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The Journal of Clinical Endocrinology & Metabolism 87(2):776 –785
Copyright © 2002 by The Endocrine Society
Body Fat Distribution and Metabolic Derangements in
Patients with Familial Partial Lipodystrophy Associated
with Mandibuloacral Dysplasia
VINAYA SIMHA
AND
ABHIMANYU GARG
Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of
Texas Southwestern Medical Center, Dallas, Texas 75390
Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder that is characterized by mandibular and clavicular hypoplasia, acroosteolysis, delayed closure of cranial
sutures, joint contractures, and mottled cutaneous pigmentation. It is also associated with partial lipodystrophy, but the
pattern of fat loss has not been well characterized. We studied
body fat distribution in two male and two female patients with
MAD by anthropometry, dual energy x-ray absorptiometry,
and magnetic resonance imaging. Blood glucose and insulin
responses during an oral glucose tolerance test and fasting
serum lipoproteins were determined. Three of the four subjects had loss of sc fat from the extremities with normal or
slight excess in the neck and truncal regions (termed type A
pattern). In contrast, one patient had generalized loss of sc fat
involving the face, trunk, and extremities (type B pattern). All
of the patients had normal glucose tolerance but had fasting
and postprandial hyperinsulinemia suggestive of insulin resistance. Elevated serum triglycerides with low high-density
lipoprotein cholesterol levels were noted in three subjects. We
conclude that familial partial lipodystrophy associated with
MAD presents with two types of body fat distribution patterns, both of which are associated with insulin resistance and
its metabolic complications. (J Clin Endocrinol Metab 87:
776 –785, 2002)
M
vestigate metabolic abnormalities associated with insulin resistance in these four patients.
ANDIBULOACRAL DYSPLASIA (MAD) is a rare autosomal recessive disorder [Mendelian Inheritance
in Man (MIM) no. 248370] that was first described by Young
et al. and Sensenbrenner and Fiorelli in 1971 (1, 2). The characteristic features of this syndrome include postnatal growth
retardation; craniofacial anomalies such as mandibular hypoplasia with dental overcrowding, bird-like facies with
prominent eyes, and beaked nose; skeletal anomalies such as
progressive osteolysis of the clavicles and terminal phalanges, delayed closure of the cranial sutures; and skin changes
such as mottled hyperpigmentation of the trunk and atrophy
over the hands and feet. Other features less commonly associated with this condition are hypogonadism or delayed
puberty (2– 4), bilateral sensory neural deafness (4, 5),
alopecia (6 – 8), high arched palate, and cutaneous calcinosis (9, 10).
Lipodystrophy and metabolic complications associated
with insulin resistance such as diabetes and hypertriglyceridemia have also been noted in some patients (5, 7, 11, 12).
However, the pattern of fat loss in these patients has not been
studied systematically and is not well characterized. The
main purpose of this investigation, therefore, was to study
distribution of adipose tissue in four patients with lipodystrophy associated with MAD by using anthropometry, dual
energy x-ray absorptiometry (DEXA), and whole-body magnetic resonance imaging (MRI) similar to our previous studies with different types of genetic lipodystrophies (13, 14).
Other aims were to describe the clinical features and to in-
Patients and Methods
Patient 1
Patient MAD 100.3 is a 20-yr-old Hispanic female, the first child of
healthy, unrelated parents. The pregnancy was uneventful; she was born
prematurely at 32-wk gestation with a birth weight of 2.6 kg. She had
normal growth and development during infancy and early childhood.
The parents first noticed rounding of her fingertips at age 4 –5 yr. She
also developed progressive micrognathia. By age 10 yr, progressive loss
of sc fat from the arms and legs was noted, which resulted in increased
muscular appearance. At the same time, excess deposition of fat was
noted in the face, neck, chest, and abdomen. She underwent surgical
excision of osteochondroma of the right hip at age 12 yr. She attained
menarche at age 13 yr and has had regular menstrual periods since. She
underwent reconstructive surgery for receding chin besides a rhinoplasty at age 15 yr. She had overcrowded teeth, necessitating extractions
of six teeth between the ages of 14 –15 yr. She was diagnosed to have
spinal cord compression at the level of the fifth cervical vertebra at age
17 yr, for which two vertebrae were removed and replaced by a bone
graft from the hip. There was no evidence of a neoplasm in the excised
vertebrae.
Physical examination revealed a height of 1.52 m and a weight of 43.5
kg. She had bird-like facies with prominent eyes, beaked nose, and a
small mouth. Fingertips were rounded with marked resorption of all
terminal phalanges, and flexion contractures of the fifth finger were
noted bilaterally (Fig. 1). The toes also had a clubbed appearance with
resorption of the terminal phalanges. There was mottled hyperpigmentation over the trunk besides acanthosis nigricans in the axillae. The liver
was palpable 7 cm below the right costal margin. Breast development
was Tanner stage 5, and pubic hair was Tanner stage 4 with no clitoromegaly. Excessive hair was noted on the face, arms, and legs, but she had
no axillary hair. There was no alopecia or premature graying. Subcutaneous fat was nearly absent from both the upper and lower extremities
with prominent muscles and superficial veins (Fig. 1). Loss of sc fat was
noted from the dorsum of the hands and feet with normal palmar and
plantar fat. She had increased fat deposition over the neck and face and
Abbreviations: DEXA, Dual energy x-ray absorptiometry; FPL, familial partial lipodystrophy; HDL, high-density lipoprotein; MAD,
mandibuloacral dysplasia; MRI, magnetic resonance imaging or image;
OGTT, oral glucose tolerance test.
776
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
J Clin Endocrinol Metab, February 2002, 87(2):776 –785 777
FIG. 1. Anterior and left lateral views of patient 1
showing loss of sc fat over the extremities leading to a
muscular appearance with prominent veins and increased fat over the neck and face. Note the mottled
skin hyperpigmentation over the trunk and the
rounded finger tips from resorption of the terminal
phalanges.
had a prominent dorsal cervical fat pad (buffalo hump) and double chin.
Radiographs and MRI studies showed clavicular hypoplasia with lateral
third of the clavicles deficient bilaterally, small mandibular rami, small
cervical vertebral bodies, and lytic defects in the skull and lower third
of the left femur.
vertebral bodies, and lucencies in the skull and femur. Routine laboratory tests revealed slightly elevated serum ␥ glutamyl transferase and
alanine amino transferase levels.
Patient 2
Patient MAD 300.4 is a 12-yr-old white male of Italian descent who
had an unremarkable birth and family history. Although his physical
growth had been normal, he had autism and mental impairment. Postnatal dysmorphic features included acro-osteolysis (resorption of terminal phalanges), stiff joints, clavicular hypoplasia, and mandibular
regression with dental overcrowding that necessitated tooth extractions.
Progressive fat loss had been noted from the limbs, with excess fat
around the face and in the submental region. His height was 1.33 m and
weight 40.5 kg. Routine laboratory tests showed a slightly elevated
serum alanine amino transferase level.
Patient MAD 100.4 is the 16-yr-old sister of the previously described
patient. She was born at full term after an uneventful pregnancy with
a birth weight of 3 kg. Rounding of the fingertips was noted at age 3– 4
yr, and like her sister, she developed crowding of the teeth leading to
dental extractions at age 8 yr. Loss of sc fat from the extremities was
noticed by age 10 yr. She had breast development at age 11 yr and
menarche at age 12 yr, but has had irregular menstrual periods. Physical
examination revealed a height of 1.41 m and weight of 42 kg. She had
similar dysmorphic features like her sister such as bird-like facies with
prominent eyes and beaked nose, resorption of the terminal phalanges
in the hands and feet, and mottled skin pigmentation. Hepatomegaly
and acanthosis nigricans in the axillae were also present. Breast development was normal, and she had Tanner stage 4 pubic hair. Subcutaneous fat loss from the extremities was accompanied by increased fat
over the supraclavicular area. Radiographs and MRI studies revealed
hypoplasia of the clavicles and mandibles, acroosteolysis, small cervical
Patient 3
Patient 4
Patient MAD 400.5 is a 25-yr-old non-Hispanic white male, the third
child of healthy, unrelated parents, born after an uncomplicated fullterm pregnancy. His birth weight was 3.2 kg, and he had normal growth
and development as a child. He had cryptorchidism, and at age 7 yr
bilateral testicular biopsies revealed rudimentary testes with growth
778
J Clin Endocrinol Metab, February 2002, 87(2):776 –785
arrest of seminiferous tubules and markedly reduced spermatogonia.
He had a normal male karyotype (46, XY) and underwent bilateral
orchiectomy with placement of testicular prosthesis at the age of 8 yr.
He has been receiving im T from age 10 yr (currently 300 mg T every
3 wk), but his muscle development and penile growth have been poor
and his height (1.7 m) is less than that of his two normal male siblings
(1.88 and 1.93 m). Besides the thin body habitus, he gradually developed
facial abnormalities such as sunken cheeks, narrow flat nose, and small
chin with crowded teeth for which he underwent reconstructive surgeries and dental extractions. Fat loss was first noticed from the arms and
legs when he was about 9 –10 yr old and has progressively involved the
face and the rest of the body. By age 15 yr, he was diagnosed to have
bilateral hearing loss due to inadequately formed auditory canals. He
was being treated for hypertriglyceridemia from age 21 yr with 600 mg
gemfibrozil twice daily.
Physical examination revealed body weight of 51.5 kg. He had a
bird-like face with a beaked nose and receding chin, besides a highpitched voice. There was no acroosteolysis, but his hands and feet were
small. There was generalized loss of sc adipose tissue, including the
palmar and plantar surfaces with calluses on the feet (Fig. 2). The skin
also showed mottled hyperpigmentation over the lower trunk and upper thighs. There was no acanthosis nigricans or hepatomegaly. He had
FIG. 2. Anterior and posterior view of patient 4 showing generalized loss of sc fat affecting the face, neck,
trunk, and extremities. Note the thin limbs as a result
of reduced muscle mass.
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
a microphallus (penile size of 2.5 cm), but body and facial hair distribution was normal.
Methods
Patients 1, 2, and 4 were admitted to the General Clinical Research
Center at University of Texas Southwestern Medical Center at Dallas for
evaluation. Information on patient 3 was obtained by a questionnaire,
telephone interview, and examination of his photographs. A written
informed consent was obtained from all of the patients, and the study
protocol was approved by the Institutional Review Board of University
of Texas Southwestern Medical Center.
Anthropometric measurements. In subjects evaluated at Dallas, height and
body weight were measured by standard procedures. Skinfold thickness
was measured with a Lange caliper (Cambridge Scientific Industries,
Cambridge, MD) at the chin, five truncal (chest, mid-axillary, abdominal,
subscapular, and suprailiac), and six peripheral (biceps, triceps, forearm,
hip, thigh, and calf) sites on the right side of the body. The mean of three
repeat measurements at each site was calculated.
DEXA. Whole-body DEXA scan was performed with a multiple detector
fan-beam Hologic QDR-2000 densitometer (Hologic, Inc., Waltham,
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
J Clin Endocrinol Metab, February 2002, 87(2):776 –785 779
MA). Data were obtained from the head, upper extremities, trunk, and
lower extremities; the proportion of fat in individual regions as well as
whole body was calculated as percentage of body mass. Data were also
obtained for measurement of lean tissue mass and bone mineral density.
Appendicular skeletal muscle mass was calculated as fat-free soft tissue
in the upper and lower extremities, and total body skeletal muscle mass
was estimated by dividing the appendicular skeletal muscle mass by
0.75 (15).
MRI. Whole-body MRI scan was performed on patients 1 and 2 with a
1.5 Tesla imaging device (Philips Medical Systems, Best, The Netherlands). The patients were evaluated using 10-mm-thick T1 imaging
techniques with TR (repetition time) of 580 msec, TE (echo time) of 8
msec and a 384 ⫻ 512 matrix combined with a 45-cm field of view.
Blood samples. Blood was collected after a 12-h overnight fast for analysis
of serum lipoproteins, insulin, leptin, glucose, and a chemistry profile.
Blood samples from patient 3 were sent by overnight mail to the University of Texas Southwestern Medical Center for analysis.
Oral glucose tolerance test (OGTT). A standard OGTT with 75-g glucose
was performed after a 12-h overnight fast. Venous blood was collected
for determination of glucose and insulin concentrations at 30 min, 15
min, and immediately before glucose administration, and at 30-min
intervals thereafter for 180 min.
Biochemical analyses. Plasma glucose was measured by the glucose oxidase method with a Beckman Coulter glucose analyzer (Beckman
Coulter, Inc., Fullerton, CA). Plasma insulin and leptin levels were
determined by RIA using commercial kits (Linco Research, Inc., St.
Charles, MO). Fasting serum samples were analyzed for cholesterol and
triglycerides by an enzymatic method using kits (Roche Molecular Biochemicals, Indianapolis, IN). Serum high-density lipoprotein (HDL)
cholesterol was measured enzymatically after lipoproteins containing
apolipoprotein B had been precipitated with phosphotungstic acid (16).
Serum chemistry was measured as a part of the systematic multichannel
analysis by a commercial laboratory (SmithKline Beecham Clinical Laboratories, Dallas, TX).
Results
The clinical features of all our patients are summarized in
Table 1 in comparison with 34 previously reported cases
(1–12, 17–25). The onset of symptoms was noticed in early
childhood in our patients. All of our patients had micrognathia suggestive of mandibular hypoplasia, but only three of
them had clavicular hypoplasia and acroosteolysis. Growth
retardation and the characteristic bird-like facies were noticed in three of the four subjects, whereas mottled cutaneous
pigmentation was seen in all of them. Joint stiffness and
flexion contractures of the fifth finger were present in three
patients. Other characteristic features of individual patients
have been described earlier.
Body fat distribution was assessed by measurement of
skinfold thickness, DEXA, and MRI studies. Figure 3 shows
the skinfold thickness in patients 1, 2, and 4. Both patients 1
and 2 had markedly reduced peripheral skinfold thickness
compared with normal women, whereas the truncal skinfold
measurements were in the normal range (26). Patient 4 had
decreased skinfold thickness at both the peripheral and truncal sites compared with normal men (27).
Table 2 shows the regional and whole body adipose tissue
distribution as estimated by DEXA scan. Compared with
normal young women (28), patients 1 and 2 had decreased
whole body fat, whereas the percentage body fat in patient
4 was comparable to normal young men (28). All of the three
patients had less fat in the arms and legs compared with
normal subjects, whereas truncal fat was within the normal
range. Patients 1 and 2 seemed to have well preserved skeletal muscle mass, although it was low in patient 4. All three
patients had decreased bone mineral density.
Whole body MRI studies were conducted in patients 1 and
2 only, and a similar pattern of adipose tissue distribution
was observed in both. The most striking finding was extreme
lack of sc adipose tissue from all the extremities (Figs. 4 and
5). Axial MRI sections through both the upper and lower
extremities, as well as through the gluteal region, revealed an
apparent excess of adipose tissue in the intermuscular fasciae. The sc truncal adipose tissue, both from the thoracic and
abdominal areas, was less conspicuously reduced, and there
was no apparent reduction of fat noted in the intra-abdominal and intrathoracic sites (Fig. 6). A slight excess of sc fat
was also noted in the posterior cervical area (Fig. 7). Normal
amounts of fat were noted in anatomic sites where mechan-
TABLE 1. Clinical features of patients with MAD
Features
Age (yr)
Sex
BMI (kg/m2)
Age of onset (yr)
Growth retardation
Micrognathia
Bird-like facies
Clavicular hypoplasia
Acroosteolysis
Wide cranial sutures
Skin atrophy
Mottled hyperpigmentation
Joint contractures
Peripheral fat loss
Excess fat over the neck
Patient ID
100.3
100.4
300.4
400.5
Previous cases
(n ⫽ 34)a
20
F
18.6
5
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
16
F
21.1
4
⫹
⫹
⫹
⫹
⫹
⫺
⫹
⫹
⫹
⫹
⫹
12
M
22.9
ND
⫺
⫹
⫺
⫹
⫹
ND
⫺
⫹
⫹
⫹
⫹
25
M
16.8
7
⫹
⫹
⫹
⫺
⫺
ND
⫹
⫹
⫺
⫹
⫺
25.5 ⫾ 16.5b
21 M, 12 Fc
17.1 ⫾ 4b,d
4.3 ⫾ 2.5b
25/28
28/29
26/29
25/30
27/30
22/24
24/26
22/26
22/28
15/16
3/15
⫹, Present; ⫺, absent; ND, not determined; BMI, body mass index; M, male; F, female.
Numerator signifies number of subjects with the clinical feature; denominator shows total number of subjects.
Mean ⫾ SD.
c
One case report (18) did not mention sex of the patient.
d
n ⫽ 22 subjects.
a
b
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J Clin Endocrinol Metab, February 2002, 87(2):776 –785
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
FIG. 3. Skinfold thickness at various
anatomical sites in the male patient 4
with type B pattern of lipodystrophy (A)
and in the two female patients 1 and 2
with type A pattern of lipodystrophy
(B). The shaded bars represent the median, 10th and 90th percentile values of
skinfold thickness for normal men aged
18 – 61 yr in A (27) and for normal
women aged 18 –55 yr in B (26).
ical adipose tissue is present, such as the orbits, palm, sole,
scalp, and periarticular regions.
Table 3 shows the metabolic variables in all four patients.
All of them had a normal fasting plasma glucose level but
elevated fasting insulin levels. All three patients who underwent an OGTT (Fig. 8) had normal glucose tolerance but
had a marked postprandial hyperinsulinemic response. The
peak plasma insulin concentrations exceeded 1500 pmol/
liter in all of them.
The fasting serum triglyceride concentrations were greater
than the 95th percentile of normal age- and sex-matched
population (29) in three of the four patients, whereas in
patient 2, it was between the 75th and 90th percentiles. Similarly, the HDL cholesterol was less than the 5th percentile in
patient 4, approximately 10th percentile in patients 1 and 2,
and between the 50th and 75th percentiles in patient 3 (29).
Serum leptin levels were similar to those reported recently
in race- and sex-matched adults, aged at least 20 yr, with a
similar sum of skinfold thickness less than the 10th decile
(30). The ratios of serum leptin levels to absolute fat mass
were also comparable to previously reported values in studies using a similar leptin assay (31). The low leptin levels seen
in our patients thus probably reflect reduced total body fat
content.
Discussion
Our evaluation of body fat distribution in patients with
familial partial lipodystrophy (FPL) associated with MAD
using anthropometry, DEXA, and whole body MRI revealed
two different patterns of loss of body fat, namely, types A and
B. Type A pattern is characterized by fat loss from the extremities with normal or increased fat in the face, neck, and
truncal region and was noted in patients 1, 2, and 3. Type B
pattern is characterized by generalized loss of sc fat involving
the face and truncal regions besides the extremities, as noted
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
J Clin Endocrinol Metab, February 2002, 87(2):776 –785 781
TABLE 2. Body composition as determined by DEXA scan in patients with mandibuloacral dysplasia
Normal valuesa (mean ⫾
Patient ID (gender)
Region/tissue
Fat (% regional mass)
Whole body
Trunk
Arms
Legs
Skeletal muscle (% body mass)
Whole body
Arms
Legs
Bone mineral density (g/cm2)
Whole body
Arms
Legs
100.3
(F)
100.4
(F)
400.5
(M)
20.6
27.5
18.0
9.1
24.8
31.8
23.4
13.7
13.9
18.7
6.0
2.8
41.8
7.1
24.3
38
6.4
22.3
35.9
5.8
21.2
0.828
0.571
0.851
0.875
0.602
0.882
1.039
0.686
1.075
F
30.3 ⫾ 1.5
29.0 ⫾ 1.6
30.2 ⫾ 1.8
33.1 ⫾ 1.5
SD)
M
13.8 ⫾ 1.4
13.5 ⫾ 1.4
11.2 ⫾ 1.5
15.2 ⫾ 1.7
42.8
5.9
26.2
52.2
8.9
30.3
1.12 ⫾ 0.01
0.76 ⫾ 0.013
1.15 ⫾ 0.012
1.23 ⫾ 0.009
0.92 ⫾ 0.018
1.36 ⫾ 0.011
F, Female; M, male.
a
Normal data are for young women and men as reported by Mazess et al. (28).
FIG. 4. Transaxial T1 MRIs at the level of the thigh
(A) and calf (C) in patient 1. B and D show similar
images at corresponding levels in a normal female
subject. Note the decreased amounts of sc adipose
tissue in the patient with preservation of intermuscular adipose tissue.
in patient 4. In previous reports of patients with MAD, some
authors failed to mention lipodystrophy (3, 9, 24), whereas
others made references to the loss of sc adipose tissue (11, 21,
22) but without a detailed description.
Skinfold thickness measurements in our patients 1 and 2
(Fig. 3) clearly demonstrated fat loss from the extremities
with sparing of the truncal regions. MRI and DEXA scan
confirmed the same, the former also revealing the slight
excess fat accumulation in the dorsal cervical region. Furthermore, the MRI studies revealed increased fat in the intermuscular fascial planes and normal amounts of intrathoracic and intra-abdominal adipose tissue. There was also no
fat loss from the orbit, palm, sole, scalp, and periarticular
regions where adipose tissue only serves a mechanical func-
tion. We are not aware of any previous reports describing
adipose tissue distribution in MAD using MRI, but a similar
pattern of body fat loss has been reported previously on
physical examination of some patients, which supports our
findings. For example, the patient described by Young et al.
(1) had diminished fat over the distal extremities but increased fat over the abdomen and chest as well as in the face
and neck region. Similarly, examination of the published
pictures of the patient described by Sensenbrenner and Fiorili (2) revealed lack of sc fat with marked muscularity of both
the upper and lower extremities. Particularly noticeable was
loss of sc fat from the gluteal region. The authors noted an
increase in sc tissue in a buffalo hump distribution over the
back and neck. The patient also had a double chin appear-
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J Clin Endocrinol Metab, February 2002, 87(2):776 –785
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
FIG. 5. Transaxial T1 MRIs at the level of the arm
(A) and forearm (C) in patient 1. B and D show
similar images at corresponding levels in a normal
female subject. Note the decreased amounts of sc
adipose tissue in the patient with preservation of
intermuscular adipose tissue.
ance. Freidenberg et al. (5) reported progressive loss of sc fat
from the extremities and trunk below the level of the nipples
by the age of 16 yr in patient 1. Examination of this patient’s
photographs (courtesy G. Freidenberg) confirmed lack of sc
fat from the extremities and gluteal region and the presence
of excess fat in the face and neck region, causing a double
chin appearance. Similarly, examination of the pictures published by Pallota and Morgese (3) and by Tudisco et al. (24)
reveals that both of these patients had marked paucity of sc
fat in the extremities and had excess fat in the trunk and neck
regions. This pattern of lipodystrophy is similar to that reported by us in patients with FPL, Dunnigan variety, who
have loss of sc fat mainly from the extremities with excess fat
in the face, neck, and truncal regions (14).
On the other hand, patient 4 had a more generalized loss
of sc fat involving the face and truncal region besides the
extremities as shown by the skinfold measurements (Fig. 3).
Also remarkable was the absence of fat from the palms and
soles. A similar pattern of fat loss has been noted in one of
the patients (patient 3) reported by Freidenberg et al. (5) and
subsequently by Ng and Stratakis (4). Examination of the
photographs of patient 2 (courtesy G. Freidenberg) in the
same case series (5) also revealed striking fat loss from
the face besides the extremities. All of these patients appear
to have thin limbs with decreased muscle mass as well. It is,
however, not clear whether this is related to disuse atrophy
from joint contractures or to the associated hypogonadism or
whether it is a distinct feature of this syndrome. This type B
pattern of FPL associated with MAD needs to be studied in
greater detail.
Interestingly, both patterns of lipodystrophies are associated with insulin resistance and its metabolic sequelae. Al-
though none of our patients had diabetes or impaired glucose
tolerance, marked hyperinsulinemia during the fasting and
postprandial states suggests moderate to severe insulin resistance. Diabetes has been reported previously in three male
patients aged 16, 17, and 41 yr (5) and in a 14-yr-old female
patient with this syndrome (11). Impaired glucose tolerance
was observed in a 26-yr-old male and a 37-yr-old female
patient (11). Furthermore, Cutler et al. (12) reported a marked
reduction in insulin-stimulated glucose uptake on euglycemic hyperinsulinemic glucose clamp studies in two patients.
Because insulin resistance in these patients occurred without
obesity, excessive levels of counter regulatory hormones, or
anti-insulin-receptor antibodies, the authors concluded that
it was caused by the accompanying lipodystrophy (12).
Three of our patients had elevated serum triglycerides and
low HDL-cholesterol levels, a lipid profile characteristic of
insulin resistance. All of these metabolic derangements including insulin resistance, tendency for diabetes mellitus,
and dyslipidemia may increase the risk of these patients to
develop coronary artery disease. Indeed, the patient described initially by Cohen et al. (17), Freidenberg et al. (5), and
most recently by Ng and Stratakis (4) had coronary artery
bypass graft for extensive coronary artery disease at age 53
yr (McKusick, V., and E. Arioglu, personal communication).
MAD is not only a rare disorder, but also has protean
manifestations, many of them overlapping with other progeroid syndromes. Patients with MAD have previously been
described as having Werner syndrome (17), craniomandibular dermatodysostosis (9), hereditary sclerosing poikiloderma (19), and Hutchinson-Gilford progeria (21). The diagnostic confusion probably results from the many
overlapping features between the various progeroid syn-
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
J Clin Endocrinol Metab, February 2002, 87(2):776 –785 783
dromes. The differential diagnosis of MAD and other progeroid syndromes has been discussed in sufficient detail by
Esterly et al. (32). As shown in Table 1, our patients had most
of the characteristic features associated with MAD. We have
also observed decreased skeletal muscle mass in the type B
pattern of lipodystrophy and decreased bone mineral density in three of our patients. Patient 4 did not have the typical
clavicular hypoplasia and acroosteolysis. But these features
were absent in some earlier case reports as well (4, 5, 10). His
features closely resemble those described by Ng and
Stratakis (4) in a 52-yr-old male who was previously described to have Werner syndrome (17). We had also considered the diagnosis of Werner syndrome in our patient, however, earlier onset of symptoms, the absence of cataracts or
premature graying, and absence of mutations in the coding
region of WRN gene (courtesy of Dr. J. Oshima, Seattle, WA)
makes the possibility of Werner syndrome highly unlikely.
Interestingly, like our patient, the patients described by Ng
and Stratakis (4) and by Freidenberg et al. (5) also had hypogonadism, bilateral sensory-neural deafness, and type B
pattern of lipodystrophy. It is possible that these patients
TABLE 3. Metabolic variables in the four patients with MAD
Metabolic variables
Patient ID
100.3
100.4
300.4
400.5
Plasma glucose (mmol/liter)
4.4
4.2
4.9
4.4
Plasma insulin (pmol/liter)
216
258
186
198
Serum triglycerides (mmol/liter)
2.69
1.34
3.24
6.24
Serum cholesterol (mmol/liter)
5.38
4.09
6.72
5.2
Serum HDL cholesterol (mmol/liter)
0.97
0.98
1.35
0.62
Serum leptin (␮g/liter)
3.41
6.00
4.05
1.83
Serum leptin/fat mass (␮g/liter 䡠 kg)
0.39
0.58 ND
0.26
FIG. 6. Transaxial T1 MRI through the abdomen of patient 1 (A)
showing normal amount of intra-abdominal fat with slight decrease
in sc fat in comparison to a corresponding image from a normal female
subject (B).
FIG. 7. T1 weighted MRI of the midline
saggital section of head and upper thorax in patient 1 (A) and a normal female
subject (B). Note the increased amount
of sc adipose tissue in the dorsal cervical
region of the patient.
All samples were obtained after a 12-hr overnight fast. Values
shown for patients MAD100.3, 100.4, and 400.5 are a mean of samples
collected on 2 d, whereas results of a single sample are reported for
patient MAD300.4 and for all leptin levels.
ND, Not determined.
784
J Clin Endocrinol Metab, February 2002, 87(2):776 –785
Simha and Garg • Mandibuloacral Dysplasia-Associated Lipodystrophy
FIG. 8. Plasma glucose (A) and insulin (B) levels during the OGTT in patients 1 (F), 2 (E), and
4 (Œ).
manifest a variant form of the typical MAD syndrome. Undescended testis (22) and hypogonadotropic hypogonadism
have been described in other patients with this syndrome
(11). Identification of the genetic basis for MAD will probably
help us in understanding the underlying molecular basis of
various different phenotypes.
In summary, FPL associated with MAD may present with
two types of body fat distribution patterns; type A pattern is
characterized by fat loss from the extremities with normal or
increased fat in the face, neck, and truncal region, whereas type
B pattern is characterized by generalized loss of sc fat. Both
types of lipodystrophies associated with MAD are associated
with insulin resistance and its metabolic complications.
Acknowledgments
We are grateful to Drs. David Feinstein and Ravi Shankar for patient
referral; Drs. Elizabeth Obialo and Dali Chen for assistance in patient
evaluation; Dr. Paul Weatherall for help with MRI studies; and Angela
Osborn, Jerri Payne, Brian Fox, and the nursing services of the General
Clinical Research Center at University of Texas Southwestern Medical
Center, Dallas, for their excellent technical support.
Received September 6, 2001. Accepted November 5, 2001.
Address all correspondence and requests for reprints to: Abhimanyu
Garg, Division of Nutrition and Metabolic Diseases, Department of
Internal Medicine, University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail:
[email protected].
This study was supported in part by NIH Grants M01-RR00633 and
R01-DK54387 and by the Southwestern Medical Foundation.
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