fetal movement had been noted from 28 weeks gestation;
multiple contractures were noted at birth,
including bilateral talipes equinovarus and
flexion contractures of the knees and hips.
Within 24 hours, she became hypoglycaemic
and hypothermic. At 12 days of age, she was
noted to be hypotonic with cholestatic jaundice, diarrhoea, poor feeding, and weight loss
(11% birth weight). Recurrent febrile illnesses
ensued and she failed to thrive, despite receiving 0.92 mJ/kg/day. At the age of 2 months she
developed polyuria and renal tubular acidosis.
A renal biopsy was undertaken at 3 months of
age, following which she bled heavily, despite
normal clotting studies and platelet numbers.
This led to a cardiac arrest from which she
could not be resuscitated. A younger sister has
recently been born with similar features, and a
maternal cousin has also had two children with
ARC syndrome.
PATIENT 6
This female infant was born by elective caesarean section, for breech presentation, with a
birth weight of 2.94 kg. The parents are first
cousins of Pakistani origin, and have one other
healthy child. The baby was noted to have lax
skin at the neck, radial deviation of the wrists,
talipes calcaneovalgus, and dislocated hips. She
had an undisplaced supracondylar fracture of
the right femur following delivery. She was
admitted at 18 days of age with poor feeding
and cholestatic jaundice. Stools were loose and
pale in colour. Blood thyroid stimulating
hormone was 65 mU/l (normal 0.4–3.5 mU/l)
with a free thyroxine of 12.4 pmol/l (normal
13.8–22.5 pmol/l). Transient hypothyroidism
was suspected and she was treated with thyroxine in addition to fat soluble vitamins, alpha
calcidol, and phenobarbitone. At 4 weeks of
age, she was noted to produce large quantities
of dilute urine, with evidence of nephrogenic
diabetes insipidus. She failed to thrive, developed cholestatic liver disease, and died at age
4–5 months.
Results
PATIENT 4
BLOOD FILMS
This male infant was born at term to
non-consanguineous Pakistani parents, with a
birth weight of 3.65 kg. There are five healthy
siblings. He was noted to be hypotonic with
right talipes equinovarus and mild flexion contractures of all limbs. He developed renal tubular acidosis and conjugated hyperbilirubinaemia by the age of 4 days. He failed to thrive
despite treatment with bicarbonate, fat soluble
vitamins, and a medium chain triglyceride
based feed. Cranial computed tomography
revealed a large porencephalic cyst in the left
cerebral hemisphere. The clinical course was
Blood films were available for patients 3, 4, 5,
and 6. In all cases these showed abnormally
large platelets, with a measured mean platelet
diameter, for patient 3, of 10 µm (normal 3
µm). Formal testing of platelet function was
not undertaken.
www.archdischild.com
RENAL INVESTIGATIONS
Table 1 summarises standard tests of renal
tubular function. Urinary protein:creatinine
ratios, measured in patients 3, 4, 5, and 6, were
raised in all (1355–4000 mg/mmol, normal
<20). Patients 1, 3, 4, and 5 had episodes of
417
ARC syndrome
Table 1
Renal and hepatic investigations
Patient
Blood pH
Bicarbonate (mmol/l)
Anion gap (mmol/l)
Urine pH
TRP (%)
Aminoaciduria
Glycosuria
Creatinine (µmol/l)
Bilirubin (µmol/l)
Total
Conjugated
Alkaline phosphatase (U/l)†
AST (U/l)
ALT (U/l)
ãGT (U/l)
1
2
Table 2
3
4
5
6
7.31
14.3
16
6.4
NK
+
+
76
7.25
16.8
15
6.4
NK
+
+
62
7.34
17.2
16
6.5
42
+
+
71
7.31
16
17
6.0
68
NK
NK
96
7.25
16
15
6.0
59.8
+
−
54
7.36
21.5
NK
5.6
74.1
−
−
69
287
183
832
NK
24
NK
95*
31
239
27
NK
24
252
204
1042
22
25
33
234
88
1475
328
273
NK
118
95
2258
68
44
58
162
154
1652
42
22
32
Normal
values
7.35–7.45
22–29
15–20
80–100
33–85
60–350
1–45
3–50
1–65
*No measurements were made beyond age 3 days.
†Serum phosphate concentrations were normal at the time of the raised alkaline phosphatase
values in all patients.
TRP, tubular reabsorption of phosphate; NK, not known; +, present; −, absent; AST, aspartate
transaminase; ALT, alanine transaminase; ãGT, ã glutamyltransferase.
hypernatraemic dehydration but nephrogenic
diabetes insipidus was proved only in patient 6
(maximum urinary osmolality after desmopressin acetate 250 mOsm/kg). Ultrasound
scans showed small dysplastic kidneys in
patients 1 and 2. In patients 3 and 4, there was
loss of corticomedullary diVerentiation and the
medulla appeared echobright, consistent with
nephrocalcinosis.
Renal histology was available for patients 4
and 5. Both biopsy specimens showed acute
and chronic inflammation of the interstitium
with focal multinucleate giant cell reaction to
the contents of an occasional ruptured tubule.
Tubular calcification was not evident. Electron
microscopic examination did not reveal any
significant abnormality. Patient 4 showed
features of multicystic dysplasia, comprising a
bar of cartilage with a few ducts and tubules
surrounded by concentric collarettes of immature mesenchyme. There was cystic dilatation
of many of the tubules. The glomeruli were
fetal in configuration and 10% showed focal
segmental and global sclerosis. The tufts were
retracted with expansion of the Bowman’s
space and occasional glomerular cysts. Renal
histology for patient 5 showed good preservation of tubules, without cystic dilatation. A few
glomeruli showed expansion of the Bowman’s
spaces, but no cysts were evident. There was no
glomerular sclerosis. Immunofluorescence for
immunoglobulins and complement components was negative.
LIVER INVESTIGATIONS
Table 1 summarises relevant biochemical
investigations. Ultrasound examination in patients 2–5 showed normal liver texture with no
biliary dilatation. Technetium labelled methyl
bromoiminodiacetic acid scans of biliary excretion were performed in patients 1, 4, 5, and 6.
In all cases, there was good uptake of isotope.
For patient 1, no isotope appeared in the gall
bladder or bowel after 48 hours, but patients 4
and 6 showed normal excretion. Patient 5
showed no excretion into the bowel at 5 weeks,
but this was shown on a repeat scan at 8 weeks
of age.
www.archdischild.com
Liver histology
Patient
2
3
4
5
Giant cell transformation
Paucity of bile ducts
Bile plugs or intracellular pigment
Bile ductule proliferation
Lipofuscin
Portal tract fibrosis
+
−
+
+
−
−
+
+
+
−
−
−
+
−
+
+
+
+
+
−
+
−
+
−
The liver biopsy specimens were examined
using haematoxylin and eosin, Masson trichrome, Elastin Van-Gieson, Reticulin, Periodic Acid-SchiV with and without diastase
digestion, Perls, Orcein, Schmorl’s, and long
Ziehl-Neelson stains. The renal biopsy specimens were examined at multiple levels using
haematoxylin and eosin, Martius scarlet blue,
silver methanamine stain, and Periodic AcidSchiV. Immunofluorescence studies were performed on patient 5. Liver and renal biopsy
specimens were examined by electron microscopy. Table 2 summarises liver histology.
NEUROMUSCULAR INVESTIGATIONS
Electromyography in patient 3 showed neurogenic changes with reduced compound muscle
action potentials. In patient 5, electromyography was normal but a muscle biopsy sample
showed atrophy with variable sized muscle
fibres, compatible with denervation. Neurogenic muscle atrophy was also seen in a muscle
biopsy sample from patient 4.
ADDITIONAL INVESTIGATIONS
Blood immunoreactive trypsin, measured in
patients 4 and 6, was raised in both (>1000 and
358 µg/l, respectively; normal <120). Sweat
chloride was not measured. In each pedigree,
investigations excluded chromosomal abnormalities, congenital infections, peroxisomal
biogenesis disorders, á1 antitrypsin deficiency,
galactosaemia, organic acidaemias, and amino
acidopathies. All patients had normal blood
lactate concentrations; normal CSF lactate
concentrations were shown in patients 3 and 5.
For patients 4 and 5, studies of the mitochondrial respiratory chain were performed on
muscle, with normal results.
Discussion
ARC syndrome is a rare autosomal recessive
condition. Over recent years it has become
apparent that the phenotype is variable; cases
may go undiagnosed as not all patients present
with the three cardinal features.1 4 5 It has also
been recognised that the condition encompasses syndromes originally thought to be distinct. Initially, patients were classified according to their hepatic histology into two groups,
characterised either by intrahepatic biliary
hypoplasia and giant cell hepatitis or cholestasis with lipofuscin deposition. In 1994, Horslen
et al found all the histological abnormalities in
a single patient and concluded that both
groups of patients had the same condition.2
Our six cases all had arthrogryposis, renal
tubular dysfunction, and cholestatic liver disease. The arthrogryposis is thought to result
from neurogenic muscle atrophy. Consistent
418
Eastham, McKiernan, Milford, Ramani, Wyllie, van’t HoV, et al
Table 3
Features in patients from the current series and those reported by Deal et al
Reference
Current series
Pedigree
1
AVected cases†
2 (1, 2)
Ethnic origin
Pakistan
Consanguineous
+
Arthrogryposis
+
Neurogenic muscle change
Fanconi syndrome
+
Nephrogenic diabetes insipidus *
Cholestasis
+
Lax skin
+
Ichthyosis
Sepsis/fevers
+
Diarrhoea
+
Failure to thrive
+
Abnormal platelets
Deal et al
2
3
4
5
1
2
3
4
1 (3)
Pakistan
+
+
+
+
*
+
+
1 (4)
Pakistan
−
+
+
+
*
+
1 (5)
Pakistan
+
+
+
+
*
+
1 (6)
Pakistan
+
+
3
Pakistan
+
+
+
+
*
+
2
Pakistan
+
+
+
+
*
+
1
Pakistan
+
+
2
Oman
+
+
+
*
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
−
+
+
+
+
+
+
+
+
*Episodes of hypernatraemic dehydration but nephrogenic diabetes insipidus not formally shown.
†Numbers in parentheses refer to case numbers in current series.
+, present; −, absent; blank, not mentioned.
with this, all our patients were hypotonic, and
in three, evidence of denervation was provided
by muscle histology or electromyography.
Most reported patients with ARC syndrome
have had multiple features of Fanconi syndrome, including aminoaciduria, glycosuria,
phosphaturia, and bicarbonate wasting. Renal
tubular acidosis has generally been the most
striking clinical abnormality, but many patients
have also had features to suggest nephrogenic
diabetes insipidus. Our patients all had renal
tubular acidosis and other features of Fanconi
syndrome, with the exception of patient 6, in
whom the principal renal tubular abnormality
was nephrogenic diabetes insipidus (table 1).
Patients 1, 3, 4, and 5 also produced large
quantities of dilute urine and had recurrent
episodes of hypernatraemic dehydration, although formal testing for nephrogenic diabetes
insipidus was not undertaken. Renal histology
is variable. Nephrocalcinosis has been noted in
several previous patients,1 3 5 7 8 but it was not
evident in either of our patients who underwent
renal biopsies. Multicystic dysplasia was the
main histological feature for patient 4, and in
patients 1 and 2, the ultrasound appearances
also suggested dysplasia. Renal histology for
patient 5 was compatible with interstitial
nephritis.
Liver histology in our patients diVered from
the usual pattern in a few minor respects. All
showed cholestasis with multinucleate giant
cell transformation of hepatocytes. Intrahepatic biliary hypoplasia and lipofuscin
Table 4
deposition were less consistent. Indeed,
patient 2 showed neither of these abnormalities. Previous cases have consistently shown at
least one of these changes.1–8 We do not
consider the absence of these changes to be
significant. The number of intrahepatic bile
ducts, for example, depends on timing and site
of the biopsy. Bile ducts develop from the hilar
region to the periphery of the liver; the
intrahepatic bile duct system is immature at
birth, and does not have an adult appearance
until one month post term.10 Histopathology,
therefore, depends on the timing and site of
the biopsy.
In addition to the three cardinal features of
ARC syndrome, our patients showed a number
of other features (table 3), most of which have
been described previously (table 4). Failure to
thrive has been a problem in all patients. Diarrhoea is common,2 5 and is probably secondary
to fat malabsorption. Presumably, this and the
renal tubular losses both contribute to the
patients’ universal failure to thrive. All our
patients and several previous patients have had
recurrent febrile illnesses.3 5 Patient 5 in our
series had ichthyosis, as did patients from four
previous pedigrees.3 7 8 Dysmorphic features
seen in our patients included lax skin (particularly in the neck), low set ears, high arched
palate, proximally placed thumbs, and cryptorchidism; all, except cryptorchidism, have
been noted previously.2 5 7 8
Features of published cases of ARC syndrome
Reference
1
2
Pedigree
1
1
AVected cases
Ethnic origin
2
Swiss
Consanguineous
+
Arthrogryposis
+
Neurogenic muscle change
Fanconi syndrome
+
Nephrogenic diabetes insipidus
Cholestasis
+
Lax skin
Ichthyosis
Sepsis/fevers
Diarrhoea
Failure to thrive
+
3, 4
6
7
8
1
1
2
3
1
1
1
2
1
2
Pakistan Asian
2
Italian
1
Italian
2
Italian
4
2
2
Portugal Lebanon
2
+
+
+
+
+
+
+
+
−
+
−
+
4
North
African
−
+
+
+/−
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
2
5
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+/−
+
+
+
+, present; −, absent; blank, not mentioned; +/−, present in some aVected members of pedigree but not others.
www.archdischild.com
+/−
419
ARC syndrome
Abnormally large platelets were seen in all
our patients for whom blood films were examined (patients 3, 4, 5, and 6). None of the
patients had thrombocytopenia and formal
studies of platelet function were not undertaken. The histories, however, suggest that the
patients may have had a bleeding tendency.
Thus, patients 3 and 5 suVered significant
bleeds following liver and renal biopsies,
respectively, despite normal clotting studies.
One previous patient with ARC syndrome also
died from haemorrhage following a liver
biopsy, despite normal clotting studies,3 and
another patient died as a result of a cerebral
bleed, though clotting studies were not reported in this case.8
In 1990, Deal et al described eight patients
with Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea.9 At the time,
few cases of ARC syndrome had been reported
and neither the variability nor the full range of
features was appreciated. Distinction was made
on the basis of liver histology and haematological findings. Liver histology in the patients of
Deal et al showed cholestasis and giant cell
transformation of hepatocytes but no lipofuscin deposition or bile duct hypoplasia. As
discussed previously, we do not now consider
these features necessary for the diagnosis of
ARC syndrome—neither was present in patient
2 from our series. The other distinguishing feature reported by Deal et al was an abnormality
of platelet morphology. Blood films were only
available in two cases. In both of these, platelets
were abnormally large, lacked alpha granules,
and had low concentrations of â thromboglobulin, platelet factor 4, and thrombospondin. The features were interpreted as
suggesting “grey platelet syndrome”, though
this is usually associated with thrombocytopenia11 (platelet numbers were normal in these
patients). As mentioned above, our patients
also had normal numbers of abnormally large
platelets. Other features reported by Deal et al,
such as dysmorphism and ichthyosis, were also
seen in our patients (table 3). We conclude that
the patients described by Deal et al suVered
from ARC syndrome.
While the pedigrees in our series and previous reports support an autosomal recessive
pattern of inheritance, the genetic basis for
ARC syndrome remains unknown. Most
causes of Fanconi syndrome involve a metabolic abnormality that reduces the availability
of ATP and thereby reduces sodium coupled
solute transport.12 We and others, however,
have been unable to identify a metabolic aetiology in ARC syndrome. A membrane transport defect might explain the combination of
Fanconi syndrome, cholestasis, neurological
dysfunction, and platelet abnormalities. In this
context, it is interesting to note that serum ã
glutamyltransferase values were consistently
normal in our patients (table 1). In most
cholestatic conditions, ã glutamyltransferase is
released from the biliary epithelium by the
detergent eVect of bile acids, leading to high
serum concentrations. Normal ã glutamyltransferase values are seen in progressive
familial intrahepatic cholestasis (PFIC), a
www.archdischild.com
group of autosomal recessive diseases characterised by progressive cholestatic liver disease
with impaired bile acid transport.13 Diarrhoea
is a major clinical feature of PFIC1, and was
seen in all our patients. PFIC1 is caused by a
mutation in a single gene, FIC1.14 FIC1 is
expressed in a wide variety of tissues, including
liver, brain, kidney, pancreas, and skeletal
muscle, and is particularly high in the small
intestine.14 It is possible that diVerent mutations in this gene may cause a more severe
phenotype, as seen in patients with ARC syndrome, and we consider the gene a good candidate.
A number of candidate genes causing
Fanconi syndrome have been identified in the
mouse. One such gene, hepatocyte nuclear factor 1 (HNF1), is a transcriptional activator of
many hepatic genes, and is predominantly
expressed in the liver and kidney.15 Mice
lacking HNF1 fail to thrive and die, around the
time of weaning, after a progressive wasting
syndrome and cholestasis. Mutant mice also
suVer from Fanconi syndrome and phenylketonuria. Raised phenylalanine concentrations
were not seen in our patients with ARC
syndrome; however, it is known that although
the mouse–man phenotype can correlate
closely, there can be discrepancies. We therefore consider that HNF1 is also a good candidate gene.
All of our patients and most of those
reported by Deal et al were immigrants from
Pakistan. This community has a high frequency
of consanguineous marriages; progress in
determining the aetiology of ARC syndrome is
most likely to result from identifying the
responsible gene by autozygosity mapping and
mutation analysis, using a candidate gene
approach.
We are grateful to Prof. PT Clayton and Drs C Close, A Duthie,
A Goldstein, and U Wariyar for allowing us to include their
patients, and to Dr C Wright for undertaking histopathology on
patient 2.
1 Lutz-Richner AR, Landolt RF. Familiare Gallengangsmissbildungen mit tubularer Neireninsurfizienz. Helv Paediatr
Acta 1973;28:1–12.
2 Horslen SP, Quarrell OWJ, Tanner MS. Liver histology in
the arthrogryposis multiplex congenita, renal dysfunction
and cholestasis (ARC) syndrome: report of three new cases
and review. J Med Genet 1994;31:62–4.
3 Di Rocco M, Callea F, Pollice B, et al. Arthrogryposis, renal
dysfunction and cholestasis syndrome: report of five
patients from three Italian families. Eur J Pediatr 1995;154:
835–9.
4 Di Rocco M, Reboa E, Barabino A, et al. Arthrogryposis,
cholestatic pigmentary liver disease and renal dysfunction:
report of a second family. Am J Med Genet 1990;37:237–
40.
5 Nezelof C, Dupart MC, Jaubert F, Elliachar E. A lethal
familial syndrome associating arthrogryposis multiplex
congenita, renal dysfunction and cholestatic pigmentary
liver disease. J Pediatr 1979;94:258–60.
6 Saraiva JM, Lenos C, Goncalves I, et al. Arthrogryposis
multiplex congenita with renal and hepatic abnormalities in
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Epilepsy and mortality
Children with epilepsy have an increased mortality rate but the
increase is largely confined to those with symptomatic epilepsy and
sudden unexpected death in epilepsy (SUDEP) seems to be rare in
childhood although adults with SUDEP often have epilepsy dating
from childhood. A Dutch study (Petra M C Callenbach and colleagues.
Pediatrics 2001;107:1259–63) has provided more data about children.
A total of 472 children aged 1 month to 16 years with newly
diagnosed epilepsy were followed up for 5 years during which nine died
(Mortality 3.8/1000 person years (seven times population expected
rate)). None of the 328 children with nonsymptomatic epilepsy died.
The nine deaths in the group of 144 children with symptomatic
epilepsy gave a mortality rate of 129/1000 person years (23 times
expected rate). Of these nine children, three had progressive
neurological disease (Niemann-Pick disease, cerebral ependymoma,
infantile ceroid lipofuscinosis) and six had a static encephalopathy.
None was thought to have died during a seizure and none was considered to be a case of SUDEP. Most deaths had a respiratory cause.
Children with nonsymptomatic epilepsy have a low risk of death
within 5 years of epilepsy onset. Children with symptomatic epilepsy
are at high risk of dying from pneumonia or other respiratory cause.
SUDEP did not occur in this series.
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