PROGERIA
Report
of a Case
with
Cephalometric
Roentgenograms
and
Abnormally
High
Concentrations
of Lipoproteins
in the
Serum
By Ira M. Rosenthal, M.D., I. Pat Bronstein, M.D., Frederick D. Dallenbach, M.D.,
Samuel Pruzansky, D.D.S., and Alan K. Rosenwald, Ph.D.
I)epartnmeot. of Pediatrics (111(1 Pathologtj 011(1 tlm(’ Cleft Palate Cenfe, of tl,(
IIoiircr.sity #{248}fllliliOiS College omf licilicine
(Stmbmiiitted January 27, accepted Februiarv26, 1956.)
ADDRESS: (1.M.R.) 840 S. \Vood Street. Chicago 12, Illinois.
565
P
IIOGE1IIA is a disease iii vimich timeafflicted! cilil(l reseliil)les a very tg(Odi
ensomi Ill tPI)1r11lce. Certain S1)ecific ab-normnahities in gro)\vtii and (ievelopmnent are regularly fotmndi. Analysis o)f cases o)f
pn-geria has l(.#{176}(lto tue belief that mnamiy of
tue
ai)IlO)rnlali ties foumid are prilnani ly
tue
resultof 1)re11itttmre aging. \Vhile cases of progenia are rare, intensive stu(!\’ of the disease is imidicate(i ill order to) ascertain viiether true
l)reliitttire agimig (iO)es actually occur in
)nOgeria. It is also) iilil)ortant that the factors
respo)ml’ii)ie for thi( etrl’lo’ 1Pi)etnimice of
atiierosclero)sis in pro)genia l)e (!eterfllimie(i audi sttl(iie(1 ill relatiomi to) the factors
re-51)Ollsii)le for the (ie\’elol)nient of atiieno-sclerosis iii admIts.
Progenia ‘as first (iescnibeoi by Hutchin-soIl’ ill 1886, audI the onigimial (!escnil)tion \‘15 amn1)lified
liv
Gihfond2 5OfllC years later.Time (!isease is also known as the
Hutciiin-somi-Giiford svmidnomne on )nogerOnlniSIii.
Sonic 27 ciSes of progeria have 1)eeli
re-I)0rtei. Time early cases of progenia have i)eeii reviewe(l amid! miiav be found!
sumnmnar-iZe(! in chart form iii
tue
articles ofSchomi-(id, Thomnsomi amid! Forfar, and! Cooke.
\Vitiiiii the l)ast few \Teans a(i(!itiOlial cases have i)eeli reported 1)’ Atkins, \Iostafa amid!
(;tbr,7’ Plunkett ef a!., Rossi,’#{176} Dotlb,’
\ltizzo arK! AlO)ml5O,’ amid Keav et a!.’
Post-niortelii studies iia’e i)eeIi reported on five cases . - 4; , I;
Patients with progenia arc remarkable in
the strikimig physical resemblance they bear to one amiother. The tpicah patient has a
sniail face, a beak-like imose, uii(ler(le\’eiope(i
ja\\’s, absemice O)f ear lobes, aiopecia, niarked
tlll(ierstature, loss o)f subcntaiieous tissue, miiuscular liVl)O)l)lasia, amid! pen articular
changes with secomidlarv comitnactures . Time
characteristic appearamice develo)ps
gnilditi-ally, amid! it is usually no)t umitil the emit! of tile first year of life that the (!iagno)sis is mnadie.
Intelligence usually appears to be withimi
tue
normal range. The clinical course O)f these
Patients is remarkably tmnifonni .
Athero-sclerosis dievelops early, aiii patiemits with )nogenia succumrll) at an early age as a result of myocardial itifarctiomi or cerebro)vascuiar
disease. \Iost of theni die imi the second
decade of life, although a fev have lived
through I)trt of their tilirdi dlecadie.
\Ve iiave had the P1)rtummiit’ to) sttidv a
case of )nogenia oven a 10-year I)enio(!, teriiiimiated! 1)1’ the accidielital (leath of the
1)ltiemit. In the course o)f the studlv,
cepliaho-nietnic studies were iiia(ie imi Or(!er to)
cluci-date tile cause of the abnormal facial
ap-peanamice amid! to d!elimieate
tue
miattire of the growth diistunbance as it affects the skulliii )rogenia. The radiioiodimie tm1)take audi the
concentrations of hipoproteimis in the serum
were measured!. A dietailed psvchologic
study ‘wits madie, a suniniarv of vhicli is included iii this report. Necrops fi ndi rigs are also) re1)orted. \V(:O believe this to) i)e the first report o)f necropsv of a Paticllt with )rOgenia where (!eatil was the result of an accident. Our studlies head! us to i)eiieve tilat
the senile 1iPeartmice of these patiemits
566 ROSENTHAL - PROGERIA
1)trtitllitrlY ill’t’Ol\’il ig iiIC (lCVelO)l)mliemit of
tue
skull, and! from a severe ntmtnitio)nal aIi(lmetabolic disturbamice as yet unknown.
History
CASE REPORT
J.
B. was first examined in the pediatric clinicof time Research and Educational Hospital of the Universitv of Illinois in April, 1944, at the age of 15 nionths. Time child was referred for examiimatiomi i)t’catmse slit’ vas not gaining
weight properly. This had been first noted1 when
she was 7 months old. There was no history of disturimmice o)f growth iii other niemi)erS of
the family. The patient had three older siblings, a i)rother tti(l tWo sisters, who are normal. The
mother 42 ears old and time father 41 at the timne of the chii(Is l)irth. Time pregnancy
amid! dleiiVerv ‘ere apparently mio)rmal. The
(.hii(l weighed :3.6 kg at birth, amid no
abmior-mnalities wei( flote(h at that time. The mieoiiatah course was not uiiiuistiil. The i)aby was breast
fed for 1 month and then was given a
formula of cow’s milk. Nd) difficulty \VdS mioted
iii the sui)seqtiellt intro(lulctiOmi of solid! foods.
The child sat up at the age of S months amid! walked! at 12 mnonths. Toward the did! of time
first year her mimother l)ecorne concerned because of time relatively poor weight gain achieved after the age of 7 months.
Physical Findings
Physical examimiation at the time o)f the first visit to the clinic (age 15 mnonths) revealed a small, frail, active white female child who even
at this time was commsidered to have a somewhat unusual facial appearance. She weighed 7.3 kg
audi was 68 cm in length. No teeth had as yet ertmptemi, aiim! the hair was sparse. No definite diagnosis vas mimamle at this time. When
re-examined 5 unomiths later at tile age of 20 miionths, she weighed 7.5 kg, and! her length was 72 cm. It was notedi that the iiose was beakedi and promninent an(i the jaws sniahl. Her hair had! i)econie more 5Putl5e She was timiable to extemidi her fingers, elbows, wrists and knees com pletelv. On tile l)asis of these characteristic findings, a diagnosis of progeria \\‘aS made.
Course
During the ensuming years she was followed iii the clinic. Her first tooth erupted at the age of
23 years. Serial determinations were made of
height alldi veig1mt. These arc chal’t(’ol in F’igtim’e
I , Wll(.rC it miiav be iO)tedl that, while gains in
1)0th height and weight were poor after the first ‘ear, weight was more severely affected than height. By the age of 103k years, the child had
attained a weight-age of 13 years amid a height-age of 33’s ‘ears. Ps’choiogic developtiielit, 011
the other hand, was relatively mio)rmal. She
entered! a school for handicapped children at
the age of 6 years and mnadle good )rogress. Tue child was relatively free from intercurrent
illness. She had! occasional respirators’ imifections with good recovery, and! ri the last 2 ‘ears of
her life suffered from mild hay fever during the ragweed season.
Physical Findings at Age 1 1 years
At the age of 1 1 years, shortly before lien
death, the child weighed 10.9 kg and was 100 cni tall. The circumference of the head was 44.5 cm and of tile chest 46.5 cm. The appear-amice was typical of patients vitii progenia (Fig. 2). The head appeared harge in comparison to the small body. The face was small, amid the thin
nose was prominent and beaked. The jaws were markedly underdeveloped; the mouth was quite
smiiahh, and all of the deciduous teeth were still
present. The lobes of the ears were absent. She
was completely bald except for sonic fine hairs
0)11 her head. The eyebrows comisisted of a few
short, barely visible hairs, and there were no eyelashes. There was also almost complete ab-sence of body hair. The skin was thin, glabrous
amid! lightly pigmemited as if tanned by exposure to the sun. The superficial venous pattern was promimiemit, especially oven the thighs amid the
scalp.
There was virtually no subcutaneous tissue. Because of this and of the tightness of the skimi, the underlying muscle was umiusualhy
conspicum-oils, although not hypertrophied. The elbows,
knees, wrists, metacanpophalangeai amid inter-)halaflgeal joints were prominent. There was limitation of motion, particularly in extension, o)f the elbows and knees. The kmiees could h)e extended to ai)out 160 degrees. The
interpha-langeal joints of time hands were enlarged, and
there was restnictiomi of motion of tile slend!er, curved fingers. The fingernails and toenails were small and atrophic.
E
U
-C
am
V I
0
I 2 3 4 5 6 7 8 9 0 II 2
Age (yr)
2 3 4 5 6 7 8 9 0 II 2
Age (yr)
-Fie. 1. Graphs of gain in weight (left) and growth in length (right) of pttiemmt
J.
B. Measuirenments are compared to :3rd tiui 50)th p(rcentiles for girls adapted from Anthropometric Charts, Children’s \Iedical Center, Boston.iitdi \VitIl her joints. She vore a wig viiich
served to some extent to soften time bizarre
imiivsicitl appearance.
Time remainder of the physical examination
‘as not remarkable. The humig fleidis were clear to percussion amid aumsctmltation. A grade 2
SVstO)hic murmur was heard at the apex and along the left sternal border. Blood pressure
was 100/60. The abdomen was soft, and neither
time spleen nor the liver was palpable. The neurologic examinatiomi was not al)normah.
Laboratory Findings
Sonic of the ntimnerous lai)oratory tests per-formed (hiring time 10 ‘ears she was followed iim
our climmic are I)ie5e1itedI below. Blood coumits were essentially normal except for mild
eosiiio-1)hilia. Repeated urinahyses were normal. In
1944 the concentration of blood glucose was
53 mg ‘100 ml, nonprotein nitrogen 31 mg’ 100 ml, carbon dioxide combining power 41 volumes/lOO ml, concentration of albumin 4.6
gm/100 ml, globulin 1.6 gm/100 ml. The
spinal fluid was normal. Blood cholesterol in
1948 was 291 mg,/100 ml. Iii 1953 tIme
concen-tration of urea iiitrogen was 9 tug ‘100 ml, i)lOod glucose 82 mg/100 ml, total protein 7:3 gm’lOO ml, amid cholesterol 270 mg/100 ml. Radioiodimie uptake was 30ff of the ad-ministered dose iii 24 hours, and time
conver-sioll ratio was normal. Analysis of hipoproteins
ill the serum was performed by
uhtraceimtriftiga-tion in August, 1953.#{176}Standard Sf 0-12 was
492 mg,/100 nil and standlardi Sf I 2-400 was 221 mg 100 nil. The atherogenic in(iex vas 88. Electrocardiograms done in 1944, 1947.
1948 and 195:3 ere normal. An electmoeim-cephalogram do)ime in 1948 SiiO\vc’(l 6 to 9 sec
activity and ‘as normal.
Roentgenographic Findings
Roentgemiographic exaniinations were nmade at irregular intervals after the first visit to time
clinic. The most recent roeiitgeumograms ‘ere oi)tained in November, 1953, and revealed! the
* This test was perfornied at time Institute of
NORMAL9 og.IO’O JB.9og.tO.9
NORMAL
-J8
following: Posteroaimterior #{128}umdlateral views of the chest showed an extremely gracihe structure of the thoracic cage. The humig fields appeared clear afldi were well aerated with no evidence O)f active I)t1i1noilarY (iisease. The cardiovascular silhouette ‘aS essentially no)rmai. Lateral amid ailteroposterior views of the thoracohummbar
Spume shoved an abnormal amount of
osteo-porosis. Irregularity of the epiphseah plates, viiich is not ahmmormal for this age group, was
also) noted. Timere was au apl)arent relative dis-proportioi I l)etween the timiderdevelopment of
the structure of the ribs and the normal devel-0I)mfletit of the spimle. No roentgenographic ab-miormahities were seen in the articuhar surfaces
of any o)f the jO)ilits o)f the i)ody.
Roentgeno-grams of time long l)ones also silowed a reha-tiveiy gracile dleveiopmetit. There was relative
Overdlevelopmiielmt of the metaphseal areas of
time long boimes compared to the shafts. Time
Sante relative expatmsiolm involving the other
bug bones \\dS tmoted throughout the phalanges
ammd meta(ar1)als. There was fairly niarkedi
ante-nor bowing iii time shafts of both femurs,
pre-Stmtllai)ls’ Secolmdlarv to osteoporosis. A marked degree of coxa ‘aiga was also 1)reselmt.
Roent-genogrammis of tue wrists audI hands showed a carpal boime age of 1 1 years. Areas of calcinosis circumnscri1)ta had i)eeml no)ted in the area of tile tuft of time (listdi phalanx of the rimig fiimger of the left imand ill roentgenograms taken in March, 1 949, atmd l)y 1953 there had been imiarked real)sor1)tion o)f these areas. In the
skull there was umiderdevelopment of the facial i)ones as compared! to the cranial vault. The
cal-variuni was thin, the anterior fontanel was still
present, aIld the sagittal suture was open. The
roentgenograms also showed a paucity of
sub-cutaneous tissue. It was felt that these findings
were consistent vith the cliimicai dhagnosis of
progenia.
Standardized cephalometric
roentgeno-grams,’7” taken ill 1953, were employed in the
analysis of the head to elucidate time tiature of
the disturbance in growth of time head! ill
progeria. Tracings of a lateral cephalometnic
roentgenogram of the patient were compared
with those of a normal female of a similar age
(
Fig. 3). It was apparent that tue patielmtdiffered from the normal imi several respects.
The calvanium was thinner, and the amount of
soft tissue over the neurocraniurn and the face
was less than in the normal. The niost striking
feature was the poor facial growth dOd! retarded
dental development.
Superpositioning of the tracing of time
pit-tient 111)011 that of the normal, utilizing time base
of the cramlium as the baseline (Fig. :3), served
to emphasize the similarity jim size of the
cranium amid the difference iimfacial skeletons of
the two subjects. The neurocrammium of the
pa-tient was of relatively normal size and
configu-ration, but the face, com1)ared! to the normal.
was markedily retarded in anterior aimd vertical
growth. However, the persistent ammterior I
tanel and the open sagittal suture suggest that
the disturbance of growth affecting the facial
bones in the patient with progeria also affects
the neurocranium. The relatively normal growtlm
of the brain in progeria apparently provides a
stimulus to the development of the
neuro-cranium during the first few years of life.
Fi(. :3. ‘l’ratings of lateral stamidardized cephalolmmetric roentgenogrammis colmm)aring time head of a normal
(/lr001eoh)qi(’
,
lye(i/ears)
Mental .lge
(years) .
Basal Age*
. (yearx)
(eilirmg Levelt (years)
i4-1O/1
11-l/1
103
91
97
1O
570 ROSENTHAL -
PROGERIA
There is no analogous stimulus for facial growth. Thus, the combination of a
neurocran-iuin of relatively mmormnal size, a facial skeletomi retarded in growth, amid! a reduction in the amount of subcutaneous tissue accounts for the
characteristic facies of progeria.
Intraoral dental roentgenogramns taken when
the patieimt was 1()”’ ears of age, revealed
timat, exce1)t for timu’ second diecidumous molars,
time decidluous teeth ere fully eru1)ted. Time crowims of the succedaimeous incisors, camiiiies, znaxihlarv biscuspids ammd mandlibumlar first i)iscuspids were calcified! amid! umnerupted. The crowns of the first amid! second permanent molars were calcified amid crowded within the
diiminutiye jawbones. Estimation of the dental
age of the patient, compared to normal stand-ardis, was difficult. In ternis of time deciduous
dielltitiO)ll, this patient had a maximal dental
devehopmemmtal age of 3 years. Iii contrast, the
stage of calcification of the crowns of the
per-manent teeth l)ltce! the diemital age at about
5 years. No gross mnahformation of the teeth was noted.
Results of Psychologic Testing
The child was first given a series of psycho-logic tests at the age of 51 ears. The tests were rel)eatedl on three separate occasions, the last examination being given when she was
years o)f age. Both intelligence and!
per-soimality tests were givemi.
Intehlectumally, the patient was within time
average range. Her stmccessive perforrnaimces on
time Stanfordi Bimiet, Form L, are given in Table
I. Aim analysis of the various successes and!
failures silo)\Ved that she had! relative difficulty
ill time executioim of motor tasks, particumlarhy those which demand the duplication of a model, e.g., time reprodluctioim of the figure of a diamo)mmdl. This ilmai)ility to cop\’ a n#{238}odelwas
paralleled by the relative difficulty in
reproduc-ing designs shown for a brief period of time and then withdrawn. In coiitrast to the rela-tivehy poor performance in these areas, the memory for words, the development of the vocabulary and certain abstract reasoning skills were relatively good.
The most significant trait of personality was
an imisatiabhe need for love and attentiomi. This
was coupled with extremely primitive feelings
of rage if the child sensed a thwarting of her desires. She was insensitive to the feelings of
others. She was comisidered a potentially
hyper-active child because she became distracted by
many stimuli, both consequential and
imiconse-(luential. No attempt will be made in this paper
to consider the relationship of progenia to the
development of personality. A detailed report of
the psychologic findings will be published
else-where by Pathman and 21
Circumstances of Death
On October 26, 1954, while attending school,
the child was accidentally pushed by a class-mate and fell, striking the right side of her head against a wooden chain. Following the accident, she complained of headache and miausea and was sent home from school. Ex-amination at home revealed no neunologic
ab-miormahities. There was no disturbance of con-sciousness. Headache persisted throughout the following day, and the child vomited several times. She was restless during the subsequent night amid died suddenly at 6 A.M. oIl October
28.
Necropsy
Findings
At necropsy, the cause of death was found to be a large oval-shaped epidural hematoma over the left panietal region. There was a fracture of
‘I’ABLE I
RESULTS OF STANFORD BINET TEST (FouM L)
tIar. 1945 3-2, 1’
()(t 1941)
Feb. 195’2
Nov. 19.53 l0-IO/1i,
* \‘ear level at 1hi(ii all tests are successfully passed.
t ‘tear l(vel at ts’lmieh all t(st ire failed,
4-6/1 7
5 9
6
time left parietal bone, Cerebral edema va pres-emit.
Other fiild!ings were comlSiSteiit vith the
diag-flOSi5 of progeria . Generalized atherosclerosis,
pirtictm!irhy iiivoivim ig tile aorta, coromiary aild miiesemmteric vessels sas present.
(
Figs. 4 and! 5). There as atro1)imy and! 1)ignlemitation of the integtmiiieiit with Iliarked d!imilmtmtiomi in anx)tmntof subctutaneous fat. There was persistence of
time anterior foimtaimel, and the sagittal simtimre
\\‘IS riot closed. Inactivity of the i)0ll\’ epiphvses
‘as foummd!. Time joints theniselves a1)1)edred nor-mal, but a considerable degree of periarticumlar fibrosis was presemlt. There was no evidence o)f hvl)ertnopimic arthritis. Tue pituitary ‘as
essen-tialhv normal. Abnormal calcificatiomi of the choroid plexus and pineal gland ‘as preseiit.
Details of tile lleCrO)1)s’ appear in an
ap-1)endix. The length amid! weight of the i)Od!v at time time of miecropsy and the weights of varioums organs are compared to average normals22 iii
Table II. It is apparent that the l)rain was of
lIC. -1 ([TP/er) Cross-section of mimesenteric artery: Eccentric hiyper)lasia of intinia with f:ll)rosis tii(l
lipoi(l (l(’1)ositiolm, (I I,&E, >‘. 125, re(incedi 3i.)
\\EIGIL’rs OF ()ue;Ns IS (‘OMPS tEl)
TO AVEiIAGE Noiisi.
.lo’erag(’ for
.\orm(1i
I’ernale’
11 Yeurx
Patiuti
1 1
Iears’
Patient
%(f Average
\TOrn,(.1
Body imeiglmt
)out 114.7 i() 70
(average)
Brain 135)
77 1331
‘I’ABLE 1I )rogenia to amialyze its relation to senilism.
It is in a sense unfortunate that this name was chosen for the disease, since it implies that true premature aging occurs. The term “progeronanism,” while better, is subject to the same criticism. It is therefore impor-tant to examine each of the features found in progenia which are suggestive of senilism in order to distinguish between those which
may be true senile characteristics and those
:k5 7 1 1 ‘31 imi which the resemblance to senihism is only superficial.
93 75 We have demonstrated by cephahometnic
195 100 .51 studies that the odd facial appearance in
i):: -‘: progeria is the result of a severe disturbance
of growth of the splanchnicranitim and the
mandible. The similar facial appearance of
the edentuhous octagenaniami results from atrophy of the alveolar processes and! subse-quient loss in vertical facial height and! ade-quate support of the cheeks andi hips, an entirely different process. Thinning of hair is frequently found in old people, and!
bald!-ness is not uncommon in aged men.
Mascu-linizing testicular hormones probably con-tribute to the hatter. The almost total alope-cia found in progeria, affecting both sexes equally, is evidently quite different.
In senihism, joint changes are largely the
result of hypertrophic arthritis. Analysis of
the roentgenograms shows no evidence of
hypertrophic arthritis in our case of pro-genia. Examination of several joints at necnopsy revealed no evidence of synovial disease. Restriction of motion appears to be the result of periarticular changes with see-ondary contractures rather than the result of primary joint disease. The prominence of many of the joints is the result of widen-ing of the metaphyses andi loss of subcutane-oils tissue. There is no apparent relationship
between these abnormalities and the joint disease found in aged people.
Atrophy, wasting and loss of
subcutamie-Oils tissue are frequently found in seniiism.
These characteristics are often associated with poor caloric intake in the aged!. In
)rOgenia these ciiamiges occur despite a
caloric intake ad!eqtmate for the miormal child!.
s’Ioreover, it is evid!ent that 1)ant of the
wasting in progeria is the result of
con-572 11OSENI’J-lAL - PROGERIA
11O(l\’ weigim t
(kg)
Organs (gum)
Ilea rt Lung (average)
Liver
l)leetm Kidimey
average weight, the heart and! kidneys
mnod!er-ateiy ummdlerweight, aimd the !ummigs and liver a)proxilnate!y one-half miorm’nal weight, itt con-trast to the total weight of the body which was less thamm one-thirdi of the average miormnal.
DISCUSSION
It is a curious fact that unrelated patieiits, male amid! femiiahe, of different racial strains froni various I)arts of the world! should dIe-velop such stnikimiglv similar physical char-actenistics that the diagmiosis of progenia can 1)e made at a glance by anyone familiar with the (!iSease. It is reasonal)le to conclude from tue available data that progenia is a specific (lisease iather than a syndrome vhichi flay result from a variety of causes.
It is cimnious that d!eterrninatioml of the etiology’ amid! pathogenesis of a dhsease which restmlts in stich an oven-all and unifonin devia-tioii from the noniiial 5lid)tmldi have I)ro\’e(! to he such a dlifficu!t task.
The diagnostic features of progenia are so well defined! that there should! be no con-fusion with cases which have one or more characteristics found! in )nogenia, but which fail to meet the classic diagnostic criteria. These cases should be otherwise reported.
If the aI)I)etrllicc of simch pttie1its i)ears
sortie reseIiil)!aiice to progenia, the tenmii “)ro)geroid syndroumie,’’ \Vhlicil dld)eS iiot illil)lv a coiiiumiomi etiology, may l)e used.
ARTICLES
timmuec! linear gruw’tim desj)ite failure to gaimm
weight.
Psychologic changes of a degenerative miature are frequently found in senile mdi-vidimals. Himler2 has listed1 poor memory vitim cO)Iifal)uhatiomi , loquacity, ralTIl)himig,
5lOWmie5s of SI)eecii, af)athiv, 10)55 of interest, dhisiike of new things, diminished! capacity for self care, neglect of personal appearance dud! pathologic emotional reactions tmnd!er
stress as tile COflilliOli sighs of senile deteni-oratiomi. Psvcho!ogic studies of our I)cttient
amid! diescniptiomis of other patients indlicate that suchi cilamiges are not orolimiarily found!
iii
Atherosclerosis is frequently found! in senile imidivid!tmais. It is miot miecessanihy I)res-emit, iiowe’en, and! many ind!ivid!tials
demon-stratimig most of the usual semiile
character-istics are remiiarkably free from
atheroscheno-515. Coiivensely, many young adults who have riO) sighs of senihismn, have a
consider-al)le d!egree of atherosclerosis. While there
is rio agneemiient as to the causes of athero-sclerosis, the theory that simple aging is the cause of this condition now has few
pro-I)Omients. Atherosclerosis appears to be in-variably 1)reseilt in cases of progenia and! re-suIts in the early d!emise of these patiemits. Gofman Ct (11.24 2 claim that elevatiomi of the
concentratiomi of hipoproteins iii the serum is related to tile d!eve!opment of athero-sclerosis. It is intenestimig tiiat elevated!
con-centnation of li)oproteinS amid! a remarkably higii atherogenic imidex were d!emonstrated!
iii otmr I)atiemit by analytical
uhtnacentnifuga-tiomi. Gofmami has also d!emonstrated! that
elevation of the concemitratiomi of hipopro-teimis in the serum is often associated! with obesity and high intake of fat. It is of inter-est that tile ehevatiomi of the concentration of hipoproteins in
tue
sentim in our case of )rogeria occurred in a wasted ind!ivic!ua! with a Iat1cit’ of ad!iI)OSe tissue. It is cvi-d!ent that there was a (!isturbance in the relationship 1)etween hipoproteins of the serum amid to)tai lipids of the body. If dc-vation of the comicentration of !ipoproteins can be dlemomlstnated! l)\’ analytical tiltracen-tnifugatiomi ill otiier patients vitii )nogenia,the relationship of the elevation of these
substances to atherosclerosis as posttiiatI by Gofman will have additional support.
Keay et a!.’3 found an elevate(! ratio of total
concentration of cholesterol to total concen-tration of cinctulating I)iiOSI)hiOliI)id!5 and an ai)normiially high coiicemitnatio)ii of
choles-terol omi the beta-iipo))r0teili fraction in tile
serum of a 3-year-old! patient with progenia.
It is evident that atherosclerosis in pnogenia, while similar to that foumid imi some senile
imid!ividuais, Inay steni from a severe
turbance in metabolisiii of hipoproteins amid
is not the result of a siml)le aging iirocess
involving the arteries.
Many theories have been proposed! to
ac-count for the severe disturbance of growth
foumid in progenia. Of these, we wish to
consider the hypothesis that a disturbance
of pituitary function is the basis of the
disease. Evidence cited for this theory is the
proved relationship of the pituitary’ to
growth and also the abnormality of
tue
sehlatuircica and the reduced number of
eosino-1)hilic pituitary cells which were foumid in some cases of progenia. Atkins has reported!
in 1 case only a slight decrease in
eosino-1)hihic pituitary cells. He points out that a
slight decrease in these cells is not goof!
evidence for hypophyseal origin of progenia.
No significant abnormality was found! in the
sella turcica nor iii the histology of the
)ituitany iii our case. Patiemits with progenia
differ consk!erably in physical appearance and clinical course from patients witii
ii’-I)Olliittiitanism. Moreover, I)atiemlts vitii
pro-geria do not show evidence of adrenal
dys-function which might be the result of
insuf-flciency of pituitary conticotnophin.
Thyroid function also appears to be nor-mal in progenia. In our case and in the case of Keay et ai.mti the uptake of nadioiod!ine
was normal. In )nOgenia there are neither
the stigmata of iiypothyrOid!ism nor of clas-sical hyperthyroidism, although it may he
noted! that marked! ic!iopathic
hypermetab-ohism was present imi at least one case.1
The thyroid gland has been examined at
574 ROSENTHAL - PROGERIA
\Vhulc mimost o)f til(’ l)atieiltS vitli
p#{176}g’
have beemi sexually immature, it is to 1w
noted that Gilfond2 and Manschottl, 2m each
described a patient with spermatogenesis.
Plunkett et (ll.’ fotmnd! the pituitary
gonado-trOI)iiiIls to) i)e witlumi norniai limits in
stud-ies of a mimic patiemit. The failure of breast
development and the imial)ility to achieve
menarche in females may be secomidary to
the poor nutritiomial state rather than to lack
of pittiitarv gomiadotropins. It is evid!ent that
theories involving a primary pituitary dis-ease as the catise for )rogenia have little
suI)port.
More logical amid niore comisisteiit with
the observed facts is the theory of Talbot
et al.’6 postulating au inborn error of me-tabohism. The markedly increased
consump-tion of oxygen found in the basal state in one
Patient in
tue
al)semice of hypenthynoidism is consistemit with this hypothesis. The ehe-vated concentration of hipoproteins fotind inour patient suggests a metabolic defect
in-volving these substances. It is evident that
the natumre of the metabolic error basic to
progeria remaimis to be elucidated.
We believe that we have demonstrated
that progenia has little in common with senilism except a basically obscure origin.
It is hardly likely that rational therapy for either comidition will be devised in the
ab-sence of umld!erstand!ing of their basic causes.
It seems safe to postulate, however, that the
etiohogic mechanism of senihism, die
corn-momi end of all who survive long enough, is
quite different from that of the medical
oddity, pnogenia.
SUMMARY
A typical case of progenia
(Hutchinson-(;iifond symid!romne) is rel)d)ntedl including the
find!ings of the necropsy. Death occurred at the age of 11 years as the result of an
acci-(lent. Analysis of cephalometnic
roentgeno-grams of this patient revealed that the
char-actenistic facies of progenia results from
marked retandlation of facial growth in the
presence of relatively normal growth of the
neunocramiium, an! is therefore not the
re-stilt of premature aging. Atherosclerosis was
fouimd in this dub! at necropsy.
Commceimtra-tions of liI)oprOteins in the serum
dieter-mined by analytical uitracentrifugation
dur-ing life were found to be abnormally high,
suggesting a metabolic error rather than
premature aging of the arteries as the cause
of the atherosclerosis. Psychologic studies
showed the patient to be of normal
intehli-gence with no evidence of senilism. Analysis
of these data leads to the conclusion that
premature aging does not occur in progeria.
APPENDIX
Necropsy
Findings
Necropsy was performed 5 hours after death. The body weighed 1 1 kg amid measured 102 cm iii lemigth. The appearance of the face and body did not differ appreciably from the de-scription givemi during life. Symmetrical bossing of the parietal and frontal regions was evident. Many of the veins of the scalp were conspicu-ously congested. No ecchymoses on lacerations
were found. The sagittal suture was open. The
anterior fontanel was soft and compressible, measuring 2 cm iii lateral dimension. The posterior fontanel was obliterated. Both pupils were round, regular and measured 3 mm in diameter. The gingiva and tongue were not
unusual. The integumemit was thin and
nfl-wrinkled.
On incision of the anterior abdominal wall, no
subcutaneous fat was evident, the thimi skin being boumid to the dark red skeletal muscle amidl fascia by a loose inelastic tissue. The omentum contaimied virtually no fat. The mesentery appeared normal. The intestines were collapsed.
The pleural and penicardial cavities were
miormal. The heart weighed 95 gm. It appeared slightly enlarged in situ. The foramen ovahe was closed. The tricuspid, pulmonic, mitral and aortic valves appeared normal amid measured 8.4, 4.5, 6.0 and 4.3 cm, respectively. The endocardium gemierahly was smooth and glisten-imig. Slightly raised, small, granular and par-tiahly calcified yellow sclerotic plaques were
rioted in the aortic intima of the sinuses of
Val-salva. More numerous, larger sclerotic plaques
were fotmnd in the descending aorta above and
artenio-sclerotic cimatiges. ‘Fhme proximmmah 1)rt)1t of timt
right coronary artery vas imiost nOtiCel1)lv
in-volved.
The right lung weighed 110 gm and the heft 90 gm. The parenchyma, when freshly see-tiolmedi, was iii general dry amid light pink. The
spleen weighed 30 gni and appeared normal. Time pancreas weighed 22 gm, amid rio
ab-normality was noted. The hiver weighed 500
gIll, was hark, red-brown and had a normal
lobular architectumre. The gall bladder was
normal. The gastrointestinal tract was normal.
Most of the Peyer’s patches in the distal ileumm were prominent. The right kidney weighed 75 gm, and the heft 80 gm. They were of mionmah size, shape and consistency. The cortex and miieduhha were well delineated, and the calyces, pelves amid ureters appeared normal. The heft adrenal weighed 2.65 gm, and the night 2.61 gm, and 1)0th appeared unusually flat and thin.
On sectioning, these glands seemed to be
corn-posed primarily of yellow cortical tissue. The
unimiarv i)ladder was normal. The extermiah geni-talia were normal prepuberal. The uterus tmleasuredl 2.0 l)y 2.8 cm amid was 4.0 mm thick. Both ovidlucts appeared normal. The ovaries were 2.:3 by 0.6 1w 0.4 cm, amid each contained two small cysts of 3 mm dimemision, which were filled with watery fluid. The vaginal rnucosa vas finely corrugated. The thyroid was dark amber amx! weighed 6 gm, and there were no
itl)Paremmt abimormalities.
The epicranial tissues were reflected without difficulty. The calvarium was unusually thin, measuring 2 to 3 mm in thickness. The un-closed! sagittah suture varied from 2 to 3 mm in width. Over the heft parietal region was a palm-sized (7 by 5 cm) oval-shaped epidural hema-torna of dark red blood. A conspicuous fracture :3 cm itt length extended vertically through the left panietah bone into the suture line of the panietotemporal junction. On reflection of the olura, a shallow depression of the left parietah lobe was evident beneath the epidural hema-toma. The brain weighed 1351 gm and was tiot unusual. Multiple cut sections after fixatiomi did not disclose any abnormalities. The
pitui-tars’ was of normal size, measuring 5.0 by 2.0 i)\’ 3.0 mm and weighed 1.91 gm.
The right knee was incised. The peniarticuhar tissues appeared miormah, although very little fat
was present. A crystal clear, somewhat viscid
fluid exuded from the joint cavity. The synovial membrane and articular surfaces were smooth
and glistening.
Iitt. \veiglmts of ‘ai’iotiS om’gans, conmparcdl L()
a’trage weights,22 are given iii
Ial)le
I I.Tisstmes were fixed! iii 10sf formahin, Bouin’s
and Zenker’s solution. Mallory Azami, Schanlach
R. and Weigert-v. Gieson stains were used as
well as hematoxvhin-eosin.
Several sections of skiim were examinedi. ‘I’hme e1)iderrnis was tiiiii, cO)flul)riSe(! of a stratuimi
malpighii amid stratum co)nneuni. The cells of the basal layer contaimied large amounts of melamlin
pigment rather uniformly d!istnibuted!. In the su-perficial dermis small groups of l)arely recogmmiz-able glands were present. Those identified as sweat glands were atrophic and were composed of distorted, tightly packed cells. Differemmtiatioim i)etween the rnyoepithehial cells and the glandui-har cells was iiot possible. In mari’ of the glands
the lining cells of the secretory portion
ap-peared to have umidergone a “ballooning” type of degeneration. Some of the lumina of time
secretory tubules contained plugs of
acidophil-ic secretion. The few sebaceous gland alveoli
found were small amid rarely commumiicated
with excretory ducts. The remnants of time atrophied hair follicles consisted merely of compact groups of elongated cells botind b dermal sheaths of dense connective tissue. These cells revealed no attempt to differentiate into distinctive or special layers. No hair shafts were evident, amid none of the follicles could be traced to the epidenmal surface. The erector pihi muscles were prominent, imbedded in fairly dense aceliuhar denmal cominective tissue. Al-though this cominective tissue was more compact than usual, it was not typical of sclenoderma. No areas of cellular imifi!tration were observed. The subcutaneous tissues contained omihy small thin bands or islets of fat cells. The fascial sheaths of the skeletal muscle seemed to be somewhat thicker than usual.
Several sections of the heart were examined. The amount of epicardial fat was moderately decreased. The mvocardium and endocardium were essemitiahlv normal. The immtima of the corollary arteries was eccentrically thickemied,
and in some places the intenmia! elastic mem-brane was disrupted by the hperphasia. No deposits of lipid or calcium were present.
The intimai coat of the aorta was irregularly
hvperphastic, bulging eccentrically in places. It consisted in greaten pant of acellular edematous collagen. The fragmented intercellular fibers were smaller, stained poorly, amid had a mucoid appearance. Spaces betweemi the split fibers
576 ROSENTHAL - PROGERIA
character of the stronia. Large d!eposits of
foammiv histiocvtes aimd basophilic amorphous cal-careous debris were observed filling the deeper levels and encroachimig in places upon the inner media. The vasa vaso)rtlm in the adventitial coat wem’e collared 1)\ siiiall aggregates of mono-nuclear leukocvtes.
Similar ciiaimges were foundl in sections of the mesetmteric vessels ( Fig. 4). With Weigert-v. Cieson staiii, patch d!estruction of the elastic filx’rs immtile ilied!iit could i)e vehl diemomlstrated! (Fig. 5).
Sectiomis of periarticular tissues and synovia ‘ere exanhilied. No cellular infiltrates were
seen. The synovial iimiing cells were small and
flattemledi, audi the synovial membrane was un-formhy thin and unbroken. The dense periartic-ular collagemi was compact and typically acel-lular, l)tlt focal regions o)f edema were visual-izedl, especially prominent ai)out the smaller
1)100(1 vessels. These regions of edema were
characterized! i)\’ a pale basophihic ground sub-stamice aix! an uiiusually fine fibnihlar
appear-amice of the collagen strands. The arterioles
were typically thick-wailed. The adipose tissue d!ld! not appear abnormal.
Sections staimied! with hematoxvhimi and eosin
were iiitciIe of the vertebrae, of ribs, of an
entire tO)e and! of the distal Liortiomi of the right
feiiitmr. The architecture and character of the
niatrix of the compact aiioh cancellous bone in timese structures appeared! essentially normal. It was only iim the sectiomis through the distal
femoral e)ipiiysial 1)!tte that any new h)omle formation was evidemit, amid! here it seemed to
lW only minimal. The o)sseous-chondlrah junction \s/as Imarrow, 1tlmd! there was virtumally mio
vascu-lar penetration of the cartilage. The columns of hvpertrophied! cartilage cells at the osseous-cilomidlral junction iii the nibs, vertebrae amid
phalanges were short, quite irregular ill size
lmi(l shia1)e, amid! consisted of from 5 to 10 cells
oIl the average. The columns of the femoral epiphsis were taller, more uniform, and ap-peared normal. The articu!ar cartilages of the phalanges aii1 femuir d!isclosed no degenerative changes. The bone marrow was cellular. The erythroid!-mveloid ratio was normal. A
moder-ate amoummit of fat tissue was seen in the marrow
cavities of the ribs aiii phalanges.
Sectioiis of the pituitary were interpreted as mmormal, although no special stains nor differen-tial cell counts were made. In the pars
glandu-!aris a cyst of moderate size was encountered.
Although the cvtomrchitectune of the adrenals
appeared! normal, the cortex was thiimner timan usual. The componeimt cells contained little lipid. Sections of the thyroid and parathynoid
were interpreted as normal. The ovaries
con-tamed many primordial ova and several
matur-ing follicles. The uteris, vagina and ovi(hmcts were normal preptibera!.
Small regiomis of alveoli filled with edlema
fluid were noted in the luings. The small bronchi
and bromichioles contained mumcoid secretion,
amid the adjacent air sacs were overdistended.
Sections of the liver were essemitiaiiy normal.
Parenchymal cells, principally in the peripheral parts of the lobules, contained! small vacuoles
of lipid. With Best’s carmine staimi for glycogen,
only small intranuclean deposits were seen. Sections of the gall bladder, pancreas,
gastnoin-testinal tract, spleen, kidneys, tmninarv tract, and
thymus were interpreted as normal.
Many sections of the brain were examined.
The sections from the cortex, cerebellum and
brain stem were not unusual. There was
comi-siderable calcification of the chonoid plexus. The pineal gland revealed a central cystic alteration with caicifications considered excessive for a 12-year-old child.
Final pathologic diagnoses were recent
frac-tune of the heft panietal bone with epidural
hematoma and cerebral edema; progenia with
atrophic pigmented integumment, gemierahized
atherosclerosis especially of the aorta, coromiar
and mesentenic vessels, periarticular brosis,
failure of closure of the anterior fontamiel amid
sagittal suture, micrognathia, alopecia, and in-activity of the bony epiphyses. Mild fatty
me-tamorphosis of the liver and abnormal
calcifi-cation of the chonoid plexums amid! pinea! gland
were also present.
REFERENCES
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69:473, 1886.
2. Gihford, H. : Progenia: A form of senihism.
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8. Cabr, \I. : Progeria; review of the literature
with report d)f a case. Arch. Pediat., 71 :35, 1954.
9, Piunkett, E. R., Sawtehle, W. E., amid Hamblen, E. C. : Report of a patiemit with typical progeria, imicluiding data from
un-miarv imormrmone sttmdbes . j. Cl iti .
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10. Rossi, E. : Uber einem mieuemi Fall you
Progeria (Hultciiinsoum-Gihford-Symmd!rom). Helvet. puediat. acta, 6:165, 1951. I 1. J)oimb, H. P.: Progenia. NI. Rad!iog. &
Pimotog., 29:60, 1953.
12. Muzzo, S., alid! Alonso, 0. : Progenia. Rev. Chiiiemia Pediat., 25:325, 1954.
13. Keay, A.
J.,
Ohiyer, M. F., amid Boyd, G. S.: Progeria and atherosclerosis. Arch . Dis.Childhood, 30:410, 1955.
14. Manschot, W. A. : A case of progeronanism (Progenia of Gilfond). Acta paediat., 39: 158, 1950.
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J.,
and Strada, F. : etudeanatomo-chiniqume smil. 1111 cas die namiisme s#{233}nule (prog#{233}nie). Arch. med. enf., 30:385, 1927. 16. Ta!bot, N. B., Bumther, A. M., Pratt, E. L.,
MacLachlan, E. A., amid Tannheimer,
J.:
Progenia; clinical, metabolic and patho-!ogic studies on a patient. Am.
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Dis. Child., 69:267, 1945.17. Broad!bemlt, B. H. : The face of the normal
child. Angle Onthodonist, 7:183, 1937. 18. Brodie, A. G. : Omi the growth pattern of
the human head!. Aunt.
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19. Crossmami, H.
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Pnuzansky’, S., and Rosen-thai, I. M. : Progeroidl syndrome; report o)f a case of psetido-senilism. PEDIATIUCS,15:413, 1955.
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Am. Dent. A., 28:1153, 1941.21. Pathman,
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22. Coppoletta, j. NI., Umidi Wo!bach, S. B.:
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SUMMARIO
IN
INTERLINGUA
Progeria
Es reportate uii caso typic de progenia (symi-drome de Hutchinson-Gilford). Es inchudite Ic constatationes necroptic. Le monte occurreva a! etate de 1 1 annos como resultato die till ac-cidente. Le analyse de roentgemiognammas cc-phahometnic de iste patiente revelava que Ic facie characteristic de progeria restmhta ab tin marcate retardation die! crescemitia facial iii Ic presentia die 1111 relativememite miormal crescemitia
del neurocranio e non I’epresenta per
conse-quemite he effecto die senescentia prematuir.
Atherosclerosis esseva trovate in iste patiente al necnopsia. Per medio de ultracentnifugatiomi aim-lytic duramite he vita del patiemite, ii esseva de-terminate que he comicemitratiomies de lipopro-teinas imi le sero esseva anormalmente alte. Isto sigmiaha, como caumsa del atherosclerosis, umi er-ror metabolic phuls tosto quue he senescentia pre-matur del antenias. Studios pschologic morn-trava que he intelhigentia del patiente esseva normal e (IUC ii habeva numhhe ilid!ication die
