THE
SYNDROMES
OF
TOTAL
LIPODYSTROPHY
AND
OF
PARTIAL
LIPODYSTROPHY
B. Senior, M.D., and S. S. Gellis, M.D.
Department of Pediatrics, Boston University School of Medicine and the Boston Unitersity Medical Center and the Pediatrics Service, Boston City Hospital
(Submitted September 30; accepted for publication October 20, 1963.)
PRESENT ADDRESS: (B.S.) The Boston Floating Hospital, Tufts-New England Medical Center, Boston.
PEDIATRICS, April 1964
REVIEW
ARTICLE
593
oss OF subcutaneous fat in the
lipodys-trophy syndromes commonly renders
the appearance of the subject sufficiently
bizarre to permit diagnosis at a glance, but knowledge of these conditions remains fragmentary. The syndrome of partial
lipo-dystrophy was first mentioned by Weir
Mitchell’ in 1885. More than 200 cases have subsequently been published. The syn-drome is described as a disorder particu-larly affecting females, with onset most
frequently between 5 and 10 years of age,
characterized by loss of facial fat alone or srith involvement of the neck, arms, chest, and abdomen, yet with normal or even in-creased fat deposition over the legs. Other than the strikingly cadaverous appearance these patients are alleged to suffer no disa-bility and to have a normal life expectancy.
Lawrence2 described the syndrome of
total lipodystrophy in 1946 and
approxi-mately 20 additional cases have been
re-ported. There is a complete loss of adipose
tissue, evident at birth or with onset later
in life, together with a number of associ-ated features commonly including
hepato-megaly, hyperglycemia, hyperlipemia, and
hypermetabolism.
With the exception of Williams’ text-book, Diabetes, which devotes a chapter
by Craig and Miller to total lipodystrophy or “Lipoatrophic Diabetes,” standard medical and pediatric textbooks either make no reference to these syndromes, or briefly mention partial lipodystrophy only.
Despite the ease of recognition, the pas-sage of time since the conditions were first recognized and the considerable number of
cases reported, neither etiology nor
patho-genesis is understood, and the clinical
fea-tures are still poorly defined.
To delineate the features of both syn-dromes, we have reviewed reports of par-tial and total lipodystrophy in the litera-hire and are presenting, in addition, the findings in 27 patients, 25 with partial
dipo-dystrophy and 2 with total lipodystrophy.
This group comprises patients seen
per-sonally or whose records have been
avail-able to us or about whom we have knowl-edge through correspondence with the at-tending physician.
Review of reports in the literature early demonstrated that a major obstacle to understanding was the variety of descrip-tive titles under which the syndromes, par-ticularly total lipodystrophy, had appeared (Table I). Variants of the terms
lipodystro-phy or lipoatrophy were not difficult to
unravel, but there are other clear examples of total lipodystrophy where
manifesta-tions other than loss of fat primarily
en-gaged the authors’ attention and were incorporated into the title. Again there are reports with features suggestive of
lipo-dystrophy but with insufficient information
to allow firm categorization. Unfortunately, too, the appellation of lipodystrophy has not been a guarantee that the patient had the syndrome. Both the wasting of mal-nutrition and of thyrotoxicosis appear to have been reported as lipodystrophy, as vell as excessive pelvic-girdle-thigh adi-posity with resultant relative facial thin-ness.413
LIPODYSTROPHY
TABLE I
‘l’ITLES UNDER WHICH PATIENTS \VITH TIIR SYN-I)IIOMES OF LIPODYSTIIOI’IIY hAVE BEEN REP0IITF:n
Tutal Lipodystrophy
Lipo(lystrophv and lepa tolllegaly wit l din I lipodystropliies”
l.ipoatrophic (liabeteS’9
All lln(liagnosed endocrinornetal)olic syIIdronI(2#{176} ( eneralized lipodystropliy2’
llvpertrophie InIISCUIa ire g#{233}ii#{233}ralis#{233}eIt debut precoce
ii \CC IipO(lySt rophie faciale22
LLpo(lystrophy alid gigalitisni with associate(l eII(locriIle Inallifestations2
(;elleralize(l lipoatrophy, hepatic cirrhosis, disturbed
carholly(lrate metabolislu and accelerated growth
(Lipoatrophic diabetes)21
tipodystrophic muscular hypert rophy2’ Lipohistio(liaresis29
A case for (liagnosis3#{176}
Possible Cases of Total Lipodystrophy
t’eber einen Fall von congerutaler Makroglossie,
coIn-binirt iiiit ailgemeiner Wahrer Muskelh.ypertrophie
110(1 Idiotic3’
Congenital Inuscular hypertrophy#{176}
La hypertrofia muscular gelleralizada (oIlgeIIita3’
IT0 caso de Elifermedad Dc LangeM
(‘ongenital muscular hypertrophy with mental de-ficiency (De Lange’s Disease)’7
(‘ongenitale Muskelhypertrophie38
Leprechaunism”
Partial Lipodystroj)hy
Progressive lipodystrophy Lipodystrophia progressiva Barraquer Sinlolls 1)iseaseM60St Lipodystropliia Faeialis’9
Cephalothoracicobrachial forrii of lipodystrophy67
Progressive ceplialothoracic lipodystrophy’8
the New Kingdom illustrates the difficulty
of retrospective diagnosis. Born Amenophis
IV (1372-1355 B.C.), he was responsible for the introduction of a monotheistic religious concept, coincidently changing his name to Ikhnaton or Akhnaton, the glory of Aton, the new and sole deity personified in the sun. He had great poetic talent and was an exemplary father and husband. His wife was the beautiful Nefertiti. Were all this not fame enough, he has been proposed as the earliest case of partial lipodystrophy.14 This presumptive diagnosis was based on his appearance after assumption to the throne. Earlier depictions were
unremark-FIG. 1. Amenophis IV. Courtesy of the Director-Ceneral. Service des Antiquit#{233}s, Cairo, Egypt.
al)le. As Pharaoh he was shown with an
ex-tremely lean visage, a long thin neck, and an
inappropriately plump abdomen and thighs (Fig. 1).
WThether his unusual appearance was a true likeness or consequent on artistic
license remains unanswered. His death
mask did not suggest lipodystrophy.517 At this time prudence dictates that no decision be made. Many reports of
twentieth-cen-tury patients have been no easier to
cate-gorize. Each case report has required evalu-ation and we have been forced to exercise some arbitrariness in deciding the assigna-tion of patients reported to have diminu-tion of facial adipose tissue. We are also certain that the variety of descriptive titles has hidden other cases from our attention.
Such information concerning these pa-tients as is available is presented to mdi-cate areas that may be significant for
in-vestigation in future patients.
TABLE 11 TOTAL LIP0DYSTII0I’HY S + + + + S + + + + . + ++ ++ + + + + Refrrencc Ziegler” Lawrence’ Corner” BerardineHi2o Berardinelli2o
Fontan et a1. Witzgall Seip” Seip” Seip2’ Craig and Miller” Craig and Miller”' IIood326 Conn’ Conn’ Schwartz ci at.’7 Senior”
llansen et at.”
F F I” M F F F F M M F F F M F F F M S S + + + + + + + + + S + + + + + + + ?+ + + + + + + + + i-I ?2,’, birth 11’, 11’, birth l)irth birth ?birth ?birth 7 6 ?birth birth ?birth birth ?5 .#{176} + + + + + + + + + + + + + + + + + + + + + . 14 6 Ii ?3 I 6 ? QI 17 55 1 28 16 41I 7 7 I-. + + + + + + + + + + C .
:
+ + + + + + + + + + + + + + + + + + + + + + + ++ ++ ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + ++ + + + + + + + + + + + + + + + + E.W. F P.P. M + + + + + + + + + + + + + + + + + + + + + + +descriptive title for each syndrome, partial lipodystrophy for the patients with loss of
facial fat with or without truncal loss but
with retention of distal fat depots, and
total lipodystrophy for the smaller group
with generalized disappearance of fat.
The use of lipodystrophy for both
syn-dromes is proposed in view both of past
precedent and of identical facial
appear-ance, and vithout implying that the
syn-dromes are necessarily related. However,
as this report will indicate, there are a
number of features common to both.
TOTAL
LIPODYSTROPHY
The group of patients in which a
diag-nosis of total lipodystrophy appears
reason-ably firm numbers 21 (Table II). Other
than 5 patients briefly mentioned by Craig
and Williams, of whom we have further
information on three, and two additional
patients now presented, E.W. and PP.,
each of the group has been reported in some detail although the diagnosis of total
lipodystrophy was not necessarily made by
the original authors.1829
Patient E.W. was first reported at the age of 8 months by Buchanan under the title of “A case for diagnosis.”3#{176} The fea-tures then recorded were an enlarged projecting tongue, marked generalized prominence of muscles, and abdominal dis-tension. The liver was considered enlarged. Lack of subcutaneous fat was mentioned as a factor contributing to the prominence of
the musculature. A diagnosis of congenital
muscular hypertrophy was favored (Fig. 2). At present the diagnosis of total
lipodys-trophy is clear (Figs. 3, 4). The features are
outlined in Table II.
FIG. 2. Patient E.W. aged 5 months.
hyperglycemia became evident. A biopsy
was interpreted as showing
Weber-Chris-tian disease. Generalized loss of fat
fol-lowed. His features have been included in
Table II.
The patients were of both sexes with a
2:1 preponderance of females. Parental
consanguinity was present in three
fam-7021 27 and possibly in another,29 and
in one of these two siblings were affected. In a further family, two siblings had the
disorder.2
The disorder was apparent at birth in six
202 1,28 and recognized at various
Fic. 4. Patient E.W. aged 7 years.
other ages in the remainder. The delay in
di-agnosis illustrated by patient E.W. suggests
that others may have been affected at birth as well. This likelihood is more remote in the adults, and in Lawrence’s patient2 a photograph documents a normal appear-ance in the twenties. The facial appearance consequent on loss of subcutaneous fat and buccal fat pads was arresting, particularly
so in the children who seemed wasted and prematurely aged. However, as the fat loss
was generalized, the marked contrast
be-tween affected proximal and normal distal
areas, so striking in patients with partial
lipodystrophy, was absent, and the
diag-nosis of total lipodystrophy was not always obvious.
During life, lack of fat was confirmed by skin biopsy, laparotomy, and bone marrow aspiration.2’ 21. iS, 29 The generalized nature
of the fat loss was evident at
Despite the disappearance of subcutane-ous fat, the skin retained normal elasticity.
a specifically sexual distribution was ob-served; scalp hair was abundant and often curly. In one patient, scalp hair curliness appeared coincidentally with loss of fat.
Generalized pigmentation was common; it was also seen in two Negro patients. An increase of pigmentation in the axillae was diagnosed as acanthosis nigricans in three patients. Mucous membranes were not in-volved.
The children were tall, tending to the
90th percentile, but a concomitant increase of bone maturation suggested curtailment of the final height achieved. In two pa-tients who were followed for some years this predicted decline of growth rate was
729
Prominence of muscles was often an outstanding feature particularly in the children. In some this aspect primarily engaged the attention of the author, seem-ing the major expression of the disorder. That the muscular appearance was solely due to the unmasking effect of loss of fat appears unlikely. Were this so, a weight age disproportionately lower than the height age should have obtained, which was not the case. Thus an actual increase of muscle mass is suggested, with further enhancement of the appearance of muscu-larity through disappearance of overlying fat. Although pictorial support for such increase derives from patient E.W. (Fig. 2), objective data are lacking. Muscle power was good and, as the process was uniform
and symmetrical, an athletic appearance
was imparted. The children exhibited marked abdominal protuberance. Although hepatomegaly was constant, the degree of distension appeared greater than expected for the liver size. Umbilical hernia was a common accompaniment. The liver was af-fected in all. There was enlargement, and the histology revealed combinations of
pe-riportal foci of round cell infiltration,
nu-clear syncytial formation, fatty infiltration, glyogen deposition, and fibrosis. The em-pirical tests of liver function were
common-ly abnormal. Fibrosis was progressive. One
patient, and possibly another, died of
he-patic 29 Two siblings of the
docu-mented patients in one family24 and a sibling of another patient2#{176} died in infancy with a picture suggesting hepatic failure. It is possible that they suffered a more severe expression of the same disorder.
The genitalia appeared affected in the majority of the younger patients and in one adult. The females had clitoridial enlarge-ment without other evidence of virilization; penile enlargement was present in the males. In neither sex was increased gonado-tropin or adrenal androgen secretion found. Whether these changes were the result of a specifically sex directed determinant, a reflection of the generalized muscularity, or merely a pseudo-enlargement through lack of fat is not known.
Hyperglycemia is commonly considered a major and constant component of total lipodystrophy. All the adults were so af-fected, but this was not evident in several of the younger patients particularly when first investigated. One child exhibited fast-ing hypoglycemia on repeated testing.28 Over a period of time the number with
hyperglycemia increased and it appeared
likely that eventually this would occur in
all. Characteristically the hyperglycemia was unaccompanied by ketosis and re-sponded but little to administration of in-sulin. Assays for insulin-like activity in the serum demonstrated increased levels in the two patients so 2427
Hyperlipemia was present in most
pa-tients even in the absence of diabetes, and
fractionation revealed that the increase was confined almost solely to the triglyceride moiety. An elevated basal metabolic rate, not ascribable to thyroid hyperfunction, was found in all but one of the adults. Pre-sumably, for technical reasons, this
investi-gation was performed on only three
chil-dren and was elevated in two.
227 two further patients were markedly retarded 28 and a hemiplegia
was present in yet 21
Renal involvement was documented in seven patients. This was not pursued in the remainder beyond a routine examination of the urine and an estimation of nonprotein nitrogenous products in the blood. In the seven patients a variety of abnormalities
emerged. A nephrotic syndrome was
pres-ent in one,23 albuminuria, hypertension, and nephromegaly at laparotomy in an-other,19 proteinuria in a third2 and the remaining four had enlarged kidneys de-tected during life or found at 18 27
The cause of such enlargement was ob-scure. Whether renal abnormalities were present but not exposed in others cannot be assessed. In one patient renal disease was not found during life and no mention of the kidneys was made in the autopsy
29
Cardiac enlargement was present in six patients-in five on 27 and at
au-topsy in one.2 In one, a ventricular septal
defect was suspected,24 but in the remain-der the cause was not apparent.
Based on the foregoing brief review of the established cases of total lipodystrophy
a composite picture of the syndrome may
be outlined. Not every feature is present in each patient, but the over-all combina-tion is distinctive. In the children, in-creased stature, advanced bone age, pig-mentation, hirsuties, prominence of mus-des, abdominal protuberance, and
hepa-tomegaly is present. Genital enlargement
and hyperlipema are commonly present, and hyperglycemia, if absent, will prob-ably develop in due course. A substantial portion of such patients exhibits disorders of the kidneys and the central nervous
system, as well as an obscure form of
cardiomegaly. In the adults increase in height is not a feature, muscularity is less obvious, and abdominal protuberance is not marked. Hyperglycemia and hyper-lipemia are the rule and hypermetabolism rarely absent. The syndrome is distmn-guished more for its similarities than
differ-ences on comparing the child and adult
forms. Even in the absence of specific men-tion of fat loss, the other features in com-bination may enable recognition of the
syndrome where the diagnosis had not
been apparent.
We examined a number of reports of additional patients in whom the predomi-nant feature was muscle prominence.31’5 The very close similarity between E.W. as reported by Buchanan#{176} and several of
these patients listed in Table III is evident.
Photographs present in the reports further
support the likeness. We have deliberately
included in Table III details of two pa-tients whom we consider did not have total
lipodystrophy. Kernicterus appears the
most likely diagnosis in retrospect. Our impression is that De Lange’s syndrome or congenital muscle hypertrophy does not represent a single entity but encompasses
several groups of disorders, including total
lipodystrophy. In making this assessment
we hasten to acknowledge that the data
allow only tentative conclusions. We have
further included in Table III two siblings
without muscular prominence who had
been reported under the title of
Lepre-chaunism.3’ The features manifested bear
an impressive resemblance to those seen in total lipodystrophy.
PARTIAL
LIPODYSTROPHY
We have suggested that for inclusion in the syndrome of partial lipodystrophy there should be symmetrical absence of facial fat with or without disappearance of fat from the arms, chest, abdomen, and hips, but with retention of distal adipose depots. This simple definition may not ac-curately delineate the syndrome, but with-out it altogether too heterogeneous a group
of patients would be considered. It
ex-cludes facial hemiatrophy, an appearance of relative thinness of the face enhanced by deposition of fat over the buttocks and legs, as well as the generalized wasting of
thyrotoxicosis or malnutrition. If
pa-Reference Title :‘ .5
Buchanan” A case for Diagno,i, F birth +
Br,,ck” Ueber einen Fall ‘on con- F birth +
genitaler Makroglossie
combinjrt mit allgemeiner
wahrer
Muskell,ypertro-phie und idiotic
Dc Lange” Congenital hypertrophy M birth 0 of the muscles
Extrapyramidal motor M birth 0
(listurbances
Mental deficiency it birth (1
Hall ‘f at.” Congenital muscular M + birth Phito.
hypertropl,y very
sugges-toe
Carrau and La l’ipertrofia muscular M birth + Otero” generalizada cong#{233}nita
Ramon Arana Un caso de Enfermeda(l M birth 0
et al. Dc Lange
Morano Brandi Un caso de Enfermedad M birth +
et at.” Dc Lange
Marshall and Congenital muscular by- M birth +
Ilodes” pertrophy with mental
de-ficiency
Goldstein’s Congenitale F birth + Muskelhypertrophie
Donohue and Leprechaunism F + l)irth +
Uchida” (Two patients)
a
S
+
+
+
+
+
+
+
+
+
+
+
..
:
.‘ . CommentH
*-‘ - .(
.
c2
+ ? ? At present dearly has Total Lipodystrophy. Patient ElY.
Table II.
? ? + + Description and picture -ery
suggestive of above. This pa-tient quoted by Dc Lange as first report of syndrome of
muscular hypertrophy an(l
retardation.
0 0 + 0 Porencephaly at autopsy. In-formation too scanty.
Pos-sible Total Lipodystrophy.
0 0 + 0 Information too scanty.
0 0 + 0 Very icteric SOC(;fl(l ,lay.
?Kernicterus
+ + + + Very closely resembles p tient E.%S. above.
+ 0 + + Closely resembles patient
E.W.
0 0 + 0 Neck kept hypere,ctended. Report suggests Kernicterus.
? ? + + Closely resembles patient
ElY.
+ + + Resembles patient ElY.
+ + Resembles patient ElY.
a I.,
+
+
+
+
0
+
+
No No + + + Nephromegaly at autopsy. Liver histology identical to
that of known Total
Lipo-dystrophy patients. Unable
to be certain, but similarities
toTotal Lipo(lystrophy
rn-pressive.
tients with the foregoing disorders resulted preferable to inclusion of all patients so in too many mislabeled as partial lipodys- termed with resultant diffusion and distor-trophy.
In reviewing case reports we have prob-ably perpetrated errors of judgment in
culling to rigorously, but felt this was
REVIEW ARTICLE
TABLE III
Pos.sIBLE EXAMPLES OF To’rAL LIPODYSTROPHY
tion of the picture.
The majority of case reports of partial
lipodystrophy appeared over thirty years
JonesU
Berger”
Wilkinson”
Author Sex Age Renal Findings
54
9
10
10
10
6
24
Ii
31 Gibson”
Brow,,”
Kinderen’4
F
F
F
M
Is,!
F
Case
(1)
male
F
F
F
F
F
Is!
reason enough for publication. These pa-tients have been reviewed in the past.4044 More recently, publication appears to have hinged on the concomitant presence of other features. In turn, such a tendency could produce an unbalanced picture with
too high a proportion of complicating fea-tures.
We have reviewed the reports of some 77 patients, published since 1930,4290
con-forming to the foregoing criteria. Even in
this relatively recent group many of the publications contained too few details to permit confident assessment.
The ratio of females to males was 4:1. Onset of the disorder was most often noted between 5 and 15 years of age, but ranged from 1 to 40 years. Three patients were reported to have had similarly affected relatives, a mother and a grandmother of one,68 an uncle of another,66 and a cousin and uncle of a third.89 In addition to the loss of fat, a number of other abnormalities was commented on.
Fourteen patients had a renal disorder
when seen or gave a history of such an episode in the past (Table IV). The
diver-sity of clinical diagnoses was remarkable,
TABLE IV
PARTIAL LIPODYSTROPHY-REPORTED RENAL DISORDERS
Igersheimer”
Schermann and Souto Major’7
Williams and Kelsey7#{176} Fowler7’
Sacerdoti Favini and Galli
Bodarenko afl(1 Maksimov”
Belenkaia”
Taylor and
Heneycutt”
Acute nephritis at 16 years.
Two previous attacks of “Pyelonephritis.” Urine, albuminuria ++. Blood urea, 21 mg/100 ml.
First and only pregnancy interrupted on account of nephritis. Urine
N.A.D. at present.
Pain left subeostal area. Frequency. IVP. Dilated left renal pelvis.
Opera-tion-vessel ligated. Follow up IVP-bilateral calyceal dilatation. Rare casts and RBC.
Urine not mentioned hut Creatinine was .25 mg/100 ml. Urea was 40 mg/100 ml.
At 4 years two attacks of unexplained gross hematuria.
At 4 years “kidney trouble” after scarlet fever. At present-fever,
at-huminuria, pyuria, and RBC. Urea 30 mg/100 ml IVP. Hydronephrosis and hydroureters. Further attack 14 months later.
Albuminuria. BP 160/96. Creatinine, 1.75 mg/100 ml. Urea nitrogen 1.4
mg/l0O ml.
Urine, albuminuria + + + ;RBC 10; WBC 30/hpf; occasional hyaline and cellular casts.
At P2 years-acute nephritis. Urea clearance now 9%. Attributed to
past nephritis.
At 6years-fever, hematuria, edema. Urine: albuminuria + + ;RBC casts. IVP: moderate dilatation of calyces, ureters. At 10 years: urine “like coffee.” Numerous blood casts. BP 140/110. Urea 74 mg/100 ml. Later,
edematous, low serum albumin. Cholesterol 300 mg/l0O ml. NPN rose.
Died.
At 10 years, albuminuria, RBC, WBC casts. Repeated exacerbations. BP
rose. Persistent albuminuria. Urea rose.
Peripheral edema. Albuminuria. Cholesterol 390 mg/100 ml. Serum albu-mm 2.16 gm/100 ml.
FIG. 5. Partial lipodystrophy.
ranging from pyelonephritis to acute and chronic glomerulonephritis and the nephrot-ic syndrome.
Intravenous pyelograms were performed in four patients and each showed some
degree of hydronephrosis with ureteric
dilatation.
In the majority of these patients the renal aspect was considered incidental to
the major disorder, partial lipodystrophy,
and accordingly was mentioned cursorily.
No biopsy or autopsy findings were
pub-lished.
Ten patients had abnormalities related to the central nervous system. Seven were mentally 81 three being
in-stitutionalized, one had epilepsy,8 and two had abnormal pneumoencephalograms.80
An increase in liver size was mentioned in the reports of eight patients58’66 71, 73, 80, 86, 87
and a single biopsy showed fatty change.87 Three patients exhibited hyperlipe-mia,7887,su one frank diabetes and four abnormal glucose tolerance 471, s7
Single patients were reported with pig-mentation,48 hirsuties,60 and diarrheal
epi-sodesca as well as multiple subcutaneous
swellings.8#{176}
The foregoing information derives from an accumulation of single and often terse
reports and it would be unwise to attempt
any detailed conclusions.
While the majority of patients vith par-tial lipodystrophy appeared otherwise well, there is evidence supporting an association
with renal disorders, disturbances of func-tion of the central nervous system, hepato-megaly, and possibly hyperlipemia and disordered glucose metabolism.
The group of patients with partial lipo-dystrophy that we are presenting numbers
25. Included in the group are the 12
pa-tients reviewed by Gellis, Green, and Walkeral who were impressed with the high incidence of kidney involvement. Seven of the 12 were so affected. There
were 17 females and 8 males, a 2:1 ratio.
No siblings were recognized to be affected
in the group, but the mother of one patient lost her facial fat when 4 years old. The onset of the disorder was commonly noticed around 5 years of age, but the
precise time of onset was often not known.
No common concurrent or preceding
events could be related to the fat loss. The disappearance of fat occurred over some months and occasioned concern regarding possible systemic causes of weight loss; not infrequently tuberculosis was sus-pected.
Of the 25 patients, 14, 6 males, 8
,
Age ofOnset ,
\ ante Sex
. Partial . Lzpodys-trophy Age
Seen Renal Further Aspects
Is! F F Is! F Is! Is! Is! F F F F F I 8 5 6 4 6 4 54 I ?6 S.G. I).R. E.H. FR. J.W. J.O’C. l)..J. R.McK. NA. V.C. .J.M. k.McS. P.A. K.K. 7 84 19 7 7 8 11 9 7 11 84 15 9
Mother lost facial
fat aged 4.
Diarrheal episodes Poor hearing in
left ear.
Regional enteritis, sinusitis.
I.Q.75.
Poor hearing II
left ear. Markedly pig-mented, Liver enlarged. Large ovarian dermoid excised Moderate mental retardation. 602 TABLE V
PARTIAL LIPODYSTROPHY-RENAL DISORDERS IN PIIE.SENT Guot- p
Repeated attacks of pyelonephritis. IVP-nil abnormal
found. NPN 36.
Pyelonephritis. Clumps of WBC. Grain negative cocci. IVP twice negative. NPN . Treated with Gantrisin.
Subsequent cultures sterile.
Fever, rash-papular erythematous on back and extretni-ties. Joint pains. Pyria and hematuria. L. E. prep. nega-tive. IVP negative. Diagnosis: ?Hypersensitivity
reac-tion ?Acute glomerulonephritis.
WBC and RBC intermittently present. Staph. aureus-twice. IVP.Dilatedureters. Moderatecalycealdilatation. Punetate petechial rash-legs, dorsum of feet, buttocks,
arms, elbows. Hematuria, blood in stools. Albuminuria. BP rose. Diagnosed as Henoch-Schonlein Syndrotne.
Treated with ACTIT. Recovered but persistent
albu-mu, and RBC in urine.
Albuminuria and hematuria on one occasion. Cleared quickly. Further urines negative.
Purulent otitis and hematuria and aihuminuria. BP rose. Edematous. Died 6 weeks after admission, in uremia.
.4utopsy.
Over approximately years, recurrent episodes of hema-tuna, albuminuria, casts, edema with retention of
nitro-geri and elevation of BP. Died in uremia. Autopsy.
Developed frequency and nocturia. Found to have + +
alburninuria and occasional RBC and WBC. Subsided. Further urines-negative. NPN 30-40.
Passed brownish-red urine. Edema. BP rose. Albumin-uria. Albuminuria, edema continued. Cholesterol 477.
Fever. Circinate rash on body. Next day-gross hema-tuna. NPN 10. Periorbital edema. RBC casts. Albu-IninUria continued. NPN 17g. BP rose. IVP poor, but
enlarged kidneys with slightly dilated calyces. Died in
uremia. No autopsy.
Edematous post partum. Albuminuria+++. Many
RBC. (;rallular casts. Many WBC. Cholesterol, 350. E.coli which cleared on treatment, but albuminuria and
RBC persisted. Retrograde Pyelogram-normal. Diag-nosis-Membranous glomerulonephritis-Nephrotic
Syndrome.
Diagnosis of acute glomerulonephritis at 6 years. Recur-rent hematuria, 8 years. Nephrotic syndrome 1 1 years
-hypoalbuminemia albuminuria+ +. Cholesterol
rose. Edema continued. IVP-hydronephrosis right
kidney.
Episodes of hematuria, casts, albumin.
FIG. 6. 11. McK. Kidney x 125. Subacute
glomerulo-nephritis with acute necrotizing changes and mod-crate interstitial resl)onse.
v,
Fig. 5). This surprisingly high incidencewas also remarkable for the wide constella-tion of renal findings. Three patients had episodes diagnosed as pyelonephritis (S.G., DR., F.R.). Three patients had a general-ized rash coinciding with the onset of glomerulonephritis (E.H., J.W., J.M.). In
one of these the eruption was most
sugges-tive of the Henoch-SchOnlein syndrome
(J.W.). Another of these three had
proges-sive renal disease and died in uremia.
An autopsy was not performed.
Three patients were diagnosed as having the nephrotic stage of glomerulonephritis (V.C., K.McS., P.A.).
Isolated episodes of albuminaria and hematuria occurred in a further three
pa-tients (J.O’C., N.A., K.K.).
Two patients developed what seemed
to be acute glomerulonepllritis with pro-gressive deterioration and death in uremia (R.McK., D.J.). At autopsy partial
lipodys-trophy was confirmed. In each case the
kidneys were enlarged and
glomerulo-nephritis present. In addition, the liver of patient D.J. showed mild fibrosis and fatty vacuolization, and of R.McK., fatty vacu-olization (Figs. 6-9). Needle biopsies of the
kidney and of the liver were performed on patient P.F., a girl aged 8 years with par-tial lipodystrophy of three years’ duration. There was no clinical or laboratory indica-tion of either renal or hepatic dysfunction.
“Vacuolization” of the liver cell nuclei was
present, and there was focal glomerular
hypercellularity and some glomerular
epi-thehial cells were enlarged (Figs. 10, 11). Pyelograms, IV or retrograde, were per-formed on eight patients. These were found normal in four, vith varying de-grees of calyceal dilatation with or without dilatation of the ureters in the remaining four.
Other than the renal findings considera-tion of the whole group disclosed several other features. Three patients had
hepato-megaly. Nerve deafness was present in two
and two more had moderate mental
re-tardation. Three patients had diarrheal
episodes, due to regional ileitis in one. Not
one of these patients had diabetes mellitus. Of partictilar interest is the patieiit
under the care of Dr. S. Aarseth now
aged 62 years. Lipodystrophy was apparent
some time after puberty, exactly when is
not known. Diabetes mellitus without ketontiria has been present for the past 12
years. Hyperlipemia was present as was
hypermetabolism; BMR (maximum) + 44.
There was marked hepatomegaly and a liver biopsy showed cirrhosis with fatty degeneration and rich deposition of PAS-positive material. She had had, for some
years, signs of a nephropathy, suggestive
of chronic pyelonephritis, with an elevated serum creatinine concentration.
pa-FIG. 7. R. NIcK. Kidney x 125. Marked vacuolar changes and hypertrophy of
phenomenon.
tubular dilatation with e1)ithelitllll is a local
tient, as the photograph illustrates (Fig. 12)
does have normal fat deposits over the lower thighs and legs and has therefore been
included in the partial hipodystrophy group.
COMMENT
In assembling a composite picture of total lipodystrophy the components derive from a relatively small total number of patients and must be weighed accordingly. With the accumulation of further patients, features flOV considered of importance to the diagnosis may be given less emphasis, others, thought more variable, may assume greater significance and presently
nude-tected biochemical abnormalities may
emerge. This consideration is stressed as at present the diagnosis rests upon the association of several variable features with two constant ones, absence of adipose tissue and evidence, histological
biochemi-cal, or even clinical, of liver involvement.
The variable features include increased height, advanced bone maturation,
hirsu-ties, pigmentation, prominence of muscles, abdominal protuberance, penile or clito-ridial enlargement, anatomical or
func-tional disturbances of the central nervous
system, a nephropathy, cardiomegaly, a
rela-tively insulin-resistant hverglycemia with minimal or absent ketonuria, hyperlipemia,
and hypermetabolism. A factor contributing to the seeming variability of the features of the syndrome was the age at vhich the pa-tient was observed. Increased height, ad-vanced bonematuration,prominence of
mus-des, abdominal protuberance, and genital
differ-Fic. 8. D. J. Kidney
x
110. Sclerosingglomerulo-nephritis with considerable tubular atrophy.
FIG. 9. D. J. Liver X 90. i’s’lild portal fibrosis and periportal fatty vacuoles.
FIG. 10. P. F. Liver x425. The liver cell nuclei next to a portal area appear empty and “vacuo-lated.” Beyond this zone, the liver cells are pale
FIG. 11. P. F. Kidney x200. Glomeruli contain occasional en-larged epithelial cells and in one there is foca hvpercellularitv.
ences were not fixed but reflected the natural progression of the disorder. Nevertheless, the patients do not appear to comprise an
entire-1y homogeneous entity. In one group the
dis-order was thought present from birth and
in the other adipose tissue was lost later
ill life. This separation is uncertain as a
measure of doubt attaches to the precise time of onset for a number of patients in each group. Where onset was tentatively al-located to the nevborn period2#{176}’24 25 27
siblings were affected 225 and
con-sanguity was present in three sets of
par-224 2 7 and possibly another,29 suggest-ing a genetically determined disorder. No parent appeared affected and the patients were of both sexes, lending plausability to
an autosomal homozygous recessive state. Inclusion of those patients from Table III in whom the diagnosis of total
hipodystro-phy appeared likely would add a further
pair of siblings and two more
consanguine-oils matings.
That the same postulated genetic defect
is responsible for the syndrome first
of presentation covered a vide range of clinical diagnoses, pyelonephritis, acute
glomerulonephritis, the nephrotic
syn-drome, or chronic nephritis and a nephrop-athy associated with a generalized
vas-culitis.
Calyceal dilatation was present in four
of the eight patie1ts in whom intravenous or retrograde pyelograms were performed. Three patients died in uremia. Autopsies were carried out on two. Nephromegaly
was present and the histopathology showed
glomerulonephritis. In addition, the liver
revealed fatty vacuolization.
Needle biopsies in one patient with no
clinical evidence of renal or hepatic
dis-ease showed enlargement of some
glom-erular epithelial cells and glomerular focal
hypercellularity as vell as “vacuolization” of liver-cell nuclei.
On combining our patients vith those in the literature, further features, though not
as commonly present, included mental
re-tardation, hepatomegaly, and a decreased tolerance to glucose. A resemblance to the
syndrome of total lipodystrophy is evident.
Aarseth’s patient#{176}2 very closely approaches
the syndrome of total lipodystrophy and
hyperlipemia and a fatty liver were noted
on restudy of Simon’s original patient some 40 years later.7
The features suggestive of the syndrome of total lipodystrophy seem more evident in the older patients with partitl
hipodys-trophy, the foregoing two patients being
the oldest of the series. Possibly many
years must elapse before the various
mani-festations of the syndrome of partial
lipo-dystrophy are expresse].
Notwithstanding a number of common
features it seems preferable to maintain the
separation between the syndromes of total and partial lipodystrophy. Certainly a di-rect genetic relationship betveen patients in either syndrome is not apparent in either the antecedents or immediate families. In
partial lipodystrophy, itself, the familial
aspect is infrequent.
The patients with total lipodystrophy
FIG. 12. Patient of Dr. S. Aarseth.
have been separated provisionally into two
groups, and those with partial
lipodystro-phy considered together. This tentative
classification is based on clinical
impres-sions and will no doubt need revision when
more objective criteria are forthcoming.
The pathogenesis of each syndrome is
(jtlite obscure and no ready hypothesis
sug-gests itself to explain satisfactorily so many
diverse features. Nevertheless
considera-tion of certain postulates is indicated if merely to outline the scope of the prob-lem. We shall consider the syndromes of total and partial lipodystrophy together. There may be scant justification for this, but loss of fat is common to both and what-ever pathophysiological explanation is sug-gested for its disappearance should be ap-plicable to both syndromes. Again clues derived from the one may give some in-sight pertinent to the other.
608
of the cells storing fat or whether the cells are normal but subjected to the action of a fat-mobilizing agent. No strong evidence can be cited to sustain either concept.
A primary disorder of the fat-storing cells might lead to hyperlipemia, hypergly-cemia, and a fatty liver as a consequence of loss of the major storage organ for calories. However, the accelerated growth and bone maturation, pigmentation, hirsuties, genital enlargement, and suggestive increase of muscle mass are not easily explicable. These features in the broadest sense are sugges-tive of a hormonal effect.
A postulate is that absence of an impor-tant target organ, adipose tissue, might re-sult in oversecretion of hormone(s) nor-mally acting thereon with a variety of other effects resulting. Of interest is the appear-ance of the syndrome of total lipodystrophy in a patient with histologically proven Weber-Christian disease and in two others with clinically similar dermatological le-sions18 29 and of partial lipodystrophy in yet a fourth such patient.86 At first glance this appears to support the view that the syn-dromes of hipodystrophy may result from destruction of adipose tissue. Unfortunately the pathogenesis of \Veber-Christian dis-ease is equally obscure. Thus an alternative
explanation is that the process responsible for disappearance of adipose tissue in the lipodystrophy syndromes may temporarily produce a picture resembling Weber-Christian syndrome.
To explain the syndrome of partial lipo-dystrophy on the basis of a primary adi-pose tissue disorder is difficult. One would need to postulate two distinct groups of fat-storing cells, an affected proximal group and an apparently normally functioning distal group. However, an autotransplant of fatty tissue to an atrophic site lost fat and atrophic tissue transplanted to an adipose site accumulated fat.87 This strongly sug-gests that in partial lipodystrophy the dis-order is based on the environment of the cell rather than on the cell itself. In par-tial lipodystrophy total body fat stores may
be quantitatively little changed yet a num-ber of the other features may be observed. This would accord poorly with the concept of absence of the adipose tissue target organ.
Another postulate for the disappearance of fat involves the action of an extracellular fat-mobilizing agent. Theoretically this might be a humoral substance formed
else-where or a local agent produced in proximity
to the fat containing cells. The various ac-companying features might then be ascribed to further effects of this hypothetical agent. A peptide has been extracted from the urine of patients with total lipodystrophy, as well as from fasting normal and obese subjects, that has fat-mobilizing activity in mice and on rat adipose tissue in vitro.93-94 A syndrome suggestive of total hipodys-trophy has been observed in patients with tumors in the area of the hypothalamus,’ and central nervous system disorders have been seen in a number of patients with total or partial lipodystrophy. Associating these two observations, each of uncertain significance, a postulate of a hypothalamic disorder causing a release of a fat-mobiliz-ing agent emerges. However, the symmetri-cal segmental loss of fat in partial lipo-dystrophy does not suggest an action by a humoral fat-mobilizing agent. The distri-bution of such loss prompts consideration of a neuronal effect. That neuronal stimu-lation or suppression profoundly affects fat release and storage is recognized.96 97 Pos-sibly fat mobilization is achieved by a hu-moral agent acting on nerve tissue and the other features appear as a result of a more direct effect of the same agent. It is quite apparent that the basis for such a hypothesis is tenuous.
609
possibly an increased susceptibility to pye-lonephritis. However, the syndromes of gb-merulonephritis lead to consideration of antibody concepts possibly relating to adi-pose tissue as well as the kidney. At this time there is no evidence to support such
a concept.
We have devoted a disproportionately
large section to a discussion of theoretical
possibilities to indicate not only how poorly
understood these syndromes are, but how
difficult to explain even on the basis of pos-tulate within our present framework of
understanding.
SUMMARY
The syndromes of partial and of total
lipodystrophy have been reviewed and 27
further patients added, 25 with partial lipodystrophy and 2 with total
hipodystro-phy. For inclusion in the syndrome of partial
lipodystrophy symmetrical loss of fat from
the face with or without truncal loss, but
with retention of distal adipose depots was required. In total lipodystrophy fat loss was generalized.
A number of additional features were
commonly present in total lipodystrophy. These included increased height, advanced bone age, hirsuties, pigmentation, promi-nence of muscles, abdominal protuberance, penile or clitoridial enlargement,
hepato-megaly, relatively insulin resistant
hyper-glycemia, hyperlipemia and
hypermetabo-lism, as well as renal disease, disturbances
of C.N.S. function and cardiomegaly.
Review of reports of patients with mus-cular hypertrophy suggested that several so described might have had total lipo-dystrophy.
A significant incidence of renal disease was encountered in the reports of partial
lipodystrophy in the literature and more
particularly in the group presented. Al-though much less frequently present, cen-tral nervous system dysfunction,
hepato-megaly and a decreased glucose tolerance
were also noted. It appears that there are
features common to both syndromes other
than disappearance of fat.
Possible pathogenetic mechanisms have been considered.
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Acknowledgments
\\_c gratefully acknowledge the co-operation of
the physicians who so generously made available
details of patients under their care:
Drs. Lee Forrest Hill, Paul Welty, and Carol
Spellman for patient E.W. with total
lipodys-trophy, and Dr. I. Zevtin for patient P.P. with
total lipodystrophy. Drs. G. H. Newns and S. A.
Plotkin for patient PA. with partial lipodvstrophy,
and Drs. P. Strong, D. W. Walker, H. Bowman, and J. D. Crawford for patients 5G., FR., J.W., and K.K.-all with partial lipodystrophy.
\Ve thank Dr. G. F. Yawter of the Children’s
Medical Center, Boston, Massachusetts, who
re-ported on the histopathology of R.J., R.McK., and
