Available via license: CC BY 4.0
Content may be subject to copyright.
Received:
19 October 2015
Revised:
06 February 2016
Accepted:
15 February 2016
Cite this article as:
Capobres T, Sabharwal G, Griffith B. A case of I-cell disease (mucolipidosis II) presenting with short femurs on prenatal ultrasound and
profound diaphyseal cloaking. BJR Case Rep 2016; 2: 20150420.
CASE REPORT
A case of I-cell disease (mucolipidosis II) presenting
with short femurs on prenatal ultrasound and profound
diaphyseal cloaking
THOMAS CAPOBRES, MD, GAURAVI SABHARWAL, MD and BRENT GRIFFITH, MD
Department of Radiology, Henry Ford Health System, Detroit, MI, USA
Address correspondence to: Dr Thomas Capobres
E-mail: thomasca@rad.hfh.edu
ABSTRACT
A 28-year-old G3 P1 SAB1 female with no prior health concerns was found to have a foetus with short femurs on
prenatal ultrasound following an abnormal maternal serum screen result. Fluid obtained by amniocentesis revealed
an elevated
a
-fetoprotein level with absence of an acetylcholinesterase band and normal male karyotype (46,XY).
Follow-up ultrasound 3 weeks later again demonstrated short femur lengths, but no other abnormalities. At birth,
the child was noted to have multiple dysmorphic features, including short humeri and femurs, coarse facial features,
retrognathia and yellowish hypertrophic gums in addition to hyperbilirubinaemia and thrombocytopenia.
Radiological studies demonstrated bony demineralization with profound diaphyseal cloaking in the long bones.
Genetic testing diagnosed I-cell disease.
BACKGROUND
Mucolipidosis II (I-cell disease) is a lysosomal storage dis-
order caused by deficiency of N-acetylglucosamine-1-
phosphotransferase. Nearly all lysosomal hydrolases are
elevated in the plasma and body fluids of affected individ-
uals because of the failure of targeting lysosomal acid
hydrolases to the lysosomes. It is characterized by the
presence of cytoplasmic inclusions in cultured fibroblasts
(I-cell phenotype).
1,2
There is a significant amount of var-
iability in the disorder in terms of age of onset, tissue/
organ involvement and radiological findings.
2
Despite the
heterogeneous manifestations, the disorder typically
presents between 6 and 12 months of age with clinical
symptoms that include marked growth deficiency, coarse
facial features, severe skeletal abnormalities, developmen-
tal delay and gingival hyperplasia.
3–5
The presenting
radiological findings at that time are often of severe dys-
ostosis multiplex, although these findings vary depending
on the stage at which they are found.
1,2
Recognizing the potential prenatal and early postnatal
findings of I-cell disease allows earlier diagnosis. Given
the universally fatal prognosis, early diagnosis is crucial in
helping affected families plan and cope with the outcome.
We present a case with both prenatal and early postnatal
findings of the disease.
CASE REPORT
Clinical presentation
A 28-year-old G3 P1 SAB1 female with no prior health
concerns was found to have an abnormal integrated mater-
nal serum screen indicating a 1 : 7 risk for trisomy 18. Foe-
tal ultrasound at 19 weeks gestation revealed short femurs
(< 2.5%) and an otherwise normal examination. A multi-
disciplinary approach was taken, including a genetics con-
sult. The family history was notable for one nephew with
“weak bones”. The patient and her husband reported that
they were of Yemeni ancestry and distantly related. A rec-
ommended amniocentesis was performed, which showed
increased
a
-fetoprotein at 2.26 MoM and absence of an
acetylcholinesterase band. Chromosome analysis revealed
a normal male karyotype (46,XY). Follow-up ultrasound at
22 weeks gestation again demonstrated short femurs, mea-
suring 3.5 cm (< 2.5%) (Figure 1). Biparietal diameter, head
and abdominal circumference measured between the 39th
and 55th percentiles. The patient chose to forgo further fol-
low-up with genetics, and the remainder of the pregnancy
was otherwise uneventful.
The baby was born by C-section at 37 4/7 weeks gestation
owing to foetal decelerations. Upon delivery, the infant was
found to have hoarse cry, weak reflexes and low tone. Mul-
tiple dysmorphic features were discovered, including short
humeri and femurs; bowed lower legs; narrow chest; large
ear lobes; retrognathia; yellowish hypertrophic gums and a
BJR|case reports http://dx.doi.org/10.1259/bjrcr.20150420
© 2016 The Authors. Published by the British Institute of Radiology. This is an open access article under the terms of the Creative Commons Attribution
4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are
credited.
low, flat palate; hypertrichosis of the bilateral temporal region;
and light hair colour that was atypical for his ethnic background.
He exhibited diffuse patchy ecchymoses on the trunk and persis-
tent thrombocytopenia as well as hyperbilirubinaemia. Echocar-
diogram showed a small atrial septal defect and a large patent
ductus arteriosis. The infant also experienced respiratory dis-
tress, requiring continuous positive airway pressure ventilation.
Investigations/imaging findings
Radiological investigation at that time revealed the following:
▪diffuse demineralization of bony structures (Figure 2)
▪profound diaphyseal cloaking of the long bones
(Figures 2 and 3)
▪relatively short humeri and femora (Figure 2)
▪poorly formed and irregular appearing proximal
humeral and femoral metaphyses (Figures 2 and 3)
▪thickened and poorly formed clavicles (Figure 2)
▪thickened and shortened ribs with an abnormally
increased cardiothoracic ratio (Figure 2)
▪poorly formed iliac bones with flattening of the
acetabular roofs (Figure 4)
▪unusual bowing of the distal ulna and radius with
metaphyseal cupping (Figure 3)
▪thickening of the proximal phalanges and
minimal narrowing at the proximal aspect of the
metacarpal bones.
Genetics service was consulted. Tests revealed elevated levels of
multiple plasma and leukocyte lysosomal hydrolases, consistent
with a diagnosis of I-cell disease. GNPTAB gene analysis
revealed homozygous c.376_379delTTAG deletion mutations.
This deleterious mutation has not been reported previously in
individuals with I-cell disease.
Outcome
The patient was eventually discharged to the care of hospice
and passed away at 5 weeks of age. Additional information
regarding the case was limited as an autopsy was declined
by the family.
However, the parents did follow-up with genetics several
months later for future family planning. When the wife became
pregnant again later that year, chorionic villous sampling was
obtained at 10 weeks gestational age and sent to test for
I-cell disease. Uridine diphosphate-N-acetylglucoseamine-1-
phosphotransferase enzyme activity was low, consistent with
I-cell disease. Soon after obtaining these results, the family
Figure 1. Prenatal ultrasound at 22 6/7 weeks gestational age
demonstrates short femurs measuring 3.5 cm (< 2.5%).
Figure 2. Skeletal survey demonstrates diffuse demineraliza-
tion of bony structures and relatively short humeri and femora.
Figure 3. The humerus demonstrates poorly formed and irreg-
ular appearing proximal metaphyses and profound diaphyseal
cloaking. The forearm demonstrates unusual bowing of the
distal ulna and radius with metaphyseal cupping.
BJR| case reports Capobres et al
2 of 4 birpublications.org/bjrcr BJR Case Rep;2:20150420
chose to terminate the pregnancy at 15 weeks. Chorionic vil-
lous testing was again obtained during a fifth pregnancy, and
testing revealed that this child was neither affected nor a carrier
of the abnormal GNPTAB gene. This child was born at full
term without any health concerns.
DISCUSSION
I-cell disease is a rare lysosomal storage disorder that typically
remains undiagnosed until later in the first year of life, as facial
features coarsen, growth failure becomes increasingly apparent
and the Hurler-like clinical picture develops.
3,5
It is caused by
mutations in the GNPTAB gene, located on chromosome 12,
and inherited in an autosomal recessive manner. In the appro-
priate clinical setting, such as when a family history of the
disorder is known, foetal I-cell disease can be suggested sono-
graphically by the demonstration of abnormally shortened
long bones and intrauterine growth retardation.
6
Other sono-
graphic features that have been described in the literature
include periosteal cloaking of the femora and humeri and tran-
sient maxillary defects.
7
In our case, the only abnormality
found on prenatal ultrasound was bilateral short femora
(< 2.5%). No other signs of intrauterine growth retardation or
additional sonographic abnormalities were present. In the
absence of a known family history, prenatal diagnosis of I-cell
disease remains difficult as many other conditions can present
with similar findings.
The postnatal features of I-cell disease are more classic and have
been better characterized in the literature. A study of nine cases
of the disease by Lemaitre et al
1
in 1978 discussed the specific
radiological features of the disorder and distinguished I-cell dis-
ease from other storage disorders.
In their study, the authors divided the radiological manifestation
of I-cell disease into two groups——Stage A, an early stage; and
Stage B, a late stage.
1
Stage A includes the neonatal period and
the first 2 months after birth, while Stage B starts after the age of
4 months.
1
The early stage is typically characterized by a storage osteopathy
with bone structural and modelling abnormalities, stippling of
the epiphyses and elements of a storage disorder.
1
These signs
evolve during the intermediate stage with disappearance of the
bone structural abnormalities and the signs of a storage disease
becoming more pronounced.
1
In the late stage, the skeletal man-
ifestations are of an early and severe dyostosis multiplex.
1
The
late stage findings, while apparent at 4–6 months, continue to
become more obvious as the patient grows older.
Despite the early stage findings described, I-cell disease typi-
cally goes undiagnosed until later in the first year of life. In the
study by Lemaitre et al,
1
seven of the nine cases were diagnosed
after the neonatal period. More recently, David-Vizcarra et al
8
attempted to better define the natural history and early osteo-
dystrophic features of I-cell disease. They described neonatal
radiographic findings in 15 cases of I-cell disease that were
similar to those seen in neonatal hyperparathyroidism.
8
Later
studies have also presented cases manifesting similar radio-
graphic findings with markedly elevated alkaline phosphatase
and parathyroid hormone levels as well as normal serum cal-
cium levels suggesting severe secondary hyperparathyroidism.
9
However, the aetiology of severe secondary hyperparathyroid-
ism in I-cell disease is unclear.
8,9
In their study, David-Vizcarra
et al
8
concluded by emphasizing the need for further studies
regarding the pathophysiology of osteodystrophy in I-cell dis-
ease and the need for more definitive characterization of the
early clinical manifestations.
8
Our case demonstrates many of the features described in the
early stage of the disease, including diffuse bony demineraliza-
tion, shortened long bones with periosteal apposition, poorly
formed metaphyses with cupping, thickened and shortened ribs
and clavicles, flattened acetabular roofs and rectangular meta-
carpals with coning of the proximal ends. However, it is the dra-
matic degree of periosteal apposition, or diaphyseal cloaking,
seen in the long bones that sets this case apart from previously
reported cases.
Diaphyseal cloaking is thought to be due to increased remodel-
ling of the bone. It is typically unilamellar, although it has been
described in some cases as general periostitis. In earlier studies,
it has been described as a poorly defined contour or a double
outline image. In addition, it is typically seen in the diaphyseal
region of the bones.
In the current case, the degree of cloaking was more dramatic
than in previously reported cases of I-cell disease. In addition,
the cloaking did not have the appearance of simple periosteal
apposition, but demonstrated a more solid appearance. Adding
to the uniqueness of the case, the cloaking was not confined to
the diaphyses but rather extended to the metaphyseal regions.
Another unique aspect of our case is the persistent thrombocy-
topenia, which has not been previously described in reported
cases of I-cell disease presenting in the neonatal period. Could
this also relate to the marked degree of periosteal cloaking in our
patient? Subperiosteal haemorrhage, as seen in cases of infantile
scurvy, can appear similar to diaphyseal cloaking, although in
the former case this appearance is not confined only to the
diaphyseal regions.
10
Perhaps the dramatic degree of periosteal
cloaking in our case represents excessive subperiosteal new bone
Figure 4. The pelvis demonstrates poorly formed iliac bones
with flattening of the acetabular roofs and irregular appearing
proximal femoral metaphyses with periosteal cloaking.
Case re port: A case of I-cell disease with characteristic f indin gs on pre natal U S BJR| case reports
3 of 4 birpublications.org/bjrcr BJR Case Rep;2:20150420
formation in the setting of subperiosteal haemorrhage either in
addition to, or even as opposed to, sequelae of secondary hyper-
parathyroidism. Unfortunately, an autopsy was not performed
on our patient. Future studies with note of any associated
thrombocytopenia as well as pathologic correlation are needed
to investigate this hypothesis.
Given the universally fatal prognosis of I-cell disease, early
diagnosis is crucial in helping affected families cope with the
outcome. While prenatal sonographic features of the disorder
are non-specific, recognizing them in the appropriate clinical
setting is paramount in making the diagnosis. When the prena-
tal diagnosis is not made, radiologists can play an important
role in suggesting the possible diagnosis. We have presented a
case with prenatal short femurs and dramatic neonatal osteo-
dystrophic features. In addition to supporting the classically
defined radiological manifestations of early I-cell disease, we
also offer a unique hypothesis that early stage finding of
diaphyseal cloaking could also relate to subperiosteal haemor-
rhage. Further studies are needed to better understand the
pathophysiology behind the characteristic early osteodystrophy
seen in I-cell disease. Larger case series are also necessary to
fully characterize the early manifestations of the disease. With
continued work in these areas, earlier diagnosis of this univer-
sally fatal disease may be possible.
LEARNING POINTS
1. I-cell disease is a rare lysosomal storage disorder that
typically goes undiagnosed until later in the first
year of life, as facial features coarsen, growth failure
becomes increasingly apparent and a Hurler-like clinical
picture develops.
2. Findings on prenatal ultrasound are variable but may
include abnormally shortened long bones, intrauterine
growth retardation, periosteal cloaking of the femora and
humeri, and transient maxillary defects.
3. The early stage from the neonatal period through
2 months after birth is typically characterized by storage
osteopathy with bone structural and modelling
abnormalities, stippling of the epiphyses and
elements of a storage disorder. The late stage starts
after the age of 4 months and is typically characterized
by skeletal manifestations of an early and severe
dyostosis multiplex.
4. The pathophysiology of the early osteodystrophy seen in
I-cell disease is currently poorly understood. Better
defining the early clinical and radiological manifestations
is key to achieving earlier diagnosis of this universally
fatal disease.
CONSENT
Despite exhaustive efforts undertaken by the researchers to con-
tact the family of the deceased patient, they could not be
reached, and thus informed consent could not be obtained.
However, the case report has been sufficiently anonymized so as
to prevent harm to the patient's family as confirmed by
Dr Ezhuthachan, Head of Neonatology at Henry Ford Hospital.
REFERENCES
1. Lemaitre L, Remy J, Farriaux JP, Dhondt JL,
Walbaum R. Radiological signs of
mucolipidosis II or I-cell disease. A study of
nine cases. Pediatr Radiol 1978; 7: 97–105.
doi: http://dx.doi.org/10.1007/BF00975678
2. Aynaci FM, Cakir E, Aynaci O. A case of
I-cell disease (mucolipidosis II) presenting
with craniosynostosis. Childs Nerv Syst 2002;
18: 707–11. doi: http://dx.doi.org/10.1007/
s00381-002-0627-7
3. Pazzaglia UE, Beluffi G, Campbell JB,
Bianchi E, Colavita N, Diard F.
Mucolipidosis II: correlation between
radiological features and histopathology of
the bones. Pediatr Radiol 1989; 19:
406–13. doi: http://dx.doi.org/10.1007/
BF02387638
4. Unger S, Paul DA, Nino MC, McKay CP,
Miller S, Sochett E. Mucolipidosis II
presenting as severe neonatal
hyperparathyroidism. Eur J Pediatr 2005;
164: 236–43. doi: http://dx.doi.org/10.1007/
s00431-004-1591-x
5. Hochman JA, Treem WR, Dougherty F,
Bentley RC. Mucolipidosis II (I-cell disease)
presenting as neonatal cholestasis. J Inherit
Metab Dis 2001; 24: 603–4. doi: http://dx.
doi.org/10.1023/A:1012428113606
6. Babcock DS, Bove KE, Hug G, Dignan PS,
Soukup S, Warren NS. Fetal mucolipidosis II
(I-cell disease): radiologic and pathologic
correlation. Pediatr Radiol 1986;
16: 32–9. doi: http://dx.doi.org/10.1007/
BF02387502
7. Chen M, Ke YY, Chang SP, Lee DJ,
Chen CH, Ma GC. Prenatal transient
alveolomaxillary defect in a case of
mucolipidosis II (I-cell disease). Ultrasound
Obstet Gynecol 2010; 36: 255–6. doi: http://
dx.doi.org/10.1002/uog.7620
8. David-Vizcarra G, Briody J, Ault J, Fietz M,
Fletcher J, Savarirayan R. The natural history
and osteodystrophy of mucolipidosis types II
and III. J Paediatr Child Health 2010; 46:
316–22. doi: http://dx.doi.org/10.1111/j.
1440-1754.2010.01715.x
9. Heo JS, Choi KY,Sohn SH, Kim C, Kim YJ,
Shin SH. A case of mucolipidosisII presenting
with prenatalskeletal dysplasiaand severe
secondaryhyperparathyroidism at birth.
Korean J Pediatr 2012; 55: 438–44. doi: http://
dx.doi.org/10.3345/kjp.2012.55.11.438
10. Ghedira Besbes L, Haddad S, Ben Meriem C,
Golli M, Najjar MF, Guediche MN. Infantile
scurvy: two case reports. Int J Pediatr 2010;
2010: 1–4. doi: http://dx.doi.org/10.1155/
2010/717518
BJR| case reports Capobres et al
4 of 4 birpublications.org/bjrcr BJR Case Rep;2:20150420
