976 Κ. Ε. SCHIRMER

4. Dobyns, B. M., and Steelman, S. : The thyroid-stimulating hormones distinct from the exophthalmos-producing factor. Endocrinology, 52:705, 1953.

5. Dobyns, B. M., and Wilson, L. A.: An exophthalmos-producing substance in the serum of patients suffering from progressive exophthalmos. J. Clin. Endocrinol., 14:1393, 1954.

6. Day, R. M.: Ocular manifestations of thyroid disease. AM A Arch. Ophth., 64:324, 1960.

INFANTILE CORTICAL HYPEROSTOSIS*

A N U N U S U A L CAUSE OF PROPTOSIS

CHARLES E . I L I F F , M.D. Baltimore, Maryland

AND

H E L E N J O H N S OSSOFSKY, M.D. Washington, D.C.

Rapidly progressive unilateral exophthal­mos in infants is usually associated with an ominous prognosis. With the exception of an acute orbital cellulitis, which should offer little difficulty in diagnosis, acute symptoms frequently are caused by malignant tumors. We have recently seen an infant who had findings suggestive of a malignant orbital tumor but who had a benign disease, in­fantile cortical hyperostosis, which is well known to the pediatrician but almost un­known to the ophthalmologist. Knowledge of the benign and completely reversible nature of the disease is necessary in saving such in­fants from orbital biopsy, and perhaps from exenteration.

CASE REPORT

T. D. was well until three weeks of age when she developed a "head cold" characterized by rhinor-rhea, fever and slight irritability. The child was treated with antibiotics and, within a few days, seemed entirely well. A week later the right eye suddenly became prominent and the lid appeared red. The infant had a low-grade fever for several days but otherwise appeared well. Over the next five weeks there was a gradual progression of proptosis and the infant was referred for consideration of orbital biopsy. The family history was noncon-tributory, except that the mother had a viral re­spiratory illness during the first trimester of this pregnancy.

When we first saw the child, she appeared to be

* From the Department of Ophthalmology, The Johns Hopkins University School of Medicine, Bal­timore, and the Department of Pediatrics, George­town University School of Medicine, Washington.

a healthy eight-week-old infant with marked prop­tosis and inferior and nasal displacement of the globe. The retinal veins were moderately distended on the right. There were small, soft, anterior cervi­cal nodes bilaterally and similar postauricular nodes on the left. Skull films were normal except for hyperostosis of the right orbit and zygoma (fig. 1) ; films of the mandibles and clavicles were normal. The diagnosis of infantile cortical hyperostosis was considered but, in the absence of mandibular in­volvement, it was felt that the infant might have a metastatic orbital tumor, possibly arising from the kidney or adrenal. The child was admitted to the Georgetown University Hospital for a more com­plete evaluation.

On admission the hemogram was normal except for a leukocytosis of 18,000 with a 62-percent poly-morphonuclear neutrophil response. The erythro-cyte sedimentation rate was normal. Urinalysis, IVP, serology and serum calcium and phosphorus were normal. The alkaline phosphatase was elevated to eight Bessey-Lowrie Units (normal, two to six). During the first few days of hospitalization the proptosis receded and the right jaw became swollen (fig. 2). The cheek overlying the right zygomatic arch was tender to firm palpation; otherwise the infant was asymptomatic. The lymph nodes noted on admission disappeared; however, several new soft axillary and occipital nodes appeared. A fresh one cm. occipital node was excised. Repeat films of the mandibles (six weeks after the onset of proptosis) showed periosteal layering of both mandibles, con­sidered pathognomonic of Caffey's disease (fig. 3). A chest X-ray film disclosed several thickened ribs with marked periosteal elevation. The infant re­mained afebrile, gained weight satisfactorily and appeared to be entirely asymptomatic throughout her brief hospitalization. No therapy was given. Several weeks after discharge, the proptosis and displacement of the globe disappeared entirely. Interestingly, both mandibles appeared to be equally involved radiologically ; however, the disease could be detected clinically only on the right. After dis-

INFANTILE CORTICAL HYPEROSTOSIS 977

Fig. 1 (Iliff and Ossofsky). Skull film of the infant at eight weeks of age, showing hyperostosis of the right orbit and zygomatic arch. Films of the clavicles and mandibles taken at the same time were normal.

charge swelling of the right jaw continued for several weeks, and then subsided spontaneously. At six months of age the infant showed no clinical or X-ray evidence of disease.

Histologie examination of the occipital lymph node (courtesy of Dr. Daniel L. Weiss) revealed hyperplasia of the reticular cells, and precocious follicle development ; the follicular centers appeared blastic. The hilar area of the node was composed of dilated lymph channels, histiocytes and clumps of eosinophiles. A definite diagnosis could not be made from this specimen; we have never seen a lymph node with these specific changes.

REVIEW OF HISTORY AND CLINICAL FEATURES

The bone lesions of infantile cortical hy-perotosis were described by Roske in Hei­delberg as early as 1930 j 1 however, the ill­ness was not recognized as a new disease until 1945 when Caffey (and, independently, Smyth) defined a syndrome of soft tissue swellings overlying bones which undergo characteristic X-ray changes.2 In 1948, the name "Caffey-Smyth's disease" was pro­posed for the syndrome,8 and since this time the disease has become known as Caffey's

Fig. 2 (Iliff and Ossofsky). The infant at 10 weeks of age. The proptosis of the right eye which had been present for seven weeks is receding and the right mandible has become acutely swollen.

disease. Over a hundred cases have been re­corded but the disease is probably more com­mon than the literature suggests ; many mild cases undoubtedly are overlooked. We have seen three infants with this disease at the Georgetown University Hospital Clinic and two patients in private practice within the past five months.

Diet, allergy, viruses, trauma, genetic and vascular factors have been suggested as play­ing a dominant role in the pathogenesis of this peculiar illness ; however, the etiology re­mains obscure. The clinical and histologie findings suggest infection. Eversole, Holman and Robinson have meticulously reviewed the histologie findings of biopsies taken at different stages of the illness.* Early the lesion appears to be an acute inflammatory reaction which destroys the periosteum. In­flammation and edema extend into the soft tissues. In the subacute and healing stages the inflammation subsides and a thick per-

978 CHARLES E. ILIFF AND HELEN JOHNS OSSOFSKY

iosteum reforms over new bone. During the acute stage, biopsies which have included only a small peripheral portion of the lesion have been misinterpreted as osteogenic sar­coma. In several instances mutilating sur­gical procedures have been done ; entire man­dibles have been excised and, in at least one child, a shoulder girdle arm amputation was performed after a thorough review of ma­terial biopsed from the scapula was inter­preted as "osteoblastic reaction, ? tumor."4

Eversole's work should contribute greatly to a better understanding and more correct histologie interpretation of biopsy specimens.

Infantile cortical hyperostosis is protean in its manifestations ; however, all patients have the following five features in common:

1. Age. The onset of symptoms occurs in very early infancy. Caffey's disease has been diagnosed radiologically in fetuses as early as the 31st week of gestation.5-6 The average age of onset is nine weeks. There is a strik­ing age limitation ; the onset of illness is not thought to occur in infants over five months of age.7

2. Soft tissue swellings. Soft tissue swell­ings appear over the affected bones and usually cause the family to seek medical ad­vice. Minimal swellings, especially if bilat­eral, may be overlooked. The swellings are firm, diffuse, and nonfluctuant. We have noted a violaceous discoloration of the skin overlying the swollen areas in some infants but heat is absent. The swellings may appear suddenly or develop insidiously. Pain fre­quently accompanies the swelling but not in­variably so.

3. Mandibular involvement. Mandibular involvement is one of the most striking fea­tures of the disease and is so universal that it is doubtful that a diagnosis of infantile cortical hyperostosis can be made unless the mandibles are involved, at least radiologi­cally, at some time during the course of the illness.

4. Characteristic X-ray features. In addi­tion to the mandibles, the disease has been seen in all the long bones, ileum,8 and skull.9

One third of Caffey's patients had the clavi­cles involved, one fourth the scapulas and one third the tubular bones, in addition to the mandibles.10 The cortical walls of the bones are thickened, and there is a character­istic periosteal layering, considered diag­nostic of this disease (fig. 3) . X-ray changes may not occur simultaneously with clinical swelling ; there may be a delay before slight periosteal elevation is detected and occasion­ally X-ray changes are seen in the absence of perceptible swelling.11 Radiologically, our patient seemed to have both mandibles in­volved equally; however, at no time could swelling or tenderness be detected over the left mandible. Epiphyseal ossification centers and the metaphyses of long bones are not involved.

5. Spontaneous recovery. Spontaneous clinical and radiologie recovery occurs in all

Fig. 3 (Iliff and Ossofsky). X-ray view of the mandibles taken when the infant was 10 weeks of age. There is periosteal layering of the rami of both mandibles which is considered pathognomonic of infantile cortical hyperostosis. Radiologically both mandibles appear to be involved equally ; how­ever, swelling of only the right mandible was de­tected clinically at the time this film was obtained.

INFANTILE CORTICAL HYPEROSTOSIS 979

patients, although the course of the disease is variable. There may be unpredictable ex­acerbations and remissions. Many bones may become involved before spontaneous healing occurs, or the disease may be confined to the mandible(s). One area of bone may heal while another becomes acutely inflamed. The duration of the illness is variable; recovery may be rapid, within a few weeks or as long as 12 or 18 months.

Caffey has reported a child in whom bone bridges developed between the ulna and radius12 but, except for the rare complica­tion of fusion of contiguous bones, no se­quelae have been observed. Burbank, Love-stedt, and Kennedy13 have examined the teeth of a group of older children who had the disease during infancy and have noted slight asymmetry of the mandibles by X-ray in eight of 11 children. The asymmetry could not be detected clinically. There is no evidence that the mandibular lesion affects the time or sequence of the eruption of teeth or the quality of the enamel.

Except for the five features of the disease described, other manifestations of illness are variable. Infantile cortical hyperostosis has been described as a triad consisting of "fever, irritability, and swelling" ;14 however, we have found that the constitutional symp­toms are usually mild and that fever and ir­ritability are absent in many infants. The symptomatology naturally varies with the number and location of the bones involved. Pseudoparalyses have occurred when bones of the extremities are affected. One febrile, irritable infant was thought to have meningi­tis, because his head was rigidly hyperex-tended, presumably to protect his painful jaws.15 Pleural thickening has been described in infants who have had extensive lesions in the ribs.2

In reviewing the literature, we have found four infants in whom the onset of illness was manifest by marked swelling about one or both eyes.8'16"18 Orbital films were not obtained in these patients. A diagnosis of infantile cortical hyperostosis was made at

a later date when mandibular swelling ap­peared ; however, a relationship between the earlier ocular findings and Caffey's disease apparently was never appreciated. In other infants periorbital edema was prominent early in the illness.15'19·20 Caffey has noted that conjunctivitis preceded facial swelling in several of his patients.10

Regional lymphadenopathy is variable. In Caffey's patients the regional lymph nodes were not involved ;10 Litton21 found that lymphadenitis may be coincident with acute swellings. We have found small regional lymph nodes in all our patients, but have examined the node of only one infant histo-logically. We are not yet able to interpret the unusual changes.

Mild anemia, leukocytosis, increased sedi­mentation rate and elevation of the alkaline phosphatase activity have been reported but these laboratory findings are variable. Serum calcium and phosphorus are always normal.

THERAPY

No therapy has proven effective in the treatment of infantile cortical hyperostosis, although claims have been made that steroids shorten the course of the disease, and modify its severity.22-24 Caffey believes that all chil­dren should be treated with 200 mg. of cor­tisone or its equivalent daily for at least two or three weeks before the drug is tapered and discontinued.10 Because of the variable and unpredictable nature of the illness, re­sults of therapy are difficult to evaluate. Until there is better evidence that steroids are of definite value, we believe these drugs should be reserved for the treatment of the severely ill infant. Had proptosis continued and threatened the vision of our patient, steroids would certainly have been worth trying.

DIFFERENTIAL DIAGNOSIS

Diagnosis should never be difficult in in­fants who present with unilateral or bilateral mandibular swelling. An X-ray film usually confirms the clinical diagnosis; biopsies are

980 CHARLES E. ILIFF AND HELEN JOHNS OSSOFSKY

not necessary. When the disease begins in ritability, and periorbital edema was mis-other bones, a difficult diagnostic problem diagnosed as having a milk allergy.26

may be encountered. In the orbit infantile cortical hyperostosis must be differentiated from malignant tumors in order that opera- A brief review of the salient features of tive interference be avoided. In the past clin- infantile cortical hyperostosis is presented. ical and biopsy evaluation has occasionally Although the disease is easy to recognize in resulted in an incorrect diagnosis of osteo- the infant who develops the typical swellings genie sarcoma, even when the lesion has oc- of the jaw, a puzzling diagnostic problem curred in the mandible.4 may be encountered when mandibular in-

Rarely, Caffey's disease has mimicked volvement does not occur until relatively late other conditions: hyperostosis in young in- in the course of the illness. fants may suggest hypervitaminosis A ; how- A case is presented of an infant who de-ever, a careful history of the child's vitamin veloped unilateral proptosis at four weeks intake should clarify this possibility. In of age. Caffey's disease was suspected as the hypervitaminosis A, the metacarpals are cause of the proptosis and hyperostosis of commonly involved ; they are rarely if ever the orbital bones ; however, confirmation was affected in Caffey's disease.19 Osteomyelitis not obtained until the characteristic X-ray is usually suspected clinically and confirmed changes appeared in the mandibles six weeks by X-ray examination and cultures. One in- later. fant had his disease confined at the onset to The Johns Hopkins Hospital (5). several ribs, and because of vomiting, ir- 4201 Cathedral Avenue, N.W. (16)

REFERENCES

1. Roske, G. : Eine eigenartige Knochenerkrankung im Säuglingsalter. Monatschr. f. Kinderh., 47:385-400, 1930.

2. Caffey, J., and Silverman, W. A.: Infantile cortical hyperostosis. Am. J. Roentgenol., 54:1-16, 1945. 3. Burke, F. G., and Ross, S.: Infantile cortical hyperostoses (Caffey-Smyth Syndrome). Clin. Proc.

Child. Hosp., Wash., 4:139-147, 1948. 4. Eversole, S. L., Jr., Holman, G. H., and Robinson, R. A.: Hitherto undescribed characteristics of

the pathology of infantile cortical hyperostosis (Caffey's disease). Bull. Johns Hopkins Hosp., 101:80-99, 1957.

5. Barba, W. P., and Freriks, D. J.: The familial occurrence of infantile cortical hyperostosis in utero. J. Pediat., 42:141-50, 1953.

6. Bennett, H. S., and Nelson, T. R.: Prenatal cortical hyperostosis. Brit. J. Radiol., 26:47-49, 1953. 7. Sidbury, J. B., Jr.: Infantile cortical hyperostosis. Postgrad. Med., 22:211-215, 1957. 8. Racely, C. A., Bilderback, J. B., and Burton, W. Y. : Infantile cortical hyperostosis with involve­

ment of the ileum. Northwest Med., 50:418-424, 1951. 9. Whipple, R. K.: Infantile cortical hyperostoses: Report of a case. New England J. Med., 236:239-

242, 1947. 10. Caffey, J.: Infantile cortical hyperostosis: A review of the clinical and radiographie features. Proc.

Royal Soc. Med., London, 50:347-354, 1957. 11. Meadors, J. L., and Weens, H. S.: Infantile cortical hyperostosis. Acta radiol., 42:43-55, 1954. 12. Caffey, J.: On some late skeletal changes in chronic infantile cortical hyperostosis. Radiology, 59:

651-657, 1952. 13. Burbank, P. M., Lovestedt, S. A., and Kennedy, R. L. J.: The dental aspects of infantile cortical

hyperostosis. Oral Surg., 11:1126-1137, 1958. 14. Sidbury, J. B., and Sidbury, J. Buren: Infantile cortical hyperostosis. North Carolina M. J., 16:

3-5, 1955. 15. Brooksaler, F., and Miller, J. E.: Infantile cortical hyperostosis. J. Pediat., 48:739-753, 1956. 16. Cayler, G. G., and Peterson, C. A.: Infantile cortical hyperostosis: Report of seventeen cases.

AMA J. Dis. Child., 91:119-125, 1956. 17. Colonna, P. C, and Richardson, B. A.: Infantile cortical hyperostosis. Am. J. Surg., 81:246-253,

1951. 18. Goluboff, N.: Infantile cortical hyperostosis (Caffey-Smyth Syndrome). Canad. M. A. J., 62:189-

191, 1950.

INFANTILE CORTICAL HYPEROSTOSTS 981

19. Allen, D. H., Browne, F. S., and Pierce, A. W.: Infantile cortical hyperostosis ; report of two cases with review of points of differential diagnosis from hypervitaminosis A. Am. J. Roent., 76:578-S82, 1956.

20. Benjamin, A., and Smith, P. G.: Infantile cortical hyperostosis of Caffey (two cases). Proc. Roy. Soc. Med., 53:61-62, 1960.

21. Litton, C:. Infantile cortical hyperostosis: A new syndrome. Am. J. Surg., 85:626-628, 1953. 22. Bush, L. G., and Merrill, O. E.: Infantile cortical hyperostosis: Case responding to treatment with

corticotropin (adrenocorticotropic hormone). J. Pediat., 40:330-333, 1952. 23. Pounders, C. M., and Delhotal, C. E.: Infantile cortical hyperostosis: Treatment with hormones.

J. Pediat., 47:157-160, 1955. 24. Sweeney, P. J.: A case of infantile cortical hyperostosis. Postgrad. M. J., London, 34:598-600,

1958. 25. Caffey, J.: Syphilis of skeleton in early infancy; nonspecificity of many of the roentgenographic

changes. Am. J. Roentgenol. & Rad. Therapy, 42:637-655, 1939. 26. Morrison, M. F.: Infantile cortical hyperostosis: Report of case misdiagnosed as milk allergy. J.

Pediat, 50:487-489, 1957.

T H E PERICYTES OF T H E HUMAN RETINA*

J. REIMER WOLTER, M.D. Ann Arbor, Michigan

Pericytes are cells of the wall of small blood vessels the function of which is un­known. They were discovered by Rouget1

in the capillaries of the membrana hyaloidea of the frog. Zimmermann2 in his fundamen­tal paper described in detail the structure and arrangement of these peculiar cells of the blood vessel wall in numerous organs of men and in several species of animals but did not mention those of the eye. Schaly3

studied the pericytes of the choroid but his description and illustrations convey little in­formation.

After having described the pericytes of the human choroid4 in T H E JOURNAL in 1956, I tried for years to stain the pericytes of the human retina. However, the retinal neuroglia (astroglia and peri vascular glia5,e) have staining characteristics with silver stain which are very similar to those of the retinal pericytes. Therefore, it was not possible to get a selective stain of the peri­cytes alone without staining the perivascular glia at the same time. Both of these elements are arranged around the wall of small retinal

♦From the Department of Ophthalmic Surgery of the University of Michigan Medical Center, Ann Arbor. This study was supported by Grant No. B-2873 of the U.S. Department of Health, Education, and Welfare.

blood vessels and appear to have close rela­tions (comp. fig. 12).

A new technique recently introduced by Kuwabara and Cogan7 makes it possible to remove all neuro-ectodermal tissues of the retina including all glia from the retinal vascular tree by trypsin digestion. The mesodermal elements of the vessel wall re­main and it is possible to get good stains of retinal pericytes in such preparations.

TECHNIQUE AND CASES The trypsin digestion method of Kuwa­

bara and Cogan7 is used as described in two earlier papers.8·9 The digestion is carefully watched and the retina is taken out of the trypsin solution from time to time and moved about in water until a stage of di­gestion is reached at which all retinal par­enchyma comes loose and only the vascular tree remains as a cobweblike structure. It seems to be important not to overdo the di­gestion since parts of the cells of the blood vessel wall may be lost by too much diges­tion. From the water the blood vessel prep­arations are transferred into a two-percent silver nitrate solution. They are kept in this at a temperature of about 50°C. until they turn brown. The preparations are then changed into ammoniacal silver solution for about three minutes. This solution is ob-