Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy
in an infant with homozygous E189X BSCL2 mutation
B. Frigulsa, W. Coroleua, R. del Alcazara, P. Hilbertb, L. Van Maldergemb,*, G. Pintos-Morella
aDepartment of Paediatrics, ‘‘Germans Trias i Pujol’’ Hospital, Badalona, Autonomous University of Barcelona, Spain
bCentre de Ge ´ne ´tique Humaine, Institut de Pathologie et de Ge ´ne ´tique, Gosselies, Belgium
a r t i c l e i n f o
Received 2 March 2008
Accepted 26 October 2008
Available online 12 November 2008
Berardinelli-Seip congenital lipodystrophy
a b s t r a c t
Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive condition associating
insulin resistance, absence of subcutaneous fat and muscular hypertrophy. Disease-causing mutations
have been described in AGPAT2 and BSCL2 genes. Hypertrophic cardiomyopathy is a classical late (third
decade) complication which has only been occasionally described in childhood. We report on a 4-month
-old Chinese male infant who presented with a severe BSCL ‘‘cardiac’’ phenotype comprising heart
failure, hypertension and hypertrophic cardiomyopathy.
? 2008 Elsevier Masson SAS. All rights reserved.
Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare
autosomal recessive metabolic disorder usually presenting at birth
or in early infancy with lipoatrophy, acromegaloid features, lack of
subcutaneousfat and hypertriglyceridemia.
comprises progressive insulin resistance leading to diabetes usually
in the second decade of life. Because of the absence of functional
adipocytes, lipid is stored in other tissues, including muscle and
liver. The syndrome was first reported by Berardinelli in 1954 
and described in greater detail by Seip in 1959 . After identifi-
cation of disease-causing mutations in two genes located in 9q34
and 11q13 (AGPAT2 and BSCL2) [3,4], patients were described
worldwide. Little information is available about putative alterations
of these genes in Asian subjects. A series of patients in Japan  and
recently one case in China  presenting BSCL2 mutations have
been described. We report a Chinese male infant with an early
onset and a severe phenotype carrying a BSCL2 mutation.
1.1. Case report
A 4-month-old male infant, born to unrelated Chinese parents,
was hospitalized because of polypnea. On admission he presented:
respiratory rate: 67/min, Hb saturation: 97%, heart rate: 200/min,
blood pressure: 150/60 mmHg (SBP was 40 mmHg over the 95th
percentile for age and gender, DBP was on the 75th percentile) and
had abundant sweating. The infant had a peculiar phenotype. The
hair was dry and thick. Hirsutism was noticed in the face (with low
frontal hairline), trunk and limbs. Hands and feet were enlarged
(acromegaloid features) (Fig. 1a). Lipoatrophy affecting trunk,
limbs, bottom and face with empty cheeks was observed (Fig. 1b),
together with prominent muscles and veins. A 3/6 heart murmur
was heard in the apex. Abdominal distension with marked hepa-
tomegaly was noted.
Laboratory results indicating profound metabolic changes at
admission compared to follow-up are shown in Table 1. Serum
leptin was not detectable. His bone age was significantly advanced.
Abdominal ultrasound revealed an enlarged liver with homoge-
neously increased echogenicity indicating severe steatosis. The
pancreas was hyperechogenic by sonography but the abdominal CT
showed no pancreatic collections or necrosis. The echocardiogram
displayed left ventricular hypertrophy, the septum (IVS: 11 mm, NV
for his BSA: 4.5–5.5 mm) more than the posterior wall (LVPW:
6 mm, NV: 4–5 mm), with a ratio of 1.83 (Fig. 2a). This classified
him as having severe asymmetrical septal hypertrophy (ASH), as
ASH is defined as a ratio ?1.4. Doppler study showed a maximum
gradient of the left ventricle outflow tract of 99.6 mmHg indicating
the presence of an obstructive dynamic pattern at mesoventricular
level (Fig. 2b). In conclusion, the cardiac ultrasound exam with
Doppler-colour showed a severe obstructive and asymmetrical
septal hypertrophic cardiomyopathy (Fig. 3).
Clinical diagnosis of Berardinelli-Seip syndrome was confirmed
by the identification of a stop codon in BSCL2 using molecular
* Corresponding author. Present address: Centre de Ge ´ne ´tique Humaine,
Universite ´ de Lie `ge, Domaine universitaire du Sart-Tilman, 4000 Lie `ge, Belgium.
E-mail address: firstname.lastname@example.org (L. Van Maldergem).
Contents lists available at ScienceDirect
European Journal of Medical Genetics
journal homepage: http://www.elsevier.com/locate/ejmg
1769-7212/$ – see front matter ? 2008 Elsevier Masson SAS. All rights reserved.
European Journal of Medical Genetics 52 (2009) 14–16
genetic testing as described by Magre ´ et al. . The patient was
found to be homozygous for the mutation c.565G>T or p.E189X in
exon 5. Both parents were heterozygous for the same mutation. The
p.E189X is a nonsense mutation replacing a glutamic acid residue
byprematurestop codon at position 189 leading tothe formation of
a truncated seipin protein. The patient had a normal 46XY
With the diagnosis of pancreatitis (serum lipase 477 U/L), we
initiated parenteral nutrition containing: 14 g/kg/day carbohy-
drates, 2 g/kg/day proteins, 2.5 g/kg/day lipids (with the minimum
amount of essential fatty acids and MCT). After 15 days the
analytical parameters improved (lipase 393 U/L, triglycerides
5.3 mmol/L), then an oral formula (Monogen?: containing 90%
MCT, 10% LCT) was introduced using standard dilution (17.5%) in 6
regular meals adjusting the caloric need for age. After 2 months
with the dietetic treatment a reduction of serum glucose, insulin
and triglycerides was observed and liver enzyme levels were
almost normalized (Table 1). The cardiac failure and the high blood
pressure were controlled with oral propranolol solution (dose
2 mg/kg/day). The haemodynamic parameters improved in 4
weeks, presenting after this time a blood pressure of 100/50 mmHg
and a heart rate 120 per min. The hyperinsulinemia with hyper-
glycemia was easily corrected with the dietary treatment, but the
HbA1c is progressively increasing suggesting a possible prediabetes
After 2-year follow-up period no more complications have been
detected. He is currently presenting normal values, returned
rapidly to normal range (Table 1), has a blood pressure of 130/80
Fig. 1. Physical appearance at an age of 4 months. (a) Triangular face, micrognatia,
enlarged tongue, low implanted ears and empty cheeks. (b) Lipoatrophy affecting
trunk and bottom, with prominent muscles.
Main laboratory results at first hospitalization and during follow-up.
Fig. 2. (a) Cardiomyopathy with asymmetrical septal hypertrophy (IVS ¼11 mm). (b)
Doppler study showed the presence of an obstructive dynamic pattern of the left
ventricle outflow tract (maximum gradient: 99.6 mmHg).
B. Friguls et al. / European Journal of Medical Genetics 52 (2009) 14–16 15
(parents withdraw beta-blocker treatment), no arrhythmias has Download full-text
been detected, and the IVS is measuring 12.5 mm thick (NV for his
BSA: 5-7). The maximum gradient of the left outflow tract detected
is 14mmHg at rest.
It is unusual to have major complications early in life in patients
with BSCL. In our case, the triad of major diagnostic criteria
(lipoatrophy, acromegaloid features, hypertriglyceridemia) lead to
the diagnosis of BSCL at the early age of 4 months. In addition he
presented life-threatening complications such as systemic arterial
hypertension, hypertrophic cardiomyopathy with heart failure and
pancreatitis. These major complications are only occasionally
reported in infants with BSCL, although they were previously
described in older patients. The pE189X mutation seems particu-
larly harmful taking into account the early onset presentation with
a severe cardiac affection and a poor prognosis. The only other case
reported having the same mutation, is a 7-year-old Chinese child
presenting early onset diabetes, liver cirrhosis and left ventricle
hypertrophy . One can speculate on the putative deleterious
nature of the pE189X mutation identified. As described, BSCL
patients are homozygous or compound heterozygous, and most of
the BSCL2 mutations are nonsense or frameshift mutations that are
expected to cause loss of function of the protein .
has been already reported in a 7-year-old female  and in a 17-
year-old male .
Cardiac involvement in CGL has been reported in the literature
[9–15] but there are no cases describing early onset cardiac failure,
as in our case. Bjornstad et al.  reported 6 cases of BSCL pre-
senting myocardial hypertrophy, and Rheuban et al.  described
4 other similar cases. The average age at diagnosis in Bjornstad’s
series, confirmed by Rheuban was 20 years. A single case with an
early onset hypertrophic cardiomyopathy has been reported in
a Portuguese child who had evidence of ventricular hypertrophy at
the age of 6 months, but she was not symptomatic until the age of
10 years . The mechanism causing hypertrophic cardiomyop-
athy in patients with genetic insulin resistance syndrome as BSCL,
and therefore with hyperinsulinemia, may result from the insulin
action in the receptors of Insulin-like growth factor I (IGF-1)
present in the myocardial tissue [10,12]. This is based on the
occurrence of myocardial hypertrophy in children of diabetic
mothers . Hypertension was also present in a few patients with
BSCL and myocardial hypertrophy at second or third decade of life
In summary, we present a male infant with severe BSCL
expression, early in life, harboring the pE189X seipin gene trun-
cating mutation. We emphasize the extremely severe cardiovas-
cular manifestation in this infant, with systemic hypertension and
hypertrophic cardiomyopathy leading to cardiac failure. Thus, the
p.E189X mutation in BSCL may be associated with serious cardio-
vascular alterations beginning very early in life.
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