The Hutchinson-Gilford progeria syndrome

April, 1972 T h e Journal o[ P E D I A T R I C S

697

The HutcN'nson-Gilford progeria syndrome Report o[ 4 cases and review o[ the literature To emphasize and clari[y the diagnostic [eatures which distinguish the Hutehinson-Gil[ord progeria syndrome [rom other conditions resembling premature aging, [our patients are described, the world literature is reviewed, and characteristics o[ 60 patients are correlated. Patients with this syndrome are remarkably similar in appearance. They may exhibit certain characteristics early in li[e, such as scleroderma-like skin, mid[acial cyanosis, and "sculptured" nasal tip. The earliest pro[ound [eature is growth deficiency in the first year o[ li[e. Characteristic radiologic changes are persistent pateney o[ anterior [ontanelles, thin ribs, disappearance o[ distal clavicles and terminal phalanges, decrease in so[t-tissue shadows, poor modeling o[ long bones, and coxa valga.

Franklin L. DeBusk, M.D., Gainesville, Fl.a.

P R o G E R I A is a term recognized by many physicians as applying to individuals who appear prematurely aged. The HutchinsonGilford progeria syndrome (HGPS) phenotype is so constant that patients with the condition bear an uncanny resemblance to one another. Nevertheless, HGPS, because it is rarely seen, is frequently diagnosed erroneously in patients with some of the features such as alopecia and skin of aged appearance. There are sufficient characteristics invariably or frequently present in H G P S to delineate it unequivocally from other conditions with a prematurely aged appearance. Three features present early in life--midFrom the Deparwnent o[ Pediatrics, University o[ Florida College o[ Medicine. Supported in part by a Developmental Physiology Training Grant, N I H T1-HDO054, and by a grant [rom the National Foundation-March o[ Dimes. Reprint address: Department of Pediatrics, University o] Florida College o[ Medicine, Gctinesville, Fla. 32601.

facial cyanosis, skin resembling scleroderma, and glyphic nasal tip--should facilitate an early diagnosis of HGPS. Although children with H G P S have an aged appearance, none of those reported have demonstrated many of the aspects of old age such as senile cataracts, presbycusis, presbyopia, arcus senilis, osteoarthritis, or senile personalities. This syndrome may only mimic portions of the aging process. REVIEW

OF THE LITERATURE

Both Hopkin Hopkin, son of the Welsh poet Lewis Hopkin, and his younger sister Joan, cited by Gilford, 1 Ghosh and Varma, 2 and Smithfl may have been examples of this syndrome. It is stated that neither of them was able to walk until 6 or 7 years of age, that they appeared prematurely aged, were very small, and died prematurely. 4-6 It is impossible to classify them as cases of HGPS on the basis of the available information. Vol. 80, No. 4, part 2, pp. 697-724

698

DeBusk

7"he Journal o[ Pediatrics April 1972

Fig. I. A and B, Case 57 at age 15 months. Note sparse hair, prominent scalp veins, micrognathia, and absent ear lobules. Marked delay in age of walking has not been described in HGPS. This syndrome was first reported in medical literature in 1886 by Hutchinson ~ as a case of "congenital absence of hair and its appendages." In 1895, Hutchinson s published a brief report of a second patient. These two boys were described further in 1897 and t904 by Gilford, 1, 9, lo who proposed the term "progeria" for the syndrome and described the postmortem characteristics. Gilford 9 included a third patient with premature aging who was unlike the two cases of progeria. In 1910, Variot and Pironneau ~, 1~ published a report of a girl closely resembling the cases of Hutchinson and Gilford and proposed the term "senile nanism" for the syndrome. The young boy reported by Schippers 13 lived to be 2 7 ~ years old and was further described by Manschot, 14, 15 who reported the autopsy findings and labeled the syndrome "progeronanism." The term "progeria" has subsequently

come into general usage for this syndrome but has also been applied to several other conditions in which there is a prematurely aged appearance. I agree with Thomson and Forfar 1~ that either the term "progeria" should be reserved for the specific phenotype described by Hutchinson and Gilford or the condition shoud be known by its eponyrn, Hutchinson-Gilford syndrome. I have chosen to use the form Hutchinson-Gilford progeria syndrome (HGPS) in order to delineate this syndrome from others characterized by aged appearance. Table I lists the reported cases which are clearly examples of HGPS. The excellent review by Thomson and Forfar lc in 1950 omitted the case of Rossiyskiy and Olesov. 22 I have excluded both cases of Schondel, sa one of which was included in Thomson and Forfar's review, because they had the Hallermann-Streiff syndrome and have even been included in a thorough review of that subject by Francois s9 in 1958. Several cases reported as "progeria" or as resembling progeria are not included in this list because of inade-

Volume 80 Number 4, part 2

Hutchinson-Gil/ord progeria syndrome

69 9

Fig. 2. A, B, and C, Case 57 at 35 months of age. Note narrow shoulders, wide stance, prominent joints, and irregular skin pigmentation.

quate or conflicting diagnostic d a t a or because p h o t o g r a p h s of the patients indicate other diagnoses. 3s' ~5, 90-14a Some of these p a tients m a y be examples of cleidocranial dysostosis, pycnodysostosis, dyscephalia m a n d i b ulooculofacialis (Hallermann-Streiff synd r o m e ) , ~47-1~~ W e r n e r ' s syndrome, as1 Cocka y n e ' s , syndrome, ~2-15. R o t h m u n d ' s syndrome, T M phlebectasia congenita generalisata, aS~ various gerodermata, aSG-159 C a m u r a t i E n g e l m a n n ' s syndrome, 1~~ the syndrome of dwarfism, oligophrenia, a n d degeneration of the elastic tissue in skin a n d cornea, x6~ ectod e r m a l dysplasia with bird facies, congenital cataract, skull anomalies, and dwarfism, 162 or b i r d - h e a d e d dwarfism with p r e m a t u r e senility. l~s CASE REPORTS

Case 57. At 2 months of age, this girl's reddish hair was noted to be fine and sparse and the veins of the scalp were prominent. Prior to that

time, nothing unusual had been noted except for a faint, diffuse, bluish tint of the perioral and nasolabial skin. By 6 months of age, it had become apparent that she was gaining weight poorly and was growing very little. At age 10 months the skin was noted to be thin, the eyes were prominent, and there was a faint midfacial cyanosis. Blood studies were all normal. Urinalysis, skull films, chest x-rays, and intravenous pyelograms were all normal. Roentgenograms of long bones revealed no abnormality except for a decreased corticomedullary ratio of the femora and humeri. At age 15 months the diagnosis of HGPS was made because of characteristic facies, sparse fine hair, prominent scalp veins (Fig. 1, A and B), and marked growth failure. At that time she had 4 upper and 1 lower incisor teeth, normal psychomotor development, and normal chromosome karyotype (46,XX). She had been born following a normal pregnancy to 27-year-old unrelated Caucasian parents. There was no family history of growth disturbance, early death, or "progeria." Her father

7 O0

DeBusk

The Journal o[ Pediatrics April 1972

Table I Emphasis

Year Case No.

] Case IReeapitu-I Origin

Authors

report

1

Hutchinson 7 Gilford 9

1886 1904

England England

X

2

Hutchinson s Gilford x Gilford 9

1895 1897 1904

England England England

X

3

V a r i o t a n d P i r o n n e a u 11

1910

France

X

4

Schippers is M a n s c h o t 14 M a n s c h o t ~5

1916 1940 1950

Netherlands Netherlands Netherlands

X

Orrico 1~ Orrico a n d S t r a d a is

1918

Argentina Argentina

X

1927

5 6

Nasso ~9

1925

Italy

X

7

C u r t i n a n d K o t z e n 2~

1929

U.S.

X

8

Strunz 21

1929

Germany

X

9

Rossiyskiy a n d Olesov 22

1930

U.S.S.R.

X

10

Schiff 23

1934

Switzerland

X

11

Exchaquet24, 28

1935

Switzerland

X

12

Broc et al. 2~

1935

Tunisia

X

13

Popek a n d H a d l i k 27

1938

Czechoslovakia

X

14

Mitchell a n d G o l t m a n 2s

1940

U.S.

X

15

Z e d e r 20

1940

Germany

X

16

T a l b o t et aL so

1945

U; S.

X

17

Schwartz a n d Cooke 31 Cooke 3~

1945 1953

U.S. U.S.

X X

18

T h o m s o n a n d Forfar 16

1950

Scotland

X

19

HughesSS, 34

1950

U.S.

X

20

Rossi35

1951

Switzerland

X

21

KSlbl et al. 86

1952

Austria

X

22

Cooke 82

1953

U.S.

X

23

D o u b ~7

1953

U.S.

X

24

D u r a n d ~s

1953

Italy

X

25

Atkins s9

1954

U.S.

X

26

G a b r 40 M o s t a f a a n d G a b r 41 G a b r et al. 42

1954 1954 1960

Egypt Egypt Egypt

X

G a b r 40 M o s t a f a a n d G a b r 41 G a b r et al. 42

1954 1954 1960

Egypt Egypt Egypt

X X

Muzzo a n d Alonso 4a

1954

Chile

X

29

P l u n k e t t et al. 44

1954

U.S.

X

30

E1-Sibale a n d M o k h t a r 4s

1954

Egypt

X

27

28

lation [Review IReview

[Autopsy I report

X

X

X X

X

X X

X X

X

X

Other*

X

RAD

X

X X X

X

X

EM

X X

X

X X X X

EM

*AS -b- atherosclerosis, AUD ~--- audiology, C ~-~ cepalometry, CV = cardiovascular, EEG ---- electroencephalogram, EM = endocrlne-metabollsm, OD = oral-dental, RAD ~ radiology, TC ~ tissue culture. tCourtesy of Dr. H. C. Friederich, Tubingen. ~Courtesy of Dr. Victor MeKusick, Baltimore, Md., and Dr. William Simon, Enid, Okla. Reported elsewhere by Dr. William Reichel.

Volume 80

Hutchinson-Gil/ord progeria syndrome

Number 4, part 2

70 1

Table I. Cont'd Emphasis

Year Case No. 31

Authors

re~

Origin

Case Recapitu[Autopsy report lation Review report X

Bronstein et al. ~6 Rosenthal et al. 47 Carlton 4s

1955 1956 1964

U.S. U.S. U.S.

32

Clement 49

1955

France

33

Keay et al. 5~ Macleod ~1

1955 1966

Scotland Scotland

X

34

Steinberg et al. 52

1957

Israel

X

35

A l b u m and H o p e 63 Makous et al. 54

1958 1962

U.S. U. S,

X

36

Gonzalez O u t o n 5s

1959

Spain

X

37

ZanolaS6, Dr

1961

Italy

X

38

Erecinski et al. 5s, ~9

1961

Poland

X

Other ~

X X

X X

Photo AS RAD

X

EM

X

39

Erecinski et al. 5s, 59

1961

Poland

X

40

Djupesland6O Brogger61, 62

1962 1963

Norway Norway

X

41

Moynahan6a, 64, ,n5

1962

England

X

4.2

Nelson 66 Nelson 6r

1962 1965

U.S. U.S.

X

43

G h o s h and V a r m a 2

xxxx

India

X

44

Nadykto 6s

1964

U.S.S.R.

X

45

Rotberg et al. 69, r0

1964

Mexico

X

X

X

OD CV

K

AiUD AUD

X

46

Bhakoo et al. zl

1965

India

X

47

KozlowskU 2

1965

Poland

X

48

Lazareva and K r a i n e v a 7~

1965

U.S.S.R.

X

49

Ozonoff and Clemetff 4

1967

U.S.

X

X

X RAD

RAD

50

R a v a z5

1967

Italy

X

51

R a v a 7~

1967

Italy

X

52

Margolin and Steinbach ~6 K a p l a n et al. 77, 7s

1968 1968

U.S. U.S.

X

RAD EM

53

Villee et al. 79 Go|dstein so

1969 1969

U.S. U.S.

X

EM TC

54

Villee et a139 Goldstein 80

1969 1969

U.S. U.S.

X

EM TC

55

Marcondes et al. sx

1969

Brazil

X

EM

56

M a c N a m a r a et al. sz

i970

England

X

57

Rosenbloom et al. s3

1970

U.S.

X

58

Noltenius'~ s4 Nolten]us and W i e d e m a n n s6 Gorlin and Sedano s7

1949 1960 1969

Germany Germany Germany

X X

59 60

--~

U.S. U.S.

X

EM EM, E E G

X X Photo

702

DeBusk

The Journal o[ Pediatrics April 1972

Fig. 3. A and B, Case 57 at 35 months of age. Note marked alopecia, prominent scalp veins, micrognathia, craniofacial disproportion, absent ear lobules, sculptured nasal tip, midfacial duskiness, prominent eyes, and irregular pigmentation of skin. had congenital nystagmus. She had a poor appetite and frequent regurgitation. By 21 months of age her hair had become more sparse, scalp veins more prominent, and eyebrows sparse. At 35 months of age (Figs. 2, A, B, and C and 3, A and B), the head, which was 46.5 cm. in circumference, appeared large compared to the face. She had prominent scalp veins, the anterior fontanelle measured 2 x 2 cm., the scalp was thin and shiny with several excoriated and crusted lesions, and the blonde hair was short, fine, and sparse. The eyes were prominent with irregular nystagmoid movements. The paranasal and perioral skin was faintly, diffusely cyanotic, and the nasal tip was angular with visible under!ying cartilage contours. She had 16 deciduous teeth which were crowded, rotated, and maloccladed. The ears were soft and thin with no lobes. She walked with a wide base, and there was limitation of full extension of the knee joints. The skin was soft and thin; over the hands and fingers it was wrinkled, Radiologic findings are illustrated in Figs. 4, 5, 6, and 7. Her Stanford-Binet I.Q. was 94. Determinations of plasma glucose, insulin, and growth hormone during normal sleep and in response to

intravenous arginine infusion, and the glucose and growth hormone response to intravenous insulin infusion were normal. Plasma insulin levels during sleep ranged from 21 to 42 microunits per milliliter. Electroencephalograms during normal sleep were appropriate for the chronologic age of the patient, sa At 4 years of age, right parietal and left temporal cephalhematomas developed after minimal head trauma. At 4 ~ years of age, alopecia was almost total, and there was thickening of subcutaneous tissues with greenish yellow scalp discoloration in the right parietal and left temporal regions. Arm and leg muscle contours were prominent, and the limbs were thin with slight stiffness of the elbows and knees. She had a grade 2/6 blowing holosystolic cardiac murmur along the left sternal border in the second and third left interspaces. The sleep electroencephalograpblc pattern was again normal for chronologic age. Case 58. At 16 months of age this boy was noted to be gaining weight poorly, and his dark hair, previously very thick (Fig. 8!, was becoming thinner. The poor weight gain and growth failure became progressively worse. By 3 ~ years

Volume 80 Number 4, part 2

Hutchinson-Gil/ord progeria syndrome

7 03

Fig. 4. Hand. At three years of age there is partial loss of the distal phalangeal tufts of the second and fifth digits (arrows). Similar changes are beginning on the third and fourth digits. of age, the scalp hair consisted only of light, sparse, downy fuzz and scalp veins were more prominent. His first tooth did not erupt until he was 20 months old, but mental and motor development were normal. He was born to unrelated parents following a normal pregnancy of 36 weeks. His father was 59 and his mother was 39 years old. Twin sisters, born prematurely 16 years earlier, died at 1 and 7 days of age, and a normal brother was born two years after the patient. No one in the family was known to have had developmental disturbances, skin diseases, or familial diseases. By 6 years of age, walking had become awkward and unsteady for him because of joint stiffness. At 7 ~ years of age, he was found to be lacking in subcutaneous fat except in the suprapubic area, the skin was tight with spotty pigmentation, and underlying muscle contours were well defined. There was limitation of motion in the wrists, fingers, knees, ankles, and hips. The joints, especially in the knees, were quite prominent. The scalp veins were prominent. Palpable arteries were not hard. He had onychogryphosis of the fingers and toes. H e tired easily with ex-

Fig. 5. Lower extremities. The long bones demonstrate a gracile appearance characterized by thinned cortices, poorly defined trabeculae, and undermineralization. The femurs are bowed slightly and there is severe coxa valga. The soft tissues, particularly about the buttocks and upper thighs, are sparse. ercise but performed moderately well in school. At age 14 H years he had virtually no hair (Fig. 9), the skin was thin, tight, and pale with prominent subcutaneous veins and a diffuse yellow-brown spotty pigmentation, and he had practically no subcutaneous fat. He could sweat slightly in response to heat. The bald head appeared large for the face, the mandible was small, the nose was narrow and "sculptured," eyelashes were sparse, and the ears were small and protruding. The appearance was that of a "naked head of a young bird." T h e anterior fontanelle was open

704

DeBusk

The Journal of Pediatrics April 1972

Fig. 6. Chest. The distal clavicles are thinned and have undergone partial resorption (arrows). The second and third ribs are narrowed posteriorIy. The heart and lungs were considered to be normal.

and pulsatile. The terminal phalanges were short and the nails were small, thin, and dystrophic. He had a systolic cardiac murmur, normal pulses, and blood pressure of 112/60. Hearing was normal and the eyes were normal except for hyperopia and astigmatism. The external genitals were small with small testes palpable bilaterally. I.Q. was 85. X-rays revealed a thin cranial vault, large compared to his face, with patent sutures and anterior fontanelle. The right heart ventricle was enlarged and the pulmonary conus prominent. On fluoroscopy a calcified heart valve could be seen. The clavicles were narrow and short, and he had several old rib fractures. The humoral metaphyses were large, he had bilateral coxa valga, femoral neck widening, metaphyseal widening, and epiphyseal growth lines of knees, slight anterior tibial bowing, enlarged metacarpal metaphyses, and the thumbs and last three fin. gers of each hand lacked unguicular tuberositiesl The bones generally were osteoporotic and bone age was 14 years. Histologic examination of the abdominal skin revealed lack of subcutaneous fat, hair follicles, and sebaceous glands, and normal sweat glands, epidermis, and papillae. There were degenerative changes of the arrectores pilorum muscles. Vessels were sparse but not sclerosed. The elastica was compressed underneath the epidermis.

Case 59. This boy was noted during the first few days of life to have circumoral cyanosis, but no other unusual characteristics appeared until wrinkled and pigmented skin at 3 months of age. He soon began to lose hair, teeth were slow to erupt, and growth became very poor. By 13 months of age scalp veins were noted to be prominent. The diagnosis of scleroderma was considered, but by the age of 2 years the diagnosis of HGPS had been made. He was the only child of nonconsanguineous parents, 31 and 29 years old. The mother had 3 older normal sons by a previous husband. Pregnancy and birth were normal. Motor and mental development were normal but growth and weight gain were poor. He developed easy fatigability and by age 4 89 years had recurrent leg cramps precipitated by exercise and episodes of substernal pain by 5 or 6 years of age. The substernal pain and leg cramps always disappeared after 10 to 15 minutes of rest. At 67/12 years of age (Fig. 10), the head appeared large for the body, fontanelles were open, he was bald except for sparse fuzz on the back and sides of the head, and scalp veins were prominent. He had eyelashes, no eyebrows, small mandible, and prominent eyes. The skin was thin with prominent subcutaneous venous pattern and minimal subcutaneous fat. Fingernails were nor-

Volume 80 Number 4, part 2

Hutchinson-Gilford progeria syndrome

Fig. 7A. Skull. At 4 ~ years of age the cranial vault is of normal size and shape, although the bones appear thinned. The sutures are patent and the fontaneI is open; the base appears normal.

Fig. 7B. There is a linear fracture of the frontal bone. The teeth are crowded, the mandible is hypoplastic, and the facial bones are underdeveloped.

705

7 06

DeBusk

Fig, 8. Case 58. At 10 months of age this boy appeared well nourished and normal. mal and toenails hypoplastic. Blood pressure was 110/70. He had marked kyphosis and all joints were stiff with limitation of motion of knees and ankles. Roentgenograms showed open fontanelles, some hypoplasia of distal phalanges, and decreased bone density. Cardiac catheterization showed questionable increased pulmonary vascular resistance with no shunt; cardiac output was 93 per cent of normal. Coronary arteriogram revealed probable incomplete short obstruction in the proximal left coronary artery. At age 7 years he had normal growth hormone responses to insulin and arginine infusions. At age 7 ~ years, his I.Q. was 135. Intermittent claudication and episodes of angina pectoris were still occuring at 8 ~ years of age. Case 60. During the first day of life this girl was noted to have thickened skin, suggestive of scleroderma, over the lower abdomen and anterior thighs. Facial skin and scalp were thin and parchment like with a diffuse faint cyanosis over the midface and tempoparietal areas. The blonde hair appeared normal. The nasal tip was angular and nasal cartilage contours were visible under

The ]ournal of Pediatrics April 1972

Fig. 9. Case 58 at 1489 years of age. Note almost total alopecia, craniofacial disproportion, thin nose with visible cartilage contours, prominent scalp veins, prominent eyes, protruding ears without lobes, and spotty skin pigmentation. the skin. She had hyperbilirubinemia secondary to hemolytic anemia from Rh incompatibility, which was treated without complications by exchange transfusion during the first day of life. She was born to healthy, unrelated parents at term following a normal pregnancy and delivery. Her mother was 36 and her father was 42 years old at the time of her birth. She had two normal sisters, 4 and 5 years older. There were no stillbirths o r abortions. There Was no family history of severe growth disturbance, early death, or premature aging. By 3 months of age, she had prominent subcutaneous veins and it was noted that she could sweat in response to heat. Her appetite was usualIy poor and growth was normal for a few months but then slowed striklngty. By 14 months of age, she had the typical "plucked-bird" appearance of HGPS with very sparse blonde scalp hairs (many of which were broken), prominent scalp veins, large anterior fontanelle, only two yellowed lower central incisor teeth, small, mandible, craniofacial dispro-

Volume 80 Number 4, part 2

Hutchinson-Gil/ord progeria syndrome

7 07

Fig. 10. Case 59 at 67A2years of age. Note alopecia, craniofacial disproportion, prominent eyes, prominent scalp veins, absent eyebrows, sculptured nose with grooved tip, and spotty skin pigmentation (in additien to freckles).

Fig. 11. Case 60 at 23 months of age. Note short, fuzzy, sparse hair, craniofacial disproportion, absence of ear lobules, prominent eyes, sculptured nose with grooved tip, sparse eyebrows, and prominent scalp veins.

portion, fine, high-pitched voice, "horse-riding" stance, and shuffling, wide-based gait. Motor, mental, and social development were normal. She had traumatic left cephalhematoma at 18 months of age which subsided spontaneously without evident complications. At 23 months of age the typical appearance of t t G P S was more striking (Fig. 11). She then had 8 deciduous teeth, no evident subcutaneous fat except in the suprapubic area, much less hair, eyebrows nearly absent, prominent eyes, and a pyriform thorax. There were hypopigmented plaques, i cm, in diameter, in the area of "scleroderma" of the lower abdomen. She had a grade 1/6 systolic heart m u r m u r and normal blood pressure and pulses. Electrocardiogram revealed relative leftward forces, P-R interval 0.14 second, atrial and ventrieular rates of 150 per minute, and flattening of S-T segments suggestive of diffuse myocardial abnormality. Chest roentgenogram was normal with no abnormality of the clavicles. Long bones were normal (Fig. 12, A) and bone age at the wrist and knee was about

2 years. Skull roentgenograms revealed the cranial vault to be large compared to the faciaI structures; the calvarium was thin except for frontal bones, and the fontanelle was open with numerous Wormian bones and some demineralization of the dorsum sellae. Biopsy of the lower abdominal skin showed flattening and distortion of rete pegs, slightly thickened epidermis, and increase in elastic fibers in the dermis. The elastic fibers were irregular and more vertically arranged than usual, and there was a decrease in subcutaneous tissue. At 52/~2 years of age, over the course of a week, she developed .weakness of the right leg and right arm. The radial arteries were hard and tortuous, the tendon insertions hard, and the limbs spindly, with prominent joints. There was no hair on the head (Fig. 13), and the anterior fontanelle was open. Blood pressure was 130/90 and a grade 2]6 systolic cardiac m u r m u r was heard in the aortic area. The electrocardiogram showed notched P waves in lead 2 and biphasic P waves in the right precordial leads, and P-R

7 08

.DeBusk

The Journal o[ Pediatrics April 1972

Fig. 12. Upper extremities. A, At 20 months of age the upper extremities have a normal roentgenographic appearance. Note the well-developed soft tissues. B, At 5 years of age the diaphyses of the humerus, radius, and ulna are narrowed. There is marked loss of soft tissue and subcutaneous fat is virtually absent. Bone age is normal. intervals 0.16 second with atrial and ventricular rates of 80 per minute. Electroencephalogram was abnormal, with generalized 2 to 3 second high-voltage slow activity. Radiologic findings are illustrated in Fig. 12, B and 14. She recovered from the hemiparesis over a period of several weeks. Three days before her seventh birthday, she

suddenly collapsed and died at home. No autopsy was done. Summary of normal laboratory data of reported cases. Case 57. At 10 months she had normal complete blood count, blood urea nitrogen, chloride, sodium, potassium, calcium, phosphorus, pH, alkaline phosphatase, and electrophoresis of se-

Volume 80 Number 4, part 2

Hutchinson-Gil/ord progeria syndrome

Fig. 13. Case 60 at 5 8 9 years of age. Note thin , beaked nose, micrognathia, alopecia, prominent scalp veins, craniofacial disproportion, absent ear lobules, and sparse eyebrows.

Fig. 14. Pelvis and hips. Severe valgus deformity is present causing slight lateral displacement of the femoral heads in the acetabulum. The ischial rami appear thinner than normal and the loose buttock folds are well seen.

7 09

7 10

DeBusk

rum proteins. At 21 months normal ancillary clinical data included complete blood count, urinalysis, total serum calcium, inorganic phosphorus, alkaline phosphatase, cholesterol, thyroxin, blood urea nitrogen, urinary 17-hydroxycorticosteroid excretion, fasting blood glucose, urine amino acid excretion, Candida, Schick, and purified protein derivative skin tests, electrocardiogram, vectorcardiogram, and phonocardiogram. At 4y2 years she had a normal complete blood count and urinalysis. Case 58. At 14~/; years of age he had a normal complete blood count, urinalysis, urine concentration test, glucose tolerance test, Wasserman, erythrocyte sedimentation rate, serum protein, calcium, phosphorus, cholesterol (106 rag. per cent), and electrocardiogram. Case 59. At 6v/12 years of age normal laboratory data included complete blood count, urinalysis, serologic test for syphilis, fasting blood sugar, serum urea nitrogen, chloride, sodium, potassium, calcium, total protein, glutamic oxaloacetic transamlnase, bilirubin, creatinine, uric acid, thyroxin, vitamin E, creatinine clearance, urine amino acids, 17-ketosteroids and hydroxysteroids, normal response of growth hormone to insulin-induced hypoglycemia, karyotype, fecal fat, Master's test, motor and sensory nerve conduction velocity, reaction time and reflex time, and oral glucose tolerance. Urine was negative for porphobilinogen, delta aminolevulinic acid, phenylketones, galactose, and mucopolysaccharides. Total serum cholesterol was 230 mg. per cent, phospholipids 250 mg. per cent, triglycerides 31 mg. per cent, and total lipids 615 mg. per cent. Pulmonary function was diminished and electroencephalogram was moderately abnormal but nonspecific. At 7 ~ years of age he had normal complete blood count, erythrocyte sedimentation rate, lupus erythematosus preparation, urinalysis, serum protein electrophoresis, beta lipoprotein, and normal resting and exercise electrocardiograms. Serum cholesterol was 203 mg. per cent and 198 mg. per cent, triglyceride 84 mg. per cent, ceruloplasmin 55 rag. per cent, creatinine 0.256 rag. per cent, and creatinine clearance 52.2 c.c. per minute, 24 hour ereatinine excretion 0.192 Gin., creatinine coefficient 16.3, lean body mass 25.10, and urine flow 0.53 c.c. per minute. Case 60. At 23 months, normal ancillary clinical data included complete blood count, urinalysis, serum thyroxin, total protein, sodium, potassium, chloride, carbon dioxide, calcium, phos-

7"he ]ournal of Pediatrics April 1972

phorus, glutamic oxaloacetic transaminase, alkaline phosphatase, magnesium, lactic dehydrogenase, blood urea nitrogen, electrophoresis og serum proteins and lipoproteius, and electroencepha.lograrn. Serum cholesterol was 220 rag. per cent. At 5 ~ 2 years she had normal bone marrow except for erythroid hyperplasia, normal serum protein, and lipoprotein; IgA was 56 nag. per cent, IgM 68 mg. per cent, and IgG 740 rag. per cent (by immunodiffusion). Fasting total serum lipids were 725 and 810 rag. per cent, cholesterol 275 rag. per cent, and fasting blood sugar 80 nag. per cent. Lupus erythematosus and rheumatoid arthritis preparations were negative, 24 hour urine creatinine was 170 rag., and alpha amino acid nitrogen 17 mg. per 100 mg. of creatinine. There was increased urine histidine and beta amino isobutyric acid. Prothrombin and partial thromboplastin times were normal. NATURAL HISTORY AND CLINICAL FEATURES

Reason for ascertainment. Sixteen of the reported cases o f H G P S were presented for medical care because of failure to thrive, six because of alopecia, six because of abnormal skin, two because of a sibling with known progeria, and one for each of the following reasons: delayed tooth eruption, spastic paraplegia, and large head. Case 60 was ascertained during routine care because of characteristic features. Incidence. From 1915 to 1967 there were 145,000,000 births in the United States. 1~4 Eighteen reported H G P S patients were born in the United States during this period. The incidence of reported cases in the United States has been 1 per 8,000,000 births and has not varied significantly during the decades since 1915. Race and geographic distribution. T w o of the reported cases (17 and 53) were American Negroes, and the remainder were Caucasian. No patients have been reported in the World medical literature from China or from Australia. There is mention in the Japanese literature 165 of normal chromosome studies in a patient with progeria, but written or photographic documentation of this case as H G P S has not been available. Sex. Of 60 patients with H G P S , 36 were

Volume 80 Number 4, part 2

Hutchinson-Gilford progeria syndrome 7 1 1

GABR

I ~,JI

M,,'6

ERECINSKI

%,%, RAVA

I

Tr

I

~r

Fig. 15. Pedigrees of the 3 reported families with more t h a n one case of H G P S . Rava IV-3, IV-4, and IV-6 were said to have died of p r o g e r i a but no documentation is available. Rava IV-9 is reported b u t cannot be confirmed on the basis of information presented. 7~

male a n d 24 were female. T h e m a l e : f e m a l e ratio was 1.5 : 1. P a r e n t a l age. I n the 20 cases in which the p a t e r n a l age at b i r t h of the p a t i e n t was known, the m e a n p a t e r n a l age was 35.6 years a n d the m e d i a n age 31 years, with a range of 23 to 59 years. T h e m e a n m a t e r n a l age was 28.8 years a n d the m e d i a n age 28 years, with a range of 20 to 42 years. I n the 7 U n i t e d States cases in which the p a t e r n a l age at birth of the p a t i e n t was known, the m e a n p a t e r n a l age was 37.1 years a n d the m e d i a n age 41 years, with a range of 97 to 47 years. T h e m e a n m a t e r n a l age in 9 U n i t e d States cases was 29.3 years a n d the m e d i a n age 27 years, with a range of 20 to 42 years.

Consanguinity,

abortions,

and

familial

incidence. O f all 58 sibships reported, a statement of the presence or absence of consanguinity was m a d e in 19. T h e r e was consanguinity in only 3 of these families. In these 19 sibships there were 20 patients with H G P S , 83 live births, a n d 24 r e p o r t e d abortions. T h e abortion ratio was 24/107. Fig. 15 presents the available pedigrees of the 3 families with more t h a n one d o c u m e n t e d case of H G P S . M o s t a f a a n d G a b r 41 stated t h a t H G P S is an autosomaI recessive trait. This m a y be true b u t the d a t a is not conclusive. Of 19 U n i t e d States sibships reported, a statement of the absence of consanguinity was m a d e in 5. I n these 5 sibships there were 5 patients with H G P S , 8 siblings, a n d no rep o r t e d abortions. T h e r e were 57 children

7 12

The Journal of Pediatrics April 1972

DeBusk

4`0-

~0% iMale 9 Female

3.6-

'5%

~0% 5.2

2.8

10% I I--

-1- 2.4 (.9 I.IJ

2.0

1.6

1.2

I

30

I

I

32

i

I

34

I

i

36

I

I

I

38

i

40

I

I

42

GESTATION TIME, WEEKS

Fig. 16. Relation of birth weight to gestation period in HOPS. Percentile curves from data of Lubchenko and associates.~Ts and 4 abortions reported in the 19 United States sibships. Gestation and birth weight. Of the 13 patients born at term whose birth weights were reported, the mean weight was 2.92 Kg., the median weight was 3.1 Kg., and the range was 1.8 to 3.855 Kg. (Fig. 16). Of all 34 patients whose birth weights were stated, the mean weight was 2.65 Kg., the median weight was 2.86 Kg., and the range was 1 to 3.855 Kg. Growth defieiency. Although there was a tendency to low birth weight, it was neither invariable nor marked. The failure to grow and gain weight at a normal rate usually appeared abruptly during the first year of life. Weight gain continued at a very slow rate with frequent losses at times of illness. There were occasional rapid but transient weight gains in patients given anabolic

agents. Linear growth tended to be about half the normal rate, was steady, and showed no rapid increases at prepubertal or pubertal ages. Weight deficit was greater than height deficit (Fig. 17). The ratio of upper segment-to-lower segment length as stated in 5 patients or as measured from full-length frontal photographs of 34 others was consistently higher than the normal median for age, but was normal for height. Clinleal features. Table I I lists characteristics of HOPS which are invariably present and Table I I I lists characteristics which are frequently present. Skin. The skin of these patients has been described in great detail in m a n y reports, often as appearing "aged," thin, warm, dry, with fewer hairs than normal, taut and shiny in some areas, but wrinkled and loose in

Volume 80

Hutchinson-Gilford progeria syndrome

Number 4, part 2

7 13

159

IaJ :>~IOU.I (.9

,//,/

.J Z LU

//.//"/// Ht. Age .......... (N--54) ~ l r c . Age ~..._..::... (N=38) \ .. 9.......... S "/~' ' N=3 '8"!'"'"~'""' ...................... /~'//

o,5laJ I.iJ Q

/ /

50 Percentile-.../ ~ i / / (Devel.Age =Chron.Age)")r J / /

03 IZ

/

ill 5_,.-::_-_-:.-:

........................ ....

~" ~ ' " _ - ~ ~ " "-----

--" - ~ - -

WtAge (N=Si")

1

I

I

5

10

15

CHRONOLOGIC AGE, YEARS

Fig. 17. Comparison of growth in height, weight, and head circumference, bone development, and intellectual development in HGPS patients with normal subjects. other areas, usually on fingers and toes. These changes accompanied the growth failure and did not precede it. Some patients had areas of thick and inelastic skin resembling scleroderma, usually over the lower abdomen, flanks, upper thighs, or upper gluteal regions. This finding was usually present at birth or in early infancy. Because of thin skin and deficient subcutaneous fat, the superficial veins in most areas were prominent. As the "aged" appearance of the skin progressed, more numerous and more prominent spots of brownish, irregular pigmentation developed, most noticeably in areas exposed to sunlight. Some patients were said to sweat in response to heat, although it has b e e n reported that sweating is diminished. Ability to develop skin erythema in response to insect bites, intradermal tests, and sunlight has been reported to be intact in several of these patients. Several have been known to sunburn easily. Subcutaneous fat. Infantile fat was rapidly lost with the onset of growth failure. Eventually, even the buccal fat pads disappeared but suprapubic fat remained. Hair. Alopecia was total except for a few white or blonde downy hairs. I t was in-

variably present and began during the first 2 years of life. In 18 patients, alopecia was observed during the first year. It was almost always diffuse and generalized but occasionally was limited at the onset to the occiput. Even when original hair was black, the sparse downy fuzz present later was white or blonde. Body hair was also sparse. One patient (Case 29) was reported to have a few pubic and facial hairs but no axillary hair at 19 years of age. No other H G P S patients have been reported to have sexual hair. Eyelashes were absent in Hutchinson, s7, s first case and have been reported to be absent in 23 subsequent patients. In 5 patients the eyelashes have been specifically reported as normal. Two of these patients were 6 years old and another was 12 years of age. Hutchinson 7 reported that his first patient had only a trace of eyebrows at age 14 years. Since then, 31 patients have been noted to have no eyebrows at ages ranging from 1 to 18 years. Three patients, 2 years old or older, were said to have normal eyebrows. Nails. The nails were described as abnormal in 36 patients. They were noted to be normal at birth in one patient and at 2~2

7 14

DeBusk

The Journal of Pediatrics April 1972

,

+2SD *~ 00

9

9

9

Mean*

9

-2SD*

%

~,Patient IQ =76

60-

*Modified from Nellhaus,G. Pediel 41:106, 1968 t

I

5

I0 AGE, YEARS

I

15

I

20

Fig. 18. Comparison of head circumference of 38 patients with t l G P S at various ages expressed as per cent of normal for height-age.

years of age in another. The terminology applied to the nail abnormalities has been markedly varied and imprecise but generally implies small, short, and thin nails, sometimes dystrophic. Occasional koilonychia or onychogryphosis and, rarely, discoloration have been reported. Both toenails and fingernails have been reported to be abnormal. Head and face. By the time growth failure had become noticeable, these children usually had a cranium which appeared large in comparison to the face and body. It was actually normal or small (Fig. 18) for age and normal for height-age with prominent forehead and a tendency to frontal bossing. The anterior fontanelles were large and remained open. The scalp veins were prominent, due partly to a progressively thinning scalp and alopecia. Noltenius s4 considered the presence of sinus perieranii to be a factor in producing the prominent, dilated, and tortuous scalp veins.

The relatively slow growth of the facial bones apparently has been the reason for the prominent eyes. The eyes were normal without findings usually associated with aging. The nose has been described as small, thin, and beaked with a glyphic or sculptured appearance, with the nasal cartilage contours visible under the thin skin. (This was present in Case 60 in the neonatal period.) The mouth has never been reported to be large and is usually small with thin lips. Micrognathia has been prominent. These phenomena have been quite marked by age 2 or 3 years and contribute to the "plucked-bird" appearance. The ears tended to protrude, and often the lobes were absent. Hearing has not been impaired. The faint, diffuse midfacial cyanosis present early in the two girls reported here (Cases 57 and 60) had been previously noted in seven other patients, r, 59, 3~, a6, 50, 58 Hutchinson's r first patient was noted to have

Volume 80 Number 4, part 2

Table II. Hutchinson-Gilford progeria syndrome

Characteristics invariably present

Hutchinson-Gil/ord progeria syndrome

7 15

Table I l L Hutchinson-Gilford progeria syndrome

Characteristics [requently present

General Short stature Weight, decreased for height Complete sexual maturation absent

Skin Thin, taut, dry, wrinkled, "sclerodermatous"; brown spotted, prominent superficial veins, decreased sweating

Skin Subcutaneous fat diminshed

Hair Hypotrichosis, generalized Eyebrows absent Eyelashes absent

Head Craniofacial disproportion Micrognathia Scalp veins prominent Alopecia Eyes prominent "Plucked-bird" appearance

Head Anterior fontanelle patent Nose glyphie, beaked Nasolabial, circumoral cyanosis Lips thin Ears protrude, lobes absent

Teeth Dentition delayed and abnormal

Voice Thin, high pitched

Trunk Thorax pyriform Clavicles short, dystrophic

Limbs Nails dystrophic Terminal phalanges radiolucent

Limbs "Horse-ridlng" stance Wide-based gait, shuffling Coxa valga Limbs thin Joints prominent and stiff

it at age 3~2 years. Keay~s5~ patient was noted to have it at age 4 months, and it was still present when the child was 3 years old. Erecinski's ~s two patients also had this finding. In the older brother it was noticed at birth and in the younger brother at 2 months of age. Zeder's 29 patient showed this cyanosis at age 5 years, Rossi's s5 patient at 3 years, and K61bl and associates 'a6 patient at 2 years of age. Dentition. There was a marked delay in onset and completion of primary dentition. Secondary dentition was usually incomplete and markedly delayed as well. The teeth, especially the anterior ones, have been reported as crowded, rotated, displaced, overlapped, and maloccluded. Caries have been frequently but not universally reported. The only recorded abnormalities of individual teeth have been discolorations, occasional anodontia, "hypoplasia," or "dystrophy." Voice and speech. Language development has been reported as normal. The voice was

usually high pitched and has been described as "piping." It did not become lower in pitch with increasing age. Trunk. The pyriform thorax was stated to be narrow at the apex with narrow shoulders and clavicles which were both thin and short. Thoracic kyphosis contributing to the "stooped" appearance has been noted. Abdomen. The abdomen has been said to be progressively more prominent in relation to the chest but otherwise normal. Nipples. Hutchinson's 7 first patient was said to have had no nipples, only "scar-like patches." Seven other patients 9, 11, 16, 2~, 20, al, 40 were said to have hypoplastic nipples. Limbs. The limbs were of proportionate length and appeared progessively thinner with prominent joints, especially the knee, elbow, and finger joints, which became progressively stiffer with increasing limitation of motion. There was always marked coxa vaIga evident by 2 or 3 years of age which, along with joint stiffness, contributed to the wide-based shuffling gait and "horse-riding" stance. Terminal phalanges tended to be short, and the nails, which were often small, brittle, thin, and occasionally "spoon shaped," often

7 16

DeBusk

disappeared. These phenomena were more apt to occur in the smaller digits of either hands or feet. Sexual development. The H G P S patients had no signs of puberty at the usual age. One girl (Case 51) had slight breast development at 27 years of age. Whether or not she had other secondary sexual development is uncertain, but it was reported that she did not have menstrual periods. One boy (Case 29) had very sparse pubic hair and scanty beard at age 19 years and nocturnal emissions at age 21. The remainder of the patients had no signs of sexual development. The patient of Schippers ~3 and Manschot~4, ~5 on autopsy at age 2 7 ~ years had all stages of normal spermatogenesis but decreased numbers of sperm. T h e 19-year-old patient of Orrico and Strada ~s had testes measuring 1.5 x 0.7 x 1.0 and 1.4 • 0.67 x 1.1 cm. at autopsy. H e was found to have only rare spermatocytes, almost no spermatogenesis, atrophic seminal vesicles, and a small prostate. The patient of Atkins, a9 autopsied at 11~2 years of age, had prepubertal genitals and no spermatogenesis. The 7 ~ - y e a r old boy reported by Talbot and associates a~ was found at autopsy to have no spermatogenesis, small duct structures, and some early spermatocytogenic cells. The 9-year-old girl whose autopsy was reported by Gabr and associates 4~ had many large ovarian follicular cysts and abundant primordial follicles; the 11-year-old girl reported by Bronstein and associates 4G and Rosenthal and associates 47 had at autopsy many primordial ova and several maturing follicles. Intelligence and personality. Twenty-four of 41 patients with H G P S were said to be of average intelligence. Sixteen of these 41 were average or above average in intelligence, and one was reported to be well above average. Ten of the reported patients had from 1 to 3 I.Q. tests with values ranging from 76 to 183. The 10 patients had a mean I.Q. of 107 with the median I.Q. 104. The only patient (Case 7) described in the literature with a low I.Q. (76) had a sibling with the same level of intelligence.

The Journal of Pediatrics April 1972

These children tended to be shy and aware of their unusual appearance. They were friendly, lively, witty, and mischievous in the company of acquaintances, and they exhibited normal emotions, becoming happy, angry, and sad in the appropriate situations. Genetics. The direct demonstration of the mode of determination of H G P S is not pos. sible at present in the absence of chromosome abnormalities, biochemical markers, and informative pedigrees. The striking similarity of the clinical picture in HGPS strongly suggests a genetic determination. Etiologic heterogeneity could also be considered, but the regularity of the total pattern of anomalies is such that this possibility appears remote. Mostafa and Gabr .1 postulated an autosomal recessive determination based on the study of a family with two affected sisters born to consanguineous parents, genz ~66 stated that the parents of the case reported by Broc and associates 26 were "closely related" to the above-mentioned family, and concluded that there is little doubt of an autosomat recessive mode of inheritance." The existing data do not support this hypothesis. Consanguinity has been found in only 3 out of 19 families in which it was sought; the vast majority of the reported cases have been sporadic. Dominant mutation would appear as the most likely mode of determination, although it cannot be proved since the affected individuals fail to reproduce. The familial cases reported by Gabr and associates 4~ and by ErecinskPS, 59 could be explained as the result of a dominant mutation occurring in one of the parents, an event which may not be rare. 1G7 The occurrence of H G P S in the offspring of two sisters reported by Rava 75 would remain difficult to explain under this hypothesis. A delayed mutation ~s in one of the grandparents could be invoked, but such a possibility is highly controversial. ~69, i70 Paternal age has been considered as the only way to test the possibility of a dominant mutation as the cause of malformations that prevent reproduction in affected individ-

Volume 80 Number 4, part 2

uals. m Increased paternal age in sporadic cases of acrocephalosyndactyly and achondroplasia was first shown by PenroseY 2 It is not possible to draw any conclusions from the available data since they include cases from different countries, and since in the few United States cases in which the parental age was known, both mean paternal and maternal ages appear elevated. Metabolism and endocrinology. Extensive metabolic investigation has not clarified the defect in HGPS. Mitochrondrial oxidative function has been described T9 and is consistent with scattered reports of elevation in basal metabolic rate. Growth h o r m o n e responses were thought to be deficient but have now been shown to be normal, ss, ~Ts A consistent finding that resembles the aging state is a degree of insulin resistance manifested by excessive tolerance to tolbutamide and injected insulin and elevated resting levels of immunoreactive insulin in the plasma. ~9, sa, ~Ta These abnormalities have not been associated with glucose intolerance. Studies of the mechanics of skin collagen from two patients have been described. 79 They had a higher shrinkage temperature at both low and high loads than normal subjects. On cooling the collagen from the patients, the material again extended to its original length. Collagen from normal children and adults did not show this reversal. Fibroblast cultures from the skin of a 9year-old patient survived only two subcultures, in contrast to 20 to 30 subcultures in age-matched control subjects, s~ We have twice failed to establish skin fibroblast cultures from a patient with HGPS. The incorporation of labeled glucose and proline into skin and bone was markedly depressed in two patients studied by Villee and associates. 79 Hyperlipidemia has been neither consistent nor marked when present. M a c N a m a r a and associatess2 showed from a long-term investigation of a patient with serial studies of serum lipids a variable hyperlipidemia, increased t - and pre-fl-lipoproteins and im-

Hutchinson-Gilford progeria syndrome

7 17

paired clearing of absorbed dietary fat. A polyunsaturated fat diet controlled the hyperlipidemia and the cIearing of fat became normal. However, pre-fi-lipoprotein could still be found occasionally. Atherosclerosis developed despite the dietary regime. No abnormality of thyroid, parathyroid, pituitary, or adrenal gland function has been reported. Roentgenographic findings. The characteristic roentgenographic abnormalities are to be found in the skull and facial bones, thoracic cage, long bones, and phalanges. Skull and facial bones (Fig. 7). The cranial cavity is generally of normal size according to the tables of G o r d o n Y 4 However, hypoplasia of facial bones results in craniofacial dysproportion which is characteristic of this syndrome. The cranial bones tend to be thinned and the fontanelles and sutures remain open longer than expected. Wormian bones and skull fractures are common. However, the base of the skull is normally developed. Hypoplasia of the mandible with crowding of the teeth is a common feature. Underdeveloped facial bones may also occur and contribute to the characteristic facies. Thoracic cage (Fig. 6.) Thinning and resorption of the distal clavicles is the most constant abnormality to be found in the thorax. This process is a progressive one. Narrowing of the ribs, especially of the posterior segments, is a less constant finding. Long bones. Thinned cortices and poorly defined trabeculae give a characteristically gracile appearance to the long bones. Broadend, poorly tubulated metaphyses are generally apparent (Figs. 5 and 12, B). Coxa valga of severe degree is a constant finding and moderate genu valgum is frequently present. The capital femoral epiphyses, however., are usually normal (Figs. 5 and 14). Phalanges. The progressive loss of bone from the distal phalanges of the fingers a n d / or toes is one of the hallmarks of this disease (Fig. 4). This abnormality is by no means Specific, however, and may be seen in a variety of other syndromes.

7 18

DeBusk

Other changes. Loss of soft tissue, both fat and muscle, occurs as patients age (Figs. 5, 12, B, and 14). Ovoid and fish-mouth vertebral bodies have been described along with diffuse osteoporosis. Bone age is generally normal. Death. Excluding the two patients (Cases 31 and 37) who died accidentally of head 9injuries, there were 18 patients whose age a t death was known. Death age ranged from 7 to 2 7 ~ years, with a median death age of 12 years and a mean of 13.4 years. Cases 38 and 39 died of "marasmus and inanition." Case 26 died of convulsions, the cause of which was not determined at autopsy. Cases 4, 35, and 56 died of congestive heart failure secondary to previous myocardial infarctions from coronary atherosclerosis. The remaining 12 patients (Cases 1, 2, 5, 7, 16, 19, 22, 23, 25, 42, 56, and 60) died of acute myocardial infarction secondary to acute coronary thrombosis with underlying coronary atherosclerosis. Pathology. The histopathologic findings in biopsies of areas of skin resembling seleroderma in 9 patients and at postmortem examination in 8 patients varied somewhat depending on the biopsy site and age of the patient but tended in general to show: (1) decreased numbers of sebaceous glands and hair follicles, (2) normal to slightly decreased numbers of sweat glands , (3) prominent arrectores pilorum muscles, (4) decreased subcutaneous fat, (5) increased melanin in basal epidermal layers, (6) disorganization, thickening, and "hyalinization" of collagen fiber bundles, (7) normal to decreased numbers of blood vessels, frequently with thickening of their walls but not obliteration of their lumens, (8) normal elastic tissue, and (9) normal or hyperkeratotic epidermis. These changes are not those described for classic advanced scleroderma ~-177 in which there occurs extensive atrophy of epidermis, varying elastic fiber involvement, varying degrees of hyalinization of arterioles and basement membrane of skin appendage, homogenization, fibrosis, and sclerosis of dermal collagen bundles which

7"he Journal o[ Pediatrics April 1972

are arranged parallel to the epidermis. Sections from areas of normal skin have shown no consistent abnormality. Autopsy reports of nine patients revealed no consistent abnormalities of the endocrine glands. However, no parathyroid glands could be found in the patients of Talbot and associates a~ and of Gabr and associates, 42 and they were small and rudimentary in the patients of Orrico and Strada 18 and of Schippers 18 (described by ManschoP 4, 1~); they were not mentioned in the cases reported by Gilford ~ and Makous and associates24 The thymus was enlarged in the patients of Gilford, 9 Talbot and associates, s~ and Gabr and associates, 42 but no specific abnormality was described. The most striking autopsy findings have been in the cardiovascular system and bones. Except for the patient of Gabr and associates, *~ varying degrees of generalized atherosclerosis, involving chiefly the larger arteries, were found in all postmortem examinations. Nephrosclerosis has been described in seven cases2 * Coronary occlusions with myocardial infarctions were found more frequently than cerebral vascular lesions. Patchy myocardial fibrosis with deposition of lipofusein in brain, adrenal cortex, kidney, testes, liver, and heart has been described in a report of two patients said to have progeria, but information to document their having H G P S was not given. 179 The cranial bones and long bone diaphyses were invariably thin. Gabr and associates .2 found the clavicles to consist of fibrous tissue surrounded by periosteum with no osseous tissue. They found the long bone cortices to be thin but unusually dense with scarce and narrow Haversian canals. Subperiosteal new bone formation was present. They also found 9abnormalities in the epiphyseal cartilage plates suggesting a decreased rate of formation of endochondral bone. Autopsy examination of joints in the patients of Rosenthal and associates 47 and Gabr and associates 42 revealed normal articular cartilages with no evidence of senile or degenerative arthritis. Bronstein and associates 4~

Volume 80 Number 4, part 2

Hutchinson-Gil[ord progeria syndrome

r e p o r t e d finding p e r i a r t i c u l a r fibrosis a n d dense collagen with thick-walled arterioles in their patient. T h e y also f o u n d the skeletal muscle fascial sheaths to be unusually thick. O n l y M a k o u s a n d associates 54 r e p o r t e d finding degenerative osteoarthritis in their p a tient. However, they did not present specific histologic findings.

creased mitotic activity, DNA synthesis, and 9cloning efficiency in progeria patients and a moderate decrease in these functions in their parents as compared to normal control subjects, suggesting respective homozygosity and heterozygosity of the cultured skin fibroblasts.

SUMMARY

T h e H u t c h i n s o n - G i l f o r d Progeria synd r o m e ( H G P S ) has been reported in 60 p a tients since first described in 1886 by Sir J o n a t h a n Hutchinson. I t has been frequently diagnosed erroneously in conditions resembling it despite the fact t h a t the H G P S p h e n o t y p e is r e m a r k a b l y constant. Patients with the condition are usually considered to be n o r m a l infants but m a y have findings at birth suspicious of the syndrome ("scleroderma," m i d f a c i a l cyanosis, a n d "sculptured n o s e " ) . A p r o f o u n d growth failure develops d u r ing the first year of life. T h e characteristic facies, alopecia, loss of subcutaneous fat, posture, stiffness of joints, a n d bone and skin changes become a p p a r e n t d u r i n g the second year of life. Dentition is a b n o r m a l a n d m a r k e d l y delayed. M o t o r and m e n t a l d e v e l o p m e n t are normal T h e r e are no demonstrable abnormalities of thyroid, p a r a t h y r o i d , pituitary, o r a d r e n a l function. T h e r e is insulin resistance, abnormal collagen, a n d increased m e t a b o l i c rate. T h e r e are variable abnormalities of serum lipids. G r o w t h h o r m o n e responses are normal. A l t h o u g h these 9 develop atherosclerosis a n d die of cardiac or cerebral vascular disease between 7 and 27 years of age, m a n y other features associated with aging are absent. Insufficient d a t a are available to verify t h a t this syndrome is inherited as an autosomal recessive trait. ADDENDUM

A recent article by B. Shannon Danes (J. Clin. Invest. 50: 2000, 197I) reports markedly de-

7 19

The author wishes to express appreciation to Dr. I{. C. Friederich for permission to report the case of Dr. G. Noltenius, to Dr. V. A. McKusick and Dr. W. H. Simon for allowing me to present their patient, to Dr. T. J. Philpot for referring his patient, to Drs. Arlan L. Rosenbloom, Alvin H. Felman, Gerold L. Schiebler, L. H. S. Van Mierop, and Jaime Frias for their excellent reviews of various sections of this paper, to Dr. J. R. Jones, Jr., for library research, and to Miss Carol Cox, Mrs. Carole Oglesby, Mrs. Jill Leitch, and Mrs. Pat Weatherby for lengthy and tedious library research and editorial assistance. REFERENCES

1. Gilford, H.: Med. Chirurg. Trans. 80: 17, 1897. (Cited in Atkinson, F. R. B.: Progeria--premature old age, Med. Press 194: 34, 1937.) 2. Ghosh, S., and Varma, K. P.: Progeria: Report of a case with review of the literature, Indian Pediatr. 1: 146, 1964. 3. Smith, D. W.: Recognizable patterns of human malformation; genetic, embryologic, and clinical aspects, Philadelphia, 1970, W. B. Saunders Company, p. 74. 4. Browning, J.: Extract of a letter from John Browning, Esq., of Barton-Hill near Bristol, to Mr. Henry Baker, F.R.S. concerning a dwarf, Phil. Trans. 47: 278, 1-751-1752. 5. Wood, E. l.: Giants and dwarfs, London, 1868, R. Bentley, p. 354. 6, James, L.: Hopkiniaid morganwg, Bangor, 1909, Jarvis and Foster, p. 108. 7. Hutchinson, J.: Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages in a boy whose mother had been almost totally bald from alopecia areata from the age of six, Med. Chirurg. Trans. 69: 36, 1886. 8. Hutchinson, J.: Arch. Surg. 6: 14, 1895. (Cited in Atkinson, F. R. B.: Progeria--premature old age, Med. Press 194: 34, 1937.) 9. Gilford, H.: Progeria: A form of senilism, Practitioner 73: 188, 1904. 10. Gilford, H.: Ateleiosis and progeria: Continuous youth and premature old age, Br. Med. J. 2: 914, 1904. 11. Variot, G., and Pironneau: Nanisme avec dystrophie osseuse et cutan6e sp6ciales. Soupcon d'ag6n6sie des capsules surr6nales, Bull Soc. Pediatr. Paris 12: 307, 1910.

7 20

DeBusk

12. VarioL G., and Pironneau: Le "nanisme type s6nile" (progeria de Gilford): Origine surr6nale probable, Bull. Soc. Pediatr. Paris 12- 431, 1910. 13. Schippers, J. C.: Een Geval van Progeria, Ned. Tijdschr. Geneeskd. 2" 2274, 1916. 14. Manschot, W. A.: Een Geval van Progeronanie (Progeria van Gilford), Ned. Tijdschr. Geneeskd. 84: 3774, 1940. 15. Manschot, W. A.: A ease of progeronanism (progeria of Gilford), Acta Paediatr. 39: 158, 1950. 16. Thomson, J., and Forfar, J'. O.: Progeria (Hutchinson-Gilford syndrome). Report of a case and review of the literature, Arch. Dis. Child. 25: 224, 1950. 17. Orrlco, J.: Sobre un caso de enanismo senile (progeria), Prensa Med. Argent. 5: 133, 1918. 18. Orrico, J., and Strada, F.: l~tude anatomoclinique sur un cas de nanisme s6nile (prog6rie), Arch. Med. Enf. 30: 385, 1927. 19. Nasso, I.: Contributo clinico allo studio delia progeria, Pediatria (Napoli) 33: 1213, 1925. 20. Cnrtin, V. T., and Kotzen, H. R.: Progeria. Review of the literature with report of a case, Am. J. Dis. Child. 38: 993, 1929. 21. Strunz, F.: Ein FalI von Progeria, beginnend mit attsgedehnter Sklerodermie, Z. Kinderheilkd. 47: 401, 1929. 22. Rosslyskly, D. M., and Olesov, N. I.: K voprosu o progerii, Russk. Klin. 13: 251, 1930. 23. Schiff, E.: Progerle, nanisme type s6nile, Schweiz. Med. Wochnschr. 64: 213, 1934. 24. Exchaquet, L.: Un cas de prog6ria, Rev. M6d. Suisse Romande 55: 248, 1935. 25. Exchaquet, L.: Un cas de prog6ria, Rev. Fr. Pediatr. 11: 467, 1935. 26. Broc, R., Nicolle, M., and Jaubert de Beaujeu, A.: Progeria; 6tude des 16sions du syst~me 6sseux, Presse Med. 43: 786, 1935. 27. Popek, K., and Hadlik, J.: Progeria (Gilford) el nanismus seniluiho typu (Variot a Pironneau), Cas. Lek. Cesk. 77: 11, 1938. 28. Mitchell, E. C., and Goltman, D. W.: Progeria: Report of a classic ease with a review of the literature since 1929, Am. J. Dis. Child. 59: 379, 1940. 29. Zeder, E.: ~ber Progerie, eine seltene Form des hypophysilren Zwergwuchses mit diffuser Sklerodermie, Monatsschr. Kinderheilkd. 81: 167, 1940. 30. Talbot, N. B., Butler, A. M., Pratt, E. L., MacLachlan, E. A., and Tannheimer, J.: Progeria. Clinical, metabolic and pathoIogic studies on a patient, Am. J. Dis. Child. 69: 267, 1945. 31. Schwartz, A. S., and Cooke, J. V.: Progeria; report of a case, Biol. Symp. 11: 96, 1945. 32. Cooke, J. V.: The rate of growth in progeria, J. PEDIATR.42: 26, 1953. 33. Wilkins, L.: The diagnosis and treatment of endocrine disorders in childhood and

The Journal of Pediatrics April 1972

34. 35. 36.

37. 38. 39. 40. 41. 42. 43. 44.

45. 46. 47.

48. 49. 50. 9 51. 52. 53. 54.

adolescence, Springfield, Ill., 1950, Charles C Thomas, Publisher, p. 136. Hughes, J. G.: Personal communication. Rossi, E.: tDber einen neuen Fall von Progeria (Hutchinson-Gilford syndrom), Helv. Paediatr. Acta 6: 165, 1951. K61bl, H., Zierhut, H., and Zweymtiller, E.: Beitrag zur Pathogenese der Progerie an Hand von zwei neuen F~llen, Oesterr. Z. Kinderheilkd. 8: 162, 1952. Doub, H. P.: Progeria, Med. Radiogr. Photogr. 29: 60, 1953. Durand, P.: Studio della progeria; considerazioni cliniche e patogenetiche, Minerva Pediatr. 5: 1021, 1953. Atkins, L.: Progeria; report of a case with post-mortem findings, N. Engl. J. Med. 250: 1065, 1954. Gabr, M.: Progeria. Review of the literature with report of a case, Arch. Pediatr. 71: 35, 1954. Mostafa, A. H., and Gabr, M.: Heredity in progeria with follow-up of two affectd sisters, Arch. Pediatr. 71: 163, 1954. Gabr, M., Hashem, N., Hashem, M., Fahmi, A., and Safouh, M.: Progeria, a pathologic study, J. PED~ATm57: 70, 1960. Muzzo, S., and Alonso, O.: Progeria, Rev. Chil. Pediatr. 25: 325, 1954. Plunkett, E. R., Sawtelle, W. E., and Hambfen, E. C.: Report of patient with typical progeria, including data from urinary hormone studies, J. Clin. Endocrinol. Metab. 14: 735, 1954. E1-Sibaie, B., and Mokhtar, N.: Progeria: Case report, Gaz. Egypt. Pediatr. Assoc. 2: 337, 1954. Bronstein, I. P., Rosenthal, I. M., Pruzansky, S., and Sanford, H. N.: Pseudosenilism of progeria, Am. J. Dis. Child. 90: 564, 1955. Rosenthal, I. M., Bronstein, I. P., Dallenbach, F. D., Pruzansky, S., and Rosenwald, A. K.: Progeria; report of a case with cephalometric roentgenograms and abnormally high concentrations of lipoproteins in serum, Pediatrics 18: 565, 1956. Carlton, T. C.: Progerla, Ala. J. Med. Sci. 1: 211, 1964. Clement, R.: S6nilit6 pr6coce et nanlsme-progeria de Gilford, Presse M6d. 63: 155, 1955. Keay, A. J., Oliver, M. F., and Boyd, G. S.: Progeria and atherosclerosis, Arch. Dis. Child. 30: 410, 1955. MacLeod, W.: Progeria, Br. J. Radiol. 39: 224, t966. Steinberg, A. H., Szelnberg, A., and Cohen, B. E.: Amino-aeiduria and hypermetabolism in progeria, Arch. Dis. Child. 32: 401, 1957. Album, M. M., and Hope, J. W.: Progeria, Oral Surg. 11: 985, 1958. Makous, N., Friedman, S., Yakovac, W., and Marls, E. P.: Cardiovascular manifestations in progeria. Report of clinical and pathologic findings in a patient with severe arterio-

Volume 80 Number 4, part 2

55. 56. 57. 58. 59. 60. 61.

62. 63. 64. 65. 66. 67. 68. 69.

70. 71.

72. 73. 74. 75. 76. 77. 78.

79.

sclerotic heart disease and aortic stenosis, Am. Heart J. 64: 334, 1962. Gonzales Outon, P. M.: Progeria: Aportacidn de un caso, Acta Pedlatr. Espafi. 17: 267, 1959. Zanola, G.: Un caso di progerla, Lattante 32" 553, 1961. , Zanola, G.: Personal communication. Erecinskl, K., Bittel-Dobrzynska, N., and Mostowiec, S.: Zespol progerii u dwoch brael, Pol. Tyg. Lek. 16: 806, 1961. Erecinskl, K.: Personal communication. Djupesland, T.: Progeria, Acta Paediatr. 51: 438, 1962. Brogger, A.: Pathological conditions with apparently normal chromosome constitution, The Human Chromosome Newsletter, December, 1963, p. 5. Brogger, A.: Personal communication. Moynahan, E. J.: Progeria (Hastings Gilford) presenting as scleroderma in early infancy, Proc. R. Soc. Med. 55: 233, 1962. Moynahan, E. J.: Progeria (Hastings Gilford) presenting as scleroderma in early infancy, Proc. R. Soc. Med. 55" 240, 1962. Moynahan, E. J.: Personal communication. Nelson, M.: Progeria, audiologic aspects, Arch. Pediatr. 79: 87, 1962. NeIson, M.: Progeria: Audiologic aspects. Final report of a case, Ann. Otol. Rhinol. Laryngol. 74: 376, 1965. Nadykto, Z. Y.: Slucha~ progerii u mal'chika 9 let, Pediatriia 43: 73, 1964. Rotberg, T., Katona, G., Robles, G. J., and Moreno, E.: Progerla. Reporte de un caso con estudio histoquimico comparativo. Revision bibliografica, Arch. Inst. Cardiol. Mex. 34: 242, 1964. Rotberg, T.: Personal communication. Bhakoo, O. N., Garg, S. K., and Sehgal, V. N.: Progeria with unusual ocular .manifestations: Report of a case with a review of the literature, Indian Pediatr. 2: 164, 1965. Kozlowski, K.: Etude radiologique d'un cas de nanisme senile (progeria), Ann. Radiol. 8" 92, 1965. Lazareva, N. S., and Kraineva, L. G.: Sluchai progerii u rebenka 1 goda 10 mesiatsev, Pediattila 44: 93, 1965. Ozonoff, M. B., and Clemett, A. R.: Progressive osteolysis in Progeria, Am. J. Roentgenol. 100" 75, 1967. Rava, G.: Su un nucleo familiare di progeria, Minerva Med. 58: 1502, 1967. Margolin, F. R., and Steinbach, H. L.: Progeria. Hutchinson-Cilford syndrome, Am. J. RoentgenoI. 103: 173, t968. Kaplan, S. L.: PersonaI c~mmunication. Kaplan, S. L., Abrams, C. A., Bell, J. J., et al.: Growth and growth hormone. I. Changes in serum level of growth hormone following hypoglycemia in 134 childrel~ with growth retardation, Pediatr. Res. 2: 43, 1968. Villee, D. B., Nichols, G., Jr., and Talbot, N. B.: Metabolic studies in two boys with

Hutchin~on-Gilford progeria syndrome

721

classical progeria, Pediatrics 43: 207, 1969. 80. Goldstein, S.: Life-span of cultured cells in progeria, Lancet 1: 424, 1969. 81. Marcondes, E., Campos, J. V., Barbieri, D., Quarentei, G., and Cavallo, A.: Prog6ria: Relato de um caso corn manifestac6es de esclerose sist~mica progressiva (esclerodermia) desde o nascimento, Rev. Hosp. Clin. Fac. Med. S. Paulo 24: 147, 1969. 82. Maenamara, B. G. P., Farn, ]~. T., Mitra, A. K., Lloyd, J. K., and Fosbrooke, A. S.: Progeria. Case report with long-term studies of serum lipids, Arch. Dis. Child. 45: 553, 1970. 83. Rosenbloom, A. L., Karacan, I. J., and DeBusk, F. L.: Sleep characteristics and endocrine response in progeria, J. PEDIATm 77: 692, 1970. 84. Noltenius, G.: Ein Fall von Gilfordscher Progerie. Inaugural-Dissertation zur Erlangung des Doktorgrades der Medizin, Chirurgie und Gebuftshilfe einer Hohen Medizinischen Fakult~it der Eberhard-Karls-Universit~t zu Ttibingen, 1949. 85. Friederich, H. C.: Personal communication. 86. Noltenius, G., and Wiedemann, H: R.: Progerie (Hutchinson-Gilford Syndrom) Medizin, Bild-Dienst, Roche 10: 3, 1960. 87. Gorlin, R. J., and Sedano, H. O.: Progeria Hutchinson-Gilford syndrome, Mod. Med. July, 1968, p. 62. 88. Schondel, A.: Two cases of progeria complicated by microphthalmus, Acta Paediatr. 30: 286, 1943. 89. Francois, J.: A new syndrome. Dyscephalia with bird face and dental anomalies, nanism, hypotrichosis, cutaneous atrophy, microphthalmia and congenital cataract, Arch. Ophthalmol. 60: 842, 1958. 90. Rand, C. W.: A case of supposed progeria (premature senility) in a girl of 8 years; with remarks, Boston Med. Surg. J. 171: 107, 1914. 91. Lereboullet, P.: Sur un cas de nanisme ~ type s~nile ou prog~ria (s~nilit~ premature), Paris M~d. 19: 118, 1917. 92. Farran-Ridge, C.: Premature senility (progeria), J. Neurol. Psychopathol. 2: 254, 1921. 93. Talbot, F. B.: Metabolism study of case simulating premature senillty, Monatsschr. Kinderheilkd. 25: 643, 1923. 94. Paterson, D.: Case of progeria, Proc. R. Soc. Med. 16: 42, 1923. 95. Apert, E., and Robin, P.: La progeria (nanisme type s~nile de Variot): Ses varietfis cliniques, Presse Med. 35: 433, I927. 96. Harris, C. F.: Progeria, Proc. R. Soc. Med. 21: 227, 1927. 97. Stoia, I., and Andreoiu, C.: Senile nanlsm (progeria): Case, Spitalnl 48: 349, 1928. 98. Hall~, J., and Odinet, J.: Ag~n~sie pilaire et malformations. Rapport possible avee la prog~ria, Bull. Soc. Pediatr. Paris 30: 327, 1932. 99. Pouzin-Mal~gue, Y.: Un cas de nanisme s~-

722

100.

101. 102. 103. 104. 105.

106. 107. 108. 109. 110. Ill. 112. 113. 114. 115. 116.

117. I18.

119. 120. 121.

DeBusk

nile ou prog6ria, Bull. Soc. Pediatr. Paris 30: 685, 1932. Thlers, J., and Nahan: l~tude radiographique due squelette dans un cas de prog6ria de Gilford (nanlsme s6nile) dysostose cldidocrani6nne assoei6e, J. Radiol. Electrol. Med. Nucl. 17: 675, 1933. Barraud, G.: Un cas de prog6ria, Bull. Soc. M6d. Chirug., Rochelle, 1933. Barraud, G.: Le nanisme s6nile ou prog6ria, Gaz. M6d. France 41: 983, 1934. Barraud, G.: Le nanisme s6nile ou prog6ria, Gaz. M6d. Languedoc. M6diter. Afrique Nord, November 15, 1934. Martinez, C. H.: Study of a case of progeria, Cron. Med. (Lima) 52: 372, 1935. Heuyer, G., Denoyelle, L., and Bernard, A.: Nanisme avec infantilisme, microe@halie, malformations osseuses et cutan6es du type de nanisme sdnile ou progdria chez deux frSres, Bull. Soc. P6diatr. Paris 34: 159, 1936. Stern, A., and Lieberman, D. P.: Case of supposed progeria in girl aged 17 months, Arch. Pediatr. 54: 169, 1937. Schachter-Nancy, M.: La prog6rle ou nanisme s6nile et la natog6rie, Bull. Med. Paris 52: 244, 1938. Sundblad, R.: Progerla de Gilford. Distrofia sifilitica, Arch. Argent. Pediatr. 9: 624, 1938. Korsgaard, R.: Et filfaelde af progeria, Ugeskr. Laeger. 102: 309, 1940. Mfiller-Hess, B.: ~ber den Zusammenhang zwischen Sklerodermia und Progerie, Z. Kinderheilkd. 62: 96, 1940. Gottron, H.: Famili~re akrogerie, Arch. Dermatol. Syph. Wien. 181: 571, 1940. Nery, O.: Nanismo corn senilidade: Progeria, Cultura M6d. 6: 186, 1944. Moehlig, R. C.: Progeria with nanism and congenital cataracts in a five year old child, J. A. M. A. 132: 640, 1946. Massera, L.: La Progeri: Studio delle lesioni del slstema scheletrico, Ateneo Parmense 18: 96, 1947. Raines, I. L.: Sluehai Progerii u Rebenka 10 Let, Pediatriia 6: 68, 1947. van Bolhuis, J. H.: Ned. Tijdschr. Geneesk. 92: 1667, 1948. (Cited in Thomson, J., and Forfar, J. O.: .Arch. Dis. Child. 25: 224, 1950.) Widemann, H. R.: Progerie, Arch. Kinderheilkd. 135: 169, 1948. Wiedemann, H. R.: Ober Greisenhaftigkeit im Kindesalter, inbesondere die Gilfordsche Progeria: zugleich ein Beitrag zum Bereich der mesodermalen Dysplasien, Z. Kinderheilkd. 65: 670, 1948. Neill, C. A., and Dingwall, M. M.: A syndrome resembling progeria: A review of two cases, Arch. Dis. Child. 25: 213, 1950. Oberdisse, K.: La s~nilit~ chez un enfant, Dtsch. Arch. Klin. Med. 197: 103, 1950. Grossman, H. J., Pruzansky, S., and Rosenthal, I. M.: Progeroid syndrome (result of severe growth disturbance): Report of case

The Journal of Pediatrics April 1972

of pseudosenilism, Pediatrics 15: 413, 1955. 122. N6el, A.: Un cas de prog6rie au Kivu, Acta Paediatr. Belg. 9: I01, 1955. 123. Ponomareva, E. D., and Sagaidachnyk, N. A.: K Klinike Progerii, Ter. Arkh. 27: 77, 1955. 124. Snkolov, D. D.: O Progeril, Probl. Endokrinol. 1: 111, 1955. 125. Gregersen, E.: Ocular abnormalities in progeria, Acta Ophthalmol. 34: 347, 1956. 126. Deschwanden-Mtiller, B. Von, and Gilardi, A.: Ober einen seit Geburt beobachten Fall von Cuffs marmorata teleangiectatica congenita mit progerieahnlichen symptomen, Schweiz. Med. Wochenschr. 87: 1464, i957. 127. Blancquaert, A.: Progeria en progeroid, Monatsschr. Kindergeneesk. 27: 157, 1959. 128. Bommer, W., Kuenzer, W., and Hauser, W.: Disease picture with signs of progeria (Hutchinson-Gilford) and Ehlers-Danlos syndrome (an unusual mesenchymal dysplasia with strong similarities to "Gottron's acrogeria"), Arch. Kinderheilkd. 165: 172, 1961. 129. Molinatti, G. M., Olivetti, M., and Camanhi, F.: Considerations cliniques sur un cas de nanisme prog6rique primordial, Ann. P6diatr. (Paris) 8: 520, 1961. 130. Wieser, D.: On the differential diagnosis and ocular symptomatology of cuffs marmorata telangiectatica congenita and progerla, Ophthalmologica 143: 300, 1962. 131. Legre, J., Padovani, J., Roussel, A., and Clement, J. P.: Prog6ria de Gilford avee dysplasie claviculaire, Marseille Med. 99: 617, 1962. 132. Roussel, A., Tremoulet, M., and Vitiello, J.: Un cas de nanisme prog6rique, Pediatric 17: 307, 1962. 133. Moynahan, E. J.: A new progeroid syndrome, characterized by dwarfism, kyphoscoliosis, universal livedo reticularis and generalized telangiectasia, early marginal alopecia and chronic nasal infection, Proc. R. Soc. Med. 55: 233, 1962. 134. Piancino, G.: Descrlzione di un case di infantilo-nanismo progerlco, Folia Endocrinol. (Roma) 15: 900, 1962. 135. Procek, J., Jakubicek, R., and Malinsky, J.: Kostni zmeny syndromu predcasneno starnuti u deft, Acta Chir. Orthop. Traum. Cech. 29: 134, 1962. 136. Jakubicek, R., and Malinsky, J.: Dva prlpady syndromu predcasneho starnuti u deti (progerie a progeroid), Cesk. Pediatr. 18: 228, 1963. 137. Li~vre, J.-A., Camus, J.-P., and Bernades, P.: Prog6ria, Bull. Soe. Mfd. Hop. Paris 114: 225, 1963. 138. Khazanov, A. I.: O progerli i progerlepodobnykh sindromakh, Pediatriia 43: 48, 1964. 139. Benazzi, A., and Martani, F.: Contributo clinico alla conoscenza dele manifestazioni odontostomatologiche nella progeria (sindrome di Hutehinson-Gilford), Riv. Ital. Stomatol. 20: 123, 1965.

Volume 80 Number 42 part 2

140. Baar, H. S., and Galindo, J.: Progeria in the adult, J. Maine Med. Assoc. 56: 44, 1965. 141. Guzetta, F.: Nanismo progerico associato ad insufficienza mentale, con monosomia parziale 17-18 e translocazione E-D, Riv. Patol. Nerv. Ment. 87: 351, 1966. 142. Koch, G., Meyer-Robisch, M., and Schwanitz, G.: Progeria, Folia Clin. Int. (Barc.) 16: 528, 1966. 143. Labunets, N. N., and Moiseeva, K. N.: Sindrom Huchinsona-Gil'forda, Ortop. Travmatol. Protez. 28: 70, 1957. 144. Kairaan, H., Lambie, R. W., and Metzl, K.: Progeria. Case description, Clin. Pediatr. 8: 411, 1959. 145. Garner, D. G., and Majka, M.: The early formation of irregular secondary dentine in progeria, Oral Surg. 28: 877, 1969. 146. Piepsz, A., Loeb, H., and Wolter, R.: Etude d'un cas de prog6ria, Acta Paediatr. Belg. 23: 27, 1969. 147. Hallermann, W.: Vogelgesicht und Cataraeta Congenita, Klin. Monatsbl. Augenheilkd. 113: 315, 1948. 148. Streiff, E. B.: Dysmorphie mandibulo-faciale (t~te d'oiseau) et alt6rations oculaires, Ophthalmologica 120: 79, 1950. 149. Falls, H. F., and Schull, W. J.: HallermannStreiff syndrome. A dyscephaly with congenital cataracts and hypotrichosis, Arch. Ophthalmol. 63: 409, 1960. 150. Hoefnagel, D., and Benirschke, K.: Dyscephalia mandibulo-oculo-facialis (Hallermann-Streiff syndrome), Arch. Dis. Child. 40: 57, 1965. 151. Thannhauser, S. J.: Werner's syndrome (progeria of the adult) and Rothmund's syndrome: Two types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and endocrine features: A critical study with five new cases. Ann. Intern. Med. 23: 559, 1945. 152. Cockayne, E. A.: Dwarfism with retinal atrophy and deafness, Arch. Dis. Child. 11: 1, 1936. 153. Cockayne, E. A.: Dwarfism with retinal atrophy and deafness, Arch. Dis. Child. 21: 52, 1946. 154. MacDonald, W. B., Fitch, K. D., and Lewis, I. C.: Coekayne's syndrome. An heredofamilial disorder of growth and development, Pediatrics 25: 997, 1960. 155. Luthardt, T.: Phlebectasia Congenita Generalisata mit Progeriezeichen, Monatsschr. Kinderheilkd. 114: 284, 1966. 156. Brocher, J. E., Klein, D., Bamatter, F., Franceschetti, A., and Boreux, G.: Rgntgenologische Befunde bei Geroderma Osteodysplastica Hereditaria, Fortschr. Roentgenstr. 109: 185, 1968. 157. Rosenstern, I.: ~)ber einen Fall yon Geroderma genito-dystrophicum im Kindesalter mit dem histologischen Befund einer erheblichen Elasticaverminderung in der Haut, Z. Kinderheilkd. 46: 481, 1928.

Hutchinson-Gilford progeria syndrome

723

158. Spyropulos, N.: Gerodermia generalisata congenita mit Hypoplasie und Hypotonie der Muskulatur, Kinderaerztl. Prax. 12: 72, 1941. 159. Boreux, G.: La g6rodermie ost6odysplasique a h6r6dit6 li6e au sexe, nouvelle entit6 clinique et g6n6tique, J. Genet. Hum. 17: 137, 1969. 160. Braham, R. L.: Multiple congenital abnormalities with diaphyseal dysplasia (CamuratiEngelmann's syndrome). Report of a case, Oral Surg. 27: 20, 1969. 161. DeBarsy, A. M., Moens, E., and Dierckx, L.: Dwarfism, oligophrenia and degeneration of the elastic tissue in skin and cornea. A new syndrome? Helv. Paediatr. Acta 23: 305, 1968. 162. Majcherski, T., Wilk-Wilczyflska, M., and Omulecki, A.: Ektodermale Dysplasie mit "Vogelgesicht," Cataracta Congenita, Sch~idelanomalien und Nanismus, Kinderaerztl. Prax. 36: 553, 1968. 163. Fitch, N., Pinsky, L., and Lachance, R. C.: A form of bird-headed dwarfism with features of premature senility, Am. J. Dis. Child. 120: 260, 1970. 164. U. S. Bureau of the Census Statistical Reports, 1967. 165. Makino, S., Kikuchi, Y., Sasaki, M. S., and Honda, J.: Pathological conditions with apparently normal chromosomes, further cases with a normal chromosome pattern, The Human Chromosomes Newsletter, December 1961, p. 4. 166. Lenz, W.: Senilidad prematura (progeria), Translation: in Becker, P. E., editor: Genetica humana, S. A. Barcelona, Espana, 1966, Ediciones Toray, vol. II, p. 68. 167. Stern, C.: Genetic mosaics, in Genetic mosaics and other essays, Cambridge, Mass., 1968, Harvard University Press, p. 61. 168. Auerbach, C.: A possible cause of delayed mutation in man, Ann. Hum. Genet. 20: 266, 1955. 169. Vogel, F.: Verzogerte mutation beim Menschen ? Einige Kritische Bemerkungen zu Ch. Auerbachs Arbeit (1956), Ann. Hum. Genet. 22: 132, 1957-1958. 170. Crow, J. F.: Mutation in man, in Steinberg, A. G., editor: Progress in medical genetics, vol. 1, New York, 1961, Grune & Stratton, Inc,

i71. Fraser, F. C.: Genetics and congenital malformations, in Steinberg, A. G., editor: Progress in medical genetics, vol. 1, New York, 1961, Grune & Stratton, Inc. 172. Penrose, L. S.: Parental age and mutation, Lancet 2: 312, 1955. 173. McKusick, V. A.: Personal communication. 174. Gordon, I. R. S.: Measurement of cranial capacity in children, Br. J. Radiol. 39: 377, 1966. 175. O'Leary, P. A., Montgomery, H., and Ragsdale, W. E., Jr.: Dermatohistopathology of various types of scleroderma, Arch. Dermatol. 75: 78, 1957.

7 24

DeBusk

176. D'Epinay, P. L.: 5 F/ille yon Sklerodermie: Zusammenstellung der klinisehen und pathologisch-anatomlschen Befunde, Schweiz. Med. Wochenschr. 96: 787, 1966. 177. Fisher, E. R., and Rodnan, G. P.: Pathologic observations concerning the cutaneous lesion of progressive systemic sclerosis: An electron microscopic histochemical and immunohistochemical study, Arthritis Rheum. 3: 536, 1960.

The Journal of Pediatrics April 1972

178. Lubchenco, L. O., Hansman, C., Dressier, M., and Boyd, E.: Intrauterine growth as estimated from Iiveborn birth-weight data at 2r to 42 weeks of gestation, Pediatrics 32: 793, 1963. 179. Reichel, W., and Garcia-Bunuel, R.: Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment, Am. J. Clin. Pathol. 53" 243, 1970.