Differential clinical expression of multiple symmetric
lipomatosis in men and women
L Busetto1*, D Stra ¨ter1, G Enzi1, A Coin1, G Sergi1, EM Inelmen1and S Pigozzo1
1Department of Medical and Surgical Sciences, University of Padova, Italy
BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disease characterised by the growth of uncapsulated masses of
adipose tissue. MSL is associated with high ethanol intake and complicated by somatic and autonomic neuropathy and the
infiltration of adipose tissue at the mediastinal level. To date, the disease is considered as largely more prevalent in men.
OBJECTIVE: To provide a detailed description of the clinical aspects of MSL in women.
PATIENTS: A total of 11 women and 58 men with MSL.
MEASUREMENTS: Morphological aspect of patient, location of the lipomatous masses, alcohol intake, extension of lipomatous
tissue to the mediastinum, association with somatic and autonomic neuropathy, and metabolic profile.
RESULTS: All female patients had the obesity-like appearance of type II MSL and the most frequent locations of lipomatous
masses in women were at the proximal arms (90.9%) and legs (54.5%). Very few female patients (27.3%) presented with the
submental deposition of lipomatous tissue typical of both type I (97.3%; Po0.001) and type II (66.7%; Po0.05) male subjects.
An extension of the lipomatus tissue around the upper airways, associated with compression or dislocation of deeply located
mediastinal structures, was observed less frequently in women than in men. The presence of a high ethanol intake, the
association with somatic and autonomic neuropathy and the occurrence of a characteristic metabolic pattern (high HDL-
cholesterol, low LDL-cholesterol, high uric acid) were similar in men and in women.
CONCLUSIONS: Female patients with MSL had a sex-specific morphological aspect, characterised by a low occurrence of the
typical ‘Madelung collar’ and a usual obesity-like appearance.
International Journal of Obesity (2003) 27, 1419–1422. doi:10.1038/sj.ijo.0802427
Keywords: adipose tissue; lipomatosis; Madelung’s disease; Launois–Bensaude syndrome; female sex
Multiple symmetric lipomatosis (MSL) is characterised by the
formation of multiple nonencapsulated lipomas with a
symmetrical distribution and with sparing of distal arms
and legs.1The disease is frequently associated with high
ethanol intake and is characterised by a substantial disease-
related morbidity. Complications are represented by the
extension of the lipomatous tissue to the mediastinum, with
compression and infiltration of mediastinal structures, and
by somatic and autonomic neuropathy.2,3The natural course
of MSL was considered as slowly progressive, but a recent
long-term longitudinal study demonstrated a significant
disease-specific mortality, mainly explained by several cases
of sudden death.4
Since the first descriptions of the disease by Brodie,5
Madelung6and Launois and Bensaude,7MSL was considered
more prevalent in males, although different male-to-female
ratios were reported. Male-to-female ratio was 4:1 in a
previous review of the literature,8but it ranged to 30:1 in a
recently published series of 32 Korean patients with the
disease.9In our most recent study on the disease,4we
confirmed a male-to-female ratio of 30:1 in a series of 66
Mediterranean subjects. Since then, however, we had the
opportunity to observe several female cases of symmetrical
lipomatosis who presented some of the usual aspects of MSL,
but demonstrated some peculiar clinical features. These new
observations permitted the detailed description of the
differential clinical expression of MSL in men and women
reported in this study.
From 1973 to December 1999, 66 males and two females
patients with MSL were identified at our institution. The
long-term longitudinal follow-up of a part of this series was
Received 13 November 2002 ; revised 29 April 2003 ; accepted 25 June
*Correspondence: Dr L Busetto, Universita ` degli Studi di Padova,
Dipartimento di Scienze Mediche e Chirurgiche, Clinica Medica I,
Policlinico Universitario, Via Giustiniani 2, 35128 Padova, Italy.
International Journal of Obesity (2003) 27, 1419–1422
& 2003 Nature Publishing Group All rights reserved 0307-0565/03 $25.00
recently reported.4From January 2000 to December 2001, we
found a further nine women with MSL. Eight male patients
had incompletely collected clinical data and the present
report therefore focused on 58 men and 11 women with
MSL. All patients gave their informed consent to the study
procedures and to the use of their clinical data for research
purposes. No active treatments were given or diagnostic tests
were performed outside of those indicated by the standard
clinical care. In both sexes, the diagnosis of MSL required the
presence of multiple nonencapsulated lipomas and the
recognition that these fat masses are symmetric and that
the distal arms and legs are spared.1The origin of the masses
from adipose tissue was always confirmed by biopsy. The age
at the onset of the disease and the daily alcohol intake, as
evaluated from the patient’s statement and relative’s inter-
view, were recorded. Alcohol intake was categorised as low
(less than 50ml of ethanol per day), moderate (51–100ml of
ethanol per day) or elevated (more than 100ml of ethanol
per day).4Previous or current alcohol dependence was also
Patients were classified, according to the distribution of
lipomatous masses, as having type I or type II MSL.
According to our previous definition,2patients were defined
as type I MSL if the fatty tumours maintain the aspect of
distinct, well-circumscribed, grossly round masses protrud-
ing from the body surface, and as type II MSL if the
lipomatous tissue involves extensively and diffusely the
subcutaneous fat layer, giving to the patients the appearance
of simple obesity. The location and the size of the
subcutaneous lipomatous fat depots were evaluated on
photographic images with standardised magnification. The
presence and extension of deeply localised lipomatous tissue
were evaluated by computerised tomography of the neck and
the thoracic inlet. If clinically indicated, compression of the
oropharyngeal tract and infiltration of oropharygeal mucosa
were evaluated with video-laryngoscopy. Somatic neuropa-
thy was evaluated by neurological examination. Electromyo-
graphy (EMG) was performed for the determination of the
motor conduction velocity (MCV) at the ulnar and peroneal
nerves and of the sensory conduction velocity (SCV) at the
left sural nerve. An MCV of 44m/s was assumed as the cutoff
value for the diagnosis of motor neuropathy and an SCV of
43m/s as the cutoff value for sensory neuropathy.3Auto-
nomic neuropathy was evaluated by the Valsalva manoeuvre,
heart rate variations on deep breathing, R–R interval changes
at EKG during lying to standing manoeuvre, diastolic blood
pressure increments in sustained handgrip and postural
hypotension.10Finally, a selected set of laboratory examina-
tions, including red blood cell count, liver function tests,
blood glucose, total cholesterol and HDL cholesterol fraction,
triglycerides and plasma uric acid, was performed.
Results are expressed as means7s.d. In all statistical
analysis, a P-value less than 0.05 was considered to be
significant. Male and female patients with MSL were
compared with unpaired Student’s t-test for numerical
variables and w2test for categorical variables. Statistical
analysis was performed by using the SSPS statistical package,
version 10.0 (SSPS, Inc.).
The approximate age at the onset of the disease was
42.179.3y (range 20–71y) in men and 43.2712.9y (range
20–62y) in women. According to the distribution of lipoma-
tous masses, 37 men (63.8%) can be classified as having type I
MSL and 21 (36.2%) as having type II MSL. In women, no
cases of type I MSL were observed and all patients had the
obesity-like appearance typical of type II MSL. Mean BMI was
higher in women than in men (34.976.9 vs 26.776.6kg/m2;
Po0.01), and all female patients were overweight (range 26.9–
47.8kg/m2). In men, BMI spanned from leanness to extreme
obesity (range 19.4–51.5kg/m2). Anthropometric data accord-
ing to sex and type of MSL are presented in Table 1. No
significant differences in body weight or BMI were observed
between men and women with type II MSL.
Mean daily ethanol intake was 167710ml (range 0–500ml)
in men and 7575ml (range 0–150ml) in women (Po0.001).
In men, two patients (3.4%) were nondrinkers, 26 patients
(44.8%) showed a moderate alcohol intake and 30 patients
(51.8%) were heavy drinkers. In women, three patients
(27.3%) were nondrinkers, seven patients (63.6%) showed a
moderate alcohol intake and one patient (9.1%) was a heavy
drinker. In both sexes, no subjects with a low ethanol intake
were found. Current or past alcohol dependence was
declared by four out of 11 women (36.4%) and by five out
of 58 men (8.6%) (Po0.05).
The location of the subcutaneous lipomatous masses in
men and women is reported in Figure 1. In women, the most
frequent location was at the proximal arms (90.9%) and legs
(54.5%), followed by the dorsal and deltoid areas (54.4%),
the nucal region (45.5%) and the mammary region (18.2%).
Very few female patients (27.3%) presented with the
submental deposition of lipomatous tissue typical of both
type I (97.3%; Po0.001) and type II (66.7%; Po0.05) male
subjects. The morphological aspect of a typical female MSL
patient, as compared with a type I and a type II MSL man, is
shown in Figure 2.
An extension of the lipomatus tissue around the upper
airways, associated with compression or dislocation of
Anthropometric data according to sex and type of MSL
Women type II MSLMen type I MSLMen type II MSL
Body weight (kg)
Data are presented as mean7s.d. Patients were categorised as type I or type II
MSL according to the distribution of lipomatous masses (see Methods
section). No women with type I MSL were observed. Women and men were
compared by two-tailed Student’s t-test: *Po0.001. Men with type I and type
II MSL were compared by two-tailed Student’s t-test:wPo0.001.
Multiple symmetric lipomatosis in women
L Busetto et al
International Journal of Obesity
deeply located mediastinal structures, was observed at
computerised tomography of the neck and the thoracic inlet
in 34.7% of men and 20.0% of women. Symptoms related to
the deep extension of lipomatous tissue at the level of the
neck and of the thoracic inlet (dysphagia, excessive snoring,
sleep apnoea with hypersomnia) were also more frequent in
male than in female subjects (43.1 vs 9.1%, Po0.05). The
reported frequency of exertional dyspnoea was similar in
both sexes (13.8% in men, 18.2% in women), despite the
much higher prevalence of obesity observed in women.
In both sexes, the most frequently reported symptoms
were related to the presence of a somatic neuropathy. The
prevalence of paraesthesias and muscular cramps was similar
in men and women (46.6 vs 54.5% and 43.1 vs 27.3%,
respectively). EMG demonstrated the presence of motor
neuropathy in 78.8% of men and 60.0% of women. Mean
MCV was similar in male (40.174.9m/s) and female
(41.074.9m/s) subjects. Sensory neuropathy was detected
in 65.2% of men and 50.0% of women. Mean SCV was also
similar in male (39.976.6m/s) and female (42.077.9m/s)
subjects. Although the main symptom of autonomic neuro-
pathy (rest tachycardia) was reported only by a minority of
men and by no women, signs of autonomic involvement
were detected by specific testing in about three quarters of
patients in both sexes.
No significant sex-related differences were observed in
haematology and serum chemistry. The prevalence of type II
diabetes (6.4 vs 10.0%), hyperuricaemia (41.7 vs 50.0%),
hypercholesterolaemia (25.5 vs 30.0%) and hypertriglycer-
idemia (27.7 vs 20.0%) was similar in men and women. The
usual sex-related difference in HDL-cholesterol levels was not
detected in MSL patients, with both men and women
63.0724.2mg/dl, respectively) and very low LDL-cholesterol
values (97.7746.2 and 74.3719.5mg/dl, respectively). No
patients had clinical coronary heart disease. Abnormalities of
liver function tests were highly prevalent both in men
(54.2%) and women (66.7%) and were strictly related to
ethanol intake. Similarly, macrocytic anaemia was found in
37.7% of men and in 22.2% of women.
In this study, a detailed description of the differential clinical
expression of MSL in men and women was presented.
Although several female cases of MSL have been previously
published,11–13this series represents the larger sample of
women with MSL never reported and permits the complete
description of the signs and the symptoms of the disease in
females. Women with MSL shared some of the typical aspects
of the disease found in men, but had also some peculiar
clinical features. The clinical expression of MSL is therefore
The main differences between men and women were
detected in the morphological aspect of the patients and in
the location of lipomatous masses. In male patients, the
typical patient with MSL was highly characterised by the
submental deposition of fat (the ‘Madelung’s collar’)6and by
the protrusion of the lipomatous masses from the rest of
a lean body (type I MSL). In female patients, the submental
fat deposition was rare and all patients had the obesity-like
appearance typical of type II MSL. The more typical
morphological feature in women was instead represented
by the fat deposition at the proximal arms and legs, with
sparing of the distal limbs, which gave to the patients a
characteristic ‘football player’ appearance (Figure 2). The
reasons for the different location of lipomatous tissue in
male and female patients were unknown.
The low prevalence of submental fat deposition observed
in women was accompanied by a reduced rate of deep
infiltration of lipomatous tissue at the mediastinal level, as
demonstrated by computerised tomography. Compression,
dislocation and infiltration of structures around upper
airways and at the thoracic inlet, responsible for dysphagia,
snoring and obstructive sleep apnoea syndrome, were also
patients (white bars), in male patients with tipe II (light grey bars) and in
male patients with type I MSL (dark grey). w2test between men and women:
*Po0.05; **Po0.01; ***Po0.001.
Location of the subcutaneous lipomatous masses in female
circumscribed fatty tumours protruding from the body surface. Middle: Type II
MSL man, with a widespread deposition of lipomatous tissue mimicking the
appearance of simple obesity. Right side: MSL woman with sparing of the
submental area and prevalent fat deposition at proximal arms and legs. The
pictures of the two men have been previously published.4
Three patients with MSL. Left side: Type I MSL man, showing
Multiple symmetric lipomatosis in women
L Busetto et al
International Journal of Obesity
less frequent in women than in men. Exertional dyspnoea Download full-text
was frequently found in women, but it was probably related
to obesity and not to local factors. We previously described
three cases of severe mediastinal involvement with superior
vena cava syndrome and tracheal stenosis in men with MSL.4
No such cases occurred in women.
The association between MSL and high ethanol intake
previously reported in men2was also found in women.
Despite a lower mean daily alcohol intake, female patients
reported previous or current alcohol dependence four times
more frequently than male subjects. In particular, previous
alcohol dependence was admitted by all the three women
who did not drink at the current examination. Long-term
follow-up of MSL patients demonstrated that alcohol
discontinuation was associated with a slight regression of
lipomatous depots.4Therefore, abstinence from alcohol
should be achieved and maintained also in women.
The most frequently reported and troublesome symptoms
in male patients with MSL related to the presence of sensory,
motor and autonomic neuropathy. Neuropathy in MSL is
unrelated to the elevated alcohol intake, is characterised by a
decrease in myelinated nervous fibres and has to be
considered as a peculiar aspect of the disease.3,10,14Our
study proved that association with somatic and autonomic
neuropathy was also present in women with MSL. Clinical
and electrophysiological signs of somatic neuropathy were
found at a similar rate in men and women, and autonomic
neuropathy was highly prevalent in both sexes. In a recent
long-term longitudinal study, we observed three cases of
sudden death in MSL men with severe autonomic neuro-
pathy and without other cardiac abnormalities.4To date, no
longitudinal data were available in women.
Female patients with MSL shared with male subjects a
characteristic metabolic pattern. In both sexes, the lipid
profile was characterised by very high HDL-cholesterol
plasma levels and very low LDL-cholesterol concentrations.
Triglyceride levels varied widely, possibly in association with
ethanol intake, but their postprandial removal rate was
increased in MSL patients compared to normal subjects of
the same sex and age.15Both the increased HDL production
and the more rapid clearance of the triglyceride-rich
lipoproteins from the circulation was related to a very high
lipoprotein lipase activity of lipomatous tissue,16
probably explained the absence of coronary heart disease
in both sexes. Finally, female MSL patients in our study had
uric acid levels similar to males and half the women
presented with hyperuricaemia. Hyperuricaemia was fre-
quently reported in men with MSL17–19and is therefore one
of the more specific metabolic alterations in this disease.
In conclusion, we described in this study 11 women with
MSL. These women presented the high ethanol intake, the
association with somatic and autonomic neuropathy and the
characteristic metabolic pattern previously described in male
patients. However, the morphological aspects of female MSL
patients were different, with a low occurrence of the very
characteristic ‘Madelung collar’ and a usual obesity-like
appearance. This sex-specific morphological aspect could
have produced a certain degree of underdiagnosis of the
disease in women. In our personal experience, the male-to-
female ratio of MSL, previously quoted as 30:1,4should be
recalculated to about 6:1. However, MSL is a rare disease and
the true epidemiological significance of these data should be
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