American Journal of Medical Genetics 40159-166 (1991)
Noonan-Like/MultipleGiant Cell Lesion Syndrome M. Michael Cohen, Jr., and Robert J. Gorlin Department of Oral Biology, Faculty of Dentistry and Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (M.M.C.); and Department of Oral Pathology and Genetics, School of Dentistry, University of Minnesota Minneapolis, Minnesota (R.J.G.)
A patient with the Noonan-like/multiplegiant cell lesion syndrome is reported and the findings in 14 cases are reviewed. Impressive manifestations include short stature,low normal intelligence or developmental delay, ocular hypertelorism, prominent posteriorly angulatedears, giant cell lesions of bones,joints, and/or soft tissues, pectus excavatum, and pulmonic stenosis. It has been difficult to delineate the syndrome because problems in identifying the condition have resulted from incomplete or truncate ascertainment by various medical specialists.
KEY WORDS: pigmented villonodular synovitis, cherubism, central giant cell granuloma INTRODUCTION In 1974 we described a patient with short stature, ocular hypertelorism, prominent posteriorly angulated ears, short webbed neck, cubitus valgus, pulmonic stenosis, multiple lentigines, several flame nevi, and giant cell lesions of both bone and soft tissue. At that time, we recognized the syndrome as a distinct entity. We said, “Although various features suggest the Noonan syndrome, the LEOPARD syndrome, and/or hyperparathyroidism, the overall pattern of abnormalities is clearly at variance with any of these diagnoses . . . in this particular syndrome, our impression is that the giant cell lesions of the fingertips and within bone have a common cause. . . . ” [Cohen et al., 19741. In 1982, the patient was again distinguished from other known syndromes; a photographic montage (Fig. 1)accompanied the text [Cohen, 19821. Since then, a number of other cases have become apparent. The purposes of the present paper are 1)to present the above-mentionedcase; 2) to review other known cases; 3) to discuss the current status of the syndrome’sdelineaReceived for publication June 7,1990; revision received August 22, 1990. Address reprint requests to Dr. M. Michael Cohen, Jr., Department of Oral Biology, Faculty of Dentistry, Dalhousie University, Halifax, Nova Scotia B3H 355 Canada.
0 1991 Wiley-Liss, Inc.
tion; 4) to provide a name for the syndrome and indicate the reasons for our choice; and 5) to discuss differential diagnosis.
CLINICAL REPORT This white girl was the product of a 40 week gestation, weighing 2.75 kg (3rd-10th centile) a t birth. She was the sixth of nine children. A 9-year-old brother was mentally retarded. Further family history could not be ascertained. At age 11 years, she developed multiple lentigines, especially on the back and the forearms; she also had several pigmented nevi (Fig. 10.Warty excrescences on the 4th and 5th fingertips of the left hand were also observed a t this time (Fig. 1D). At age 15 years, height was 136 cm (50th centile for age 9.6 years), weight 36 kg (50th centile for age 11.6 years), and head circumference 55 cm (approximately 50th centile). Ocular hypertelorism, epicanthic folds, alternating exotropia, heterochromia irides, broad nasal bridge with lateral bony projections, prominent posteriorly angulated ears, large mouth, wide palate, and mild mandibular prognathism were observed. The neck was short with mild webbing (Fig. 1B). Pectus excavatum, dorsal kyphoscoliosis, marked cubitus valgus (Fig. lA), limitation of motion at the elbows, and hyperextensibility at the metacarpophalangeal joints were evident. Several small depigmented areas were observed on the forearms, trunk, and legs. Three nevus flammeus lesions were observed on the left thigh. The nipples appeared widely spaced. The breasts were small and the genitalia hypoplastic and immature. Cardiac findings were consistent with pulmonic stenosis. Moderate mental retardation was evident. Borderline hearing loss, probably sensorineural, was also noted. Skeletal survey showed generalized hypomineralization with somewhat thickened trabeculae. The growth plates were slightly wide. Mild subperiosteal and ungual tuft resorption and scattered cyst-like lesions in the short tubular bones (especially the phalanges) (Fig. 1G) and the mandible (Fig. 1F) were observed. The lamina dura surrounding the teeth was mildly deficient. Metacarpals (especially 3rd and 4th) were moderately short. Osseous maturation was low normal (13-13% years at age 15 years). Serum calcium was repeatedly low and no response to parathormone was elicited (Table I). Adrenal function was borderline low on baseline studies. Response to ACTH was inadequate, and there was no
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Fig. 1. A: Patient at age 15 years. Short neck with mild webbing, widely spaced small breasts, pectus excavatum, immature genitalia, marked cubitus valgus, kyphoscoliosis, and nevus flammeus lesions on left thigh. B: Ocular hypertelorism, epicanthic folds, strabismus, broad nasal bridge with lateral bony projections,large mouth, and laterally protruding posteriorly angulated ears. C:Multiple lentigines and a few scattered nevi; mild webbing of the neck. D Warty excrescencesof fingertip. E: Giant cell lesion of fingertip shown in D. Note giant cells (arrow)subjacentto epithelium. F:Multiple radiolucencies (arrows) of mandible. G.Radiolucent cyst-likeareas (arrows)of phalanges. H. Giant cell (arrows)lesion of mandible (see F). (Reproduced from Cohen, 1982, with permission of the publisher.)
response to metyrapone (Table 111, which suggested pituitary insufficiency. Chromosomes were normal. The pigmented lesions of the skin were confirmed microscopically as lentigines. Histologic examination of tissue from the jaw cysts was consistent with central giant cell granuloma or hyperparathyroidism (Fig. 1H). Identical giant cell lesions were observed histologically on biopsy of the fingertip lesions (Fig. 1E) and on excisional biopsies of the lateral bony projections on the nose.
Dunlap et al. (4 cases) U989I.l Falace [19891 re-examined the patient reported by Walls and Nogi [19851, reviewed the literature on the subject, and called the condition to the attention of clinical geneticists. Chuong et al. 119861 studied central giant cell lesions of the jaws in 17 patients and noted that two of these occurred in patients with Noonan syndrome. These latter patients probably represent the entity under discussion. Findings in one unpublished instance [Kaban, 19771, sum-
SUMMARY OF KNOWN CASES To date, including our original patient, we have recognized 14 instances of this syndrome. The findings are summarized in Table 111. Published cases include those of Leszczynski et al. 119751, Lindenbaum and Hunt [19771, Wagner et al. [19811,Hoyer and Neukem [19821, Walls and Nogi [19851,Wendt et al. (3 cases) 119861,and
'In a few instances, findings were interpreted from facial photographs. In three instances, euryopia or frank hypertelorism were determined from canthal index measurements [(inner canthal distance/outer canthal distance) x 1001 of facial photographs. Further information about a few cases was secured from several of the authors.
Nooiian-LikeMultiple Giant Cell Lesion Syndrome
161
TABLE I. Serum and Urinary Ca and P Response to Intramuscular Parathormone Injection*
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On day 2, 150 units were administered intravenously (i.v.) at 7:OO AM and at 7:OO PM.
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17 OHCS 1.0 1.5 0.9
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marized in Table 111,may describe one of the two Noonan pathologists have ascertained the condition by jaw insyndrome patients mentioned by Chuong et al. [19861. volvement and called it either “central giant cell granuOf the 14 cases of this syndrome (Table 1111,eight are loma” or “cherubism.”’ If the patient already carried the females and six are males. Although we have tabulated diagnosis of Noonan syndrome, the condition was somethe available findings in all 14 cases, we have not pro- times called “cherubism with Noonan syndrome” vided numerator and denominator figures (because of (thought to concur by chance). These types of specialty incomplete reporting, which is discussed later in this bias are reinforced by the fact that central giant cell paper). However, impressive manifestations include granuloma, cherubism, and pigmented villonodular short stature, low normal intelligence or development synovitis are specific clinicopathologic entities which do delay, ocular hypertelorism, prominent posteriorly an- accurately diagnose, with histopathologic confirmation, gulated ears, giant cell lesions of bones, joints, and/or the conditions present in the jaws and in the joints, soft tissues, pectus excavatum, and pulmonic stenosis. respectively, when the lesions are limited to those locaTo date, most cases have occurred sporadically. A no- tions. table exception is the family reported by Wendt et al. In the syndrome under discussion, giant cell lesions [19861. An affected father had two affected children, a may occur: 1) in the maxilla and mandible; 2) in the boy and a girl, a finding that is consistent with autoso- joints, sometimes with soft tissue extension andlor eroma1 dominant inheritance. A possibly affected father sive changes of contiguous bone; 3) in bones other than and son were mentioned by Dunlap et al. [19891. Con- the jaws as primary, non-erosive, cyst-like lesions; and firmation is not available. In discussing their case 3, 4) in soft tissue independently of soft tissue extension of Dunlap et al. noted that the proband‘s father “also had synovial involvement. If the patient is seen by an oral cherubism.” Only biopsy material and a panoramic ra- and maxillofacial surgeon or reviewed by an oral padiograph of the jaws were available to Dunlap et al. thologist, the histopathologically confirmed diagnosis is Since the material was examined in a service oral pa- likely to be “central giant cell granuloma, rule out hythology laboratory, neither the proband nor the father perparathyroidism,” as in our case report [Cohen et al., could be examined. 19741, or “cherubism,” as in the four cases reviewed by Dunlap et al. [19891. If the patient is seen by an orthoPROBLEMS IN NOSOLOGY pedic surgeon, the histopathologically confirmed diagWe do not think this syndrome is particularly rare. nosis is likely to be pigmented villonodular synovitis Rather, problems in identifying the condition have re- [Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; sulted from incomplete or truncate ascertainment by Walls and Nogi, 1985;Wendt et al., 19861. It is clear that various specialists. Some pediatricians have labelled cyst-like, giant cell lesions of bones other than the jaws the disorder as “Noonan syndrome.” Some orthopedic may be involved, for example, the short tubular bones, surgeons and some pathologists have ascertained the condition by involvement of the joints and have diagnosed it as “pigmented villonodular synovitis.” Finally, ’Less commonly, it has been called “familial fibrous dysplasia” some oral and maxillofacial surgeons and some oral or even “fibrous dysplasia.”
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a N = normal. bMR = mental retardation, LN = low normal, N = Normal, DL = delayed learning. CLesions of tubular bones and/or long bones and/or ribs. d At the metacarpophalangeal joints. 'At the elbows. 'C = pectus carinatum. g Hypertrophic subaortic stenosis, atrial septa1 defect, and probable aortic regurgitation. hMitral valve prolapse. 'Ventricular septa1 defect. Jocular proptosis, unerupted teeth. kHighly arched palate. 'Lymphedema, highly arched palate. m Widely spaced nipples. nunerupted teeth. ODown-slanting palpebral fissures, eyelid ptosis, cryptorchidism PHigh birth weight, eyelid ptosis, unerupted teeth. qHigh birth weight, epicanthic folds. rOcular proptosis.
Skeletal Giant cell lesions Long and tubular bones, ribs" Jaws Joints with or without soft tissue extension Soft tissue only Hyperextensibility Limitation of motion Pectus excavatum Cubitus valgus Scoliosis Cardiovascular Pulmonic stenosis Other congenital heart defect Genitourinary Incomplete sexual development Double collecting system Other rn
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particularly phalanges [Cohen et al., 1974; Kaban, 19771, radius [Wagner et al., 19811, humerus [Kaban, 19771, ribs [Dunlap et al., 19891, and even the region around the nasal bones [our case]. Soft tissue giant cell lesions (separate from joint involvement with contiguous soft tissue extension) are illustrated by the fingertip lesions in our case (Fig. 1D,E).3All of the aforementioned are giant cell lesions of similar histologic type regardless of the name used for specific localized forms and regardless of location. In the syndrome under discussion, all the giant cell lesions found have a common pathogenesis. In the literature, there are clues about cherubism, central giant cell granuloma, pigmented villonodular synovitis, and Noonan syndrome that suggest the possibility of the syndrome under discussion. For example, cherubism is an uncommon autosomal dominant condition that affects almost exclusively the maxilla and mandible. However, extremely unusual cases have been noted with additional extra-oral lesions involving the ribs [McClendon et al., 1962,Thompson, 19591,humerus [Bloom et al., 1962; Brannin and Christensen, 1954; Bruce et al., 1953;Thompson, 19621,femur [Bloom et al., 19621, and carpals [Riveros et al., 19501. Bianchi et al. [19871 reported a case of cherubism associated with pulmonic stenosis. Dukart et al. [1974] described a case of cherubism and indicated that the jaw lesions were histologically compatible with either central giant cell granuloma or cherubism. Facial photographs of the patient showed ocular hypertelorism and prominent ears. Salinas et al. [19831 observed a patient (also reported by Dunlap et al. [19891)with cherubism, cyst-like lesions of the ribs, ocular hypertelorism, eyelid ptosis, short neck, cardiovascular defect (? pulmonic stenosis), and cryptorchidism. Finally, we are aware of an unpublished male with cherubism, eyelid ptosis, pulmonic stenosis, and short stature. The mother had short stature, pulmonic stenosis, and a nevus flammeus of the forehead. We have also seen, in an unrelated sporadic instance, a 14-yearold girl with short stature, mental deficiency, ocular hypertelorism, paranasal eminences, cherubism, pulmonic stenosis, and dir dup(18)q12.1-+12.3. Davis and Tideman [1977] reported multiple central giant cell granulomas of the jaws in a patient whose mother had an extensive central giant cell granuloma of the maxilla. The authors did not mention any other findings. Hjprrting-Hansen and Worspre-Petersen [ 19671 observed a woman with giant cell lesions of the jaws, humerus, radius, femur, and phalanges; she had short stature and incomplete development of secondary sexual characteristics. Weldon and Cozzi [ 19821noted multiple giant cell lesions of the jaws associated with pulmonic stenosis. 3Pigmented villonodular synovitis can involve the tendon sheaths of the fingers and results, on occasion, in an overlying soft tissue lesion of the skin of the fingers [Fort and Rodman, 1977; King et al., 19781. Thus, it is conceivable (although unlikely in our view) that the fingertip lesions in our patient represent soft tissue extension of pigmented villonodular tenosynovitis. Such lesions apparently occur in the interphalangeal regions, not on the fingertips.
Pigmented villonodular synovitis is an uncommon disorder that almost always affects a single joint, predominantly the knee. Peak incidence occurs during the third and fourth decades [Johansson et al., 19821. Multiple joint involvement, particularly at relatively young ages, is rare [Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981; Walls and Nogi, 1985; Wendt et al., 19861. Bobechko and Kostuik [19681 reported two boys and one girl (ages 4, 5, and 10 years, respectively) who developed pigmented villonodular synovitis in one knee. Overlying hemangiomas of the skin were observed at birth in each case. Kelikian and Lewis [19491 briefly mentioned bilateral knee involvement with pigmented villonodular synovitis in two sibs; a third sib was known to have bilateral wrist and knee involvement. It is not stated whether other anomalies were present or not. Hoza (personal communication) observed polyarticular pigmented villonodular synovitis associated with ocular hypertelorism, cavernous hemangioma of the orbit, and pulmonic stenosis. Some cases have been ascertained as Noonan syndrome, for example, those of Dunlap et al. [19891 and Salinas et al. [19831: Other cases have nothing t o do with the syndrome under discussion. For example, Connor et al. [1982] described a case of Noonan syndrome with multiple odontogenic keratocysts. This patient represents an example of the nevoid basal cell carcinoma syndrome. Nelson et al. [1978] observed a case of Noonan syndrome in which xanthomas of the skin and tongue were additional findings. In the final analysis, it is clear that unusual distribution of any of the various types of giant cell lesions suggests that the syndrome under discussion should be considered. Certainly, a full skeletal radiographic survey is indicated in any suspected case. It should also be noted that in this syndrome giant cell lesions evolve with time; they may not be present at any one point, but may appear later.
NAMING THE SYNDROME We have designated the syndrome as the Noonan-like/ multiple giant cell lesion syndrome. We cannot recommend using terms such as Noonan syndrome, pigmented villonodular synovitis, central giant cell granuloma, or cherubism for two reasons. First, each is a specific diagnostic entity sui generis and does not accurately reflect the syndrome under discussion.Second,we strongly suspect that, in the past, the use of these terms-particularly pigmented villonodular synovitis, central giant cell granuloma, and cherubism-has resulted in nosologic blinders that tended to limit the workup of these patients. Nor can we recommend compounding these terms as, for example, in polyarticular pigmented villonodular synovitis/cherubism/Noonan syndrome. We prefer the term Noonan-like/multiple giant cell lesion syndrome because it generalizes the findings in the syndrome; the condition is Noonan-like and has multiple giant cell lesions in various parts of the body. 4The aatient reDorted bv Salinas et al. 119831 is also one of the four patients reported by"Dun1ap et al. [19891.
Noonan-LikelMultipleGiant Cell Lesion Syndrome
165
DIFFERENTIAL DIAGNOSIS Conditions that enter into the differential diagnosis are listed in Table IV. The Noonan-like/multiple giant cell lesion syndrome shares several obvious characteristics in common with the Noonan and LEOPARD syndromes, including short stature, ocular hypertelorism, pectus excavatum, pulmonic stenosis, and delayed development of secondary sexual characteristics. However, neither syndrome has multiple giant cell lesions of bones, jaws, and soft tissues. Pigmented villonodular synovitis, central giant cell granuloma, and cherubism as specific clinicopathologic entities have already been discussed. Advanced hyperparathyroidism with “brown tumors” of bone are histologically identical to central giant cell granulomas of the jaws. In the typical case, hyperparathyroidism is commonly ruled out. In the Noonan-like/multiple giant cell lesion syndrome, there is no evidence of hyperparathyroidism. The Jaffe-Campanacci syndrome consists of caf6-aulait spots, multiple non-ossifying fibromas of bone (including long bones and jaws), and pathological fractures. The lesions are of the giant cell type histologically and are identical to central giant cell granulomas. Other reported changes in some cases have included mental retardation, hypogonadism, cryptorchidism, cardiovascular defects (mitral insufficiencyor aortic stenosis), different types of ocular defects, and miscellaneous anomalies. To date, all cases have been sporadic and no patient has had skin nodules or documented neurofibromas [Campanacci et al., 1983, Mirra et al., 1982, Steinmetz et al., 19881. Ramon syndrome consists of growth deficiency, moderate mental retardation, major seizures, hypertrichosis, gingival fibromatosis, and cherubism. The condition appears to have autosomal recessive inheritance [Ramon et al., 1967, Pina-Net0 et al., 19861. However, some of the patients in the family reported by Pina-Net0 et al. [19861 had juvenile rheumatoid arthritis. They noted palpable subcutaneous nodules around the joints of both hands. Further delineation is necessary to determine if the findings are those of juvenile rheumatoid arthritis or possibly polyarticular pigmented villonodular synovitis. The neurofibromatosis-Noonan syndrome has been reported by a number of authors [Allanson et al., 1985; Kaplan and Rosenblatt, 1985; Mendez, 1985; Opitz and Weaver, 1985; Saul, 1985; Meinecke, 1987; Proud et al., 1987; Quattrin et al., 19871. Opitz and Weaver [1985]
enumerated four possible interpretations: (1) chance concurrence of Noonan syndrome and neurofibromatosis; (2) neurofibromatosis-Noonan syndrome as an unusual variant of Noonan syndrome; (3) neurofibromatosis-Noonan syndrome as an unusual type of neurofibromatosis; and (4) neurofibromatosis-Noonan syndrome as a distinct entity suigeneris. Vertical transmission of complete neurofibromatosis-Noonan syndrome was reported by Quattrin et al. [1987]. Neurofibromatosis-Noonan syndrome has also been reported with classic neurofibromatosis in other relatives [Meinecke,19871or with neurofibromatosis and partial Noonan findings in other relatives [Kaplan and Rosenblatt, 1985; Proud et al., 1987; Abuelo and Meryash, 19881.Sporadic instances have been observed [Allanson et al., 1985; Mendez, 1985; Saul, 19851. The cardio-facial-cutaneous (CFC) syndrome is characterized by high forehead with bitemporal constriction, hypoplastic supraorbital ridges, ptosis of the eyelids, downslanting palpebral fissures, posteriorly angulated ears with prominent helices, and neck webbing in some instances. The facial appearance is reminiscent of that observed in Noonan syndrome. Other manifestations include growth deficiency, mental retardation, cardiovascular defects, and dry hyperkeratotic skin. Most cases have been sporadic to date [Reynolds et al., 1986; Mucklow, 19891, but dominant inheritance has been suggested in one family [Verloes et al., 19881. The patient with Noonan-like/multiple giant cell lesion syndrome reported by Walls and Nogi [19851 and later examined by Falace [19891 was originally diagnosed erroneously as having fetal hydantoin syndrome at birth, presumably because of ocular hypertelorism, broad nasal bridge, highly arched palate, and pulmonic stenosis, all of which were present in the patient.
TABLE IV. Differential Diagnosis
Abuelo DN, Meryash DL (1988): Neurofibromatosis with fully expressed Noonan syndrome. Am J Med Genet 29:937-941. Allanson J E , Hall JG, Van Allen MI (1985):Noonan phenotype associated with neurofibromatosis. Am J Med Genet 21:457-462. Bianchi SD, Boccardi A, Mela F, Romagnoli R (1987): The computed tomographic appearance of cherubism. Skeletal Radio1 16:6-10. Bloom J, Chacker FM, Thomas KH (1962): Multiple giant-cell lesions of bone; report of a case. Oral Surg 15 [Suppl 21:74-83. Bobechko WP, Kostuik JP (1968): Childhood villonodular synovitis. Cana J Surg 11:480-486. Brannin DE, Christensen RO (1954):Bilateral giant cell tumors of the mandible in siblings; report of cases. J Oral Surg 12:247-251.
Noonan syndrome LEOPARD syndrome Pigmented villonodular synovitis Cherubism Central giant cell granuloma Hyperparathyroidism Jaffe-Campanacci syndrome Ramon syndrome Neurofibromatosis-Noonan syndrome Cardio-facio-cutaneous (CFC) syndrome
CONCLUSIONS We have defined a syndrome of short stature, low normal intelligence or developmental delay, ocular hypertelorism, prominent posteriorly angulated ears, giant cell lesions of bones,joints, andlor soft tissues, pectus excavatum, and pulmonic stenosis. To date, most cases have occurred sporadically, although one affected family is consistent with autosomal dominant inheritance. The syndrome is probably not rare but is incompletely understood, for the most part, because of ascertainment by various specialties in the past. The Noonan-like/multiple giant cell lesion syndrome needs to be further delineated. REFERENCES
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Bruce KW, Bruwer A, Kennedy R U (1953): Familial intraosseous fibrous swellings of the jaws (“cherubism”).Oral Surg 6:995-1014. Campanacci M, Laus M, Boriani S (1983): Multiple non-ossifying fibromata with extraskeletal anomalies: A new syndrome? J Bone Joint Surg [Brl 65B:627-632. Chuong R, Kaban LB, Kozakewich H, Perez-Atayde A (1986):Central giant cell lesions of the jaws: A clinicopathologic study. J Oral Maxillofac Surg 44:708-713. Cohen MM Jr (1982): “The Child with Multiple Birth Defects.” New York: Raven Press, pp 78-85. Cohen MM J r , Ruvalcaba RHA, Graham CB, Harrison MT, Morgan AF (1974): A new syndrome simulating the Noonan syndrome, the Leopard syndrome, and hyperparathyroidism. Syndrome Ident 2:14-17. Connor JM, Price Evans DA, Goose DH (1982): Multiple odontogenic keratocysts in a case of the Noonan syndrome. Br J Oral Surg 20:213-216. Davis GB, n d e m a n H (1977): Multiple recurrent central giant cell granulomas of the jaws. J Max-Fac Surg 5127-129. Dukart RC, Kolodny SC, Polte HW, Hooker SP (1974): Cherubism: report of a case. J Oral Surg 32:782-785. Dunlap C, Neville B, Vickers RA, O’Neil D, Barker B (1989): The Noonan syndrome-cherubism association. Oral Surg 67:698-705. Falace PB (1989):Polyarticular pigmented villonodular synovitis, jaw cysts, cardiac defects, mild developmental delay and distinctive facies: A recognizable syndrome. 10th Annual David W. Smith Workshop on Malformations and Morphogenesis, Madrid, Spain, May 23-29, 1989. Fort SL, Rodman OG (1977):Erythema elevatum diutinum. Arch Dermatol 113:819-822. HjldrtingHansen E, Worslde-PetersenJ (1967):Recurrent benign giantcell lesions of the jaws with metastasis‘’ J Laryngol Otol81:10331042. Hoyer PF, Neukam FW (1982): Cherubismuseine osteofibrose Kiefererkrankung im Kindesalter. Klin Padiatr 194:128-131. Johansson JE, Ajoub S, Coughlin LP, Wener JA, Cruess RL (1982): Pigmented villonodular synovitis of joints. Clin Orthop 163:159166. Kaban LB (1977): Unpublished data. Kaplan P, Rosenblatt B (1985): A distinctive facial appearance in neurofibromatosis von Recklinghausen. Am J Med Genet 21:463-470. Kelikian H, Lewis EK (1949): Arthrograms. Radiology 52:465-487. King DT, Millman AJ, Gurevitch AW, Hirose FM (1978): Giant cell tumor of the tendon sheath involving skin. Arch Dermatol 114:944-946. Leszczynski J , Huckell JR, Percy JS, LeRiche JC, Lentle BC (1975): Pigmented villonodular synovitis in multiple joints. Occurrence in a child with cavernous haemangioma of lip and pulmonary stenosis. Ann Rheum Dis 34:269-272. Lindenbaum BL, Hunt T (1977):An unusual presentation ofpigmented villonodular synovitis. Clin Orthop 122:263-267. McClendon JL, Anderson DE, Cornelius EA (1962): Cherubism-hereditary fibrous dysplasia of the jaws. 11 Pathologic considerations. Oral Surg 15 (Suppl 2):17-42. Meinecke P (1987):Evidence that the “Neurofibromatosis-Noonansyndrome” is a variant of von Recklinghausen neurofibromatosis. Am J Med Genet 26:741-745.
Mendez HMM (1985):The neurofibromatosis-Noonan syndrome. Am J Med Genet 21:471-476. Mirra JM, Gold RH, Rand F (1982): Disseminated nonossifying fibromas in association with cafe-au-lait spots (Jaffe-Campanacci syndrome). Clin Orthop 168:192-205. Mucklow ES (1989):A case of cardio-facio-cutaneous syndrome. Am J Med Genet 33:474-475. Nelson J F , Tsaknis PJ, Konzelman J L (1978): Noonan’s syndrome: report of a case with oral lesions. J Oral Med 33:94-96. Opitz JM, Weaver DD (1985): Editorial comment: The neurofibromatosis-Noonan syndrome. Am J Med Genet 21:477-490. Pina-Net0 JM, Moreno AFC, Silva LR, Velludo MASL, Petean EBL, Ribeiro VM, AthaydeJunior L, Voltarelli J C (1986): Cherubism, gingival fibromatosis, epilepsy, and mental deficiency (Ramon syndrome) with juvenile rheumatoid arthritis. Am J Med Genet 25:433-442. Proud VK, Gulati A, Nance WE, Pellock J M (1987): Complications of Noonan syndrome-neurofibromatosis in a family with neurofibromatosis. Proc Greenwood Genet Ctr 6:160-161. Quattrin T, McPherson E, Putnam T (1987): Vertical transmission of the neurofibromatosis/Noonan syndrome. Am J Med Genet 26: 645-649. Ramon Y, Berman W, Bubis JJ (1967):Gingival fibromatosis combined with cherubism. Oral Surg 24:436-448. Reynolds J F , Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986):New multiple congenital anomalies-mental retardation syndrome with cardio-facio-cutaneous involvement the CFC syndrome. Am J Med Genet 25413-428. Riveros M, Codas Thompson Q, Boggino J (1950): Consideraciones clinicas, radiologicas sobre osteodistrofia poliostotica familiar. Rev Ortop Traumatol 2O:l-17. Salinas CF, Bradford BF, Laden SA, Neville BW (1983): Cherubism associated with rib anomalies. Proc Greenwood Genet Ctr 2: 129-130 (Case 1). Saul RA (1985):Letter to the editor: Noonan syndrome in apatient with hyperplasia of the myenteric plexuses and neurofibromatosis.Am J Med Genet 21:491-492. Steinmetz JC, Pilon VA, Lee, J K (1988):Jaffe-Campanacci syndrome. J Pediatr Orthop 8:602-604. Thompson ER (1962):Multiple giant-cell tumors: Report of a case. Oral Surg 15 [Suppl 21:69-73. Thompson N (19591: Cherubism: Familial fibrous dysplasia of the jaw. Br J Plast Surg 12:89-103. Verloes A, LeMerrer M, Soyeur D, Kaplan J , Pangalos C, Rig0 J , Briard M-L (1988): CFC syndrome: A syndrome distinct from Noonan syndrome. Ann Genet 31:230-234. Wagner ML, Harlan JS, Dutton RV, Glassman AL, Askew J B (1981): Polyarticular pigmented villonodular synovitis. Am J Roentgen01 136:821-823. Walls JP, Nogi J (1985):Multifocal pigmented villonodular synovitis in a child. J Pediatr Orthop 5229-231. Weldon L, Cozzi G (1982):Multiple giant cell lesions of the jaws. J Oral Maxillofac Surg 40:520-522. Wendt RG, Wolfe F, McQueen D, Murphy P, Solomon H, Housholder M (1986):Polyarticular pigmented villonodular synovitis in children. Evidence for a genetic combination. J Rheumatol 13:921-926.
Noonan-Like/MultipleGiant Cell Lesion Syndrome M. Michael Cohen, Jr., and Robert J. Gorlin Department of Oral Biology, Faculty of Dentistry and Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada (M.M.C.); and Department of Oral Pathology and Genetics, School of Dentistry, University of Minnesota Minneapolis, Minnesota (R.J.G.)
A patient with the Noonan-like/multiplegiant cell lesion syndrome is reported and the findings in 14 cases are reviewed. Impressive manifestations include short stature,low normal intelligence or developmental delay, ocular hypertelorism, prominent posteriorly angulatedears, giant cell lesions of bones,joints, and/or soft tissues, pectus excavatum, and pulmonic stenosis. It has been difficult to delineate the syndrome because problems in identifying the condition have resulted from incomplete or truncate ascertainment by various medical specialists.
KEY WORDS: pigmented villonodular synovitis, cherubism, central giant cell granuloma INTRODUCTION In 1974 we described a patient with short stature, ocular hypertelorism, prominent posteriorly angulated ears, short webbed neck, cubitus valgus, pulmonic stenosis, multiple lentigines, several flame nevi, and giant cell lesions of both bone and soft tissue. At that time, we recognized the syndrome as a distinct entity. We said, “Although various features suggest the Noonan syndrome, the LEOPARD syndrome, and/or hyperparathyroidism, the overall pattern of abnormalities is clearly at variance with any of these diagnoses . . . in this particular syndrome, our impression is that the giant cell lesions of the fingertips and within bone have a common cause. . . . ” [Cohen et al., 19741. In 1982, the patient was again distinguished from other known syndromes; a photographic montage (Fig. 1)accompanied the text [Cohen, 19821. Since then, a number of other cases have become apparent. The purposes of the present paper are 1)to present the above-mentionedcase; 2) to review other known cases; 3) to discuss the current status of the syndrome’sdelineaReceived for publication June 7,1990; revision received August 22, 1990. Address reprint requests to Dr. M. Michael Cohen, Jr., Department of Oral Biology, Faculty of Dentistry, Dalhousie University, Halifax, Nova Scotia B3H 355 Canada.
0 1991 Wiley-Liss, Inc.
tion; 4) to provide a name for the syndrome and indicate the reasons for our choice; and 5) to discuss differential diagnosis.
CLINICAL REPORT This white girl was the product of a 40 week gestation, weighing 2.75 kg (3rd-10th centile) a t birth. She was the sixth of nine children. A 9-year-old brother was mentally retarded. Further family history could not be ascertained. At age 11 years, she developed multiple lentigines, especially on the back and the forearms; she also had several pigmented nevi (Fig. 10.Warty excrescences on the 4th and 5th fingertips of the left hand were also observed a t this time (Fig. 1D). At age 15 years, height was 136 cm (50th centile for age 9.6 years), weight 36 kg (50th centile for age 11.6 years), and head circumference 55 cm (approximately 50th centile). Ocular hypertelorism, epicanthic folds, alternating exotropia, heterochromia irides, broad nasal bridge with lateral bony projections, prominent posteriorly angulated ears, large mouth, wide palate, and mild mandibular prognathism were observed. The neck was short with mild webbing (Fig. 1B). Pectus excavatum, dorsal kyphoscoliosis, marked cubitus valgus (Fig. lA), limitation of motion at the elbows, and hyperextensibility at the metacarpophalangeal joints were evident. Several small depigmented areas were observed on the forearms, trunk, and legs. Three nevus flammeus lesions were observed on the left thigh. The nipples appeared widely spaced. The breasts were small and the genitalia hypoplastic and immature. Cardiac findings were consistent with pulmonic stenosis. Moderate mental retardation was evident. Borderline hearing loss, probably sensorineural, was also noted. Skeletal survey showed generalized hypomineralization with somewhat thickened trabeculae. The growth plates were slightly wide. Mild subperiosteal and ungual tuft resorption and scattered cyst-like lesions in the short tubular bones (especially the phalanges) (Fig. 1G) and the mandible (Fig. 1F) were observed. The lamina dura surrounding the teeth was mildly deficient. Metacarpals (especially 3rd and 4th) were moderately short. Osseous maturation was low normal (13-13% years at age 15 years). Serum calcium was repeatedly low and no response to parathormone was elicited (Table I). Adrenal function was borderline low on baseline studies. Response to ACTH was inadequate, and there was no
160
Cohen and Gorlin
Fig. 1. A: Patient at age 15 years. Short neck with mild webbing, widely spaced small breasts, pectus excavatum, immature genitalia, marked cubitus valgus, kyphoscoliosis, and nevus flammeus lesions on left thigh. B: Ocular hypertelorism, epicanthic folds, strabismus, broad nasal bridge with lateral bony projections,large mouth, and laterally protruding posteriorly angulated ears. C:Multiple lentigines and a few scattered nevi; mild webbing of the neck. D Warty excrescencesof fingertip. E: Giant cell lesion of fingertip shown in D. Note giant cells (arrow)subjacentto epithelium. F:Multiple radiolucencies (arrows) of mandible. G.Radiolucent cyst-likeareas (arrows)of phalanges. H. Giant cell (arrows)lesion of mandible (see F). (Reproduced from Cohen, 1982, with permission of the publisher.)
response to metyrapone (Table 111, which suggested pituitary insufficiency. Chromosomes were normal. The pigmented lesions of the skin were confirmed microscopically as lentigines. Histologic examination of tissue from the jaw cysts was consistent with central giant cell granuloma or hyperparathyroidism (Fig. 1H). Identical giant cell lesions were observed histologically on biopsy of the fingertip lesions (Fig. 1E) and on excisional biopsies of the lateral bony projections on the nose.
Dunlap et al. (4 cases) U989I.l Falace [19891 re-examined the patient reported by Walls and Nogi [19851, reviewed the literature on the subject, and called the condition to the attention of clinical geneticists. Chuong et al. 119861 studied central giant cell lesions of the jaws in 17 patients and noted that two of these occurred in patients with Noonan syndrome. These latter patients probably represent the entity under discussion. Findings in one unpublished instance [Kaban, 19771, sum-
SUMMARY OF KNOWN CASES To date, including our original patient, we have recognized 14 instances of this syndrome. The findings are summarized in Table 111. Published cases include those of Leszczynski et al. 119751, Lindenbaum and Hunt [19771, Wagner et al. [19811,Hoyer and Neukem [19821, Walls and Nogi [19851,Wendt et al. (3 cases) 119861,and
'In a few instances, findings were interpreted from facial photographs. In three instances, euryopia or frank hypertelorism were determined from canthal index measurements [(inner canthal distance/outer canthal distance) x 1001 of facial photographs. Further information about a few cases was secured from several of the authors.
Nooiian-LikeMultiple Giant Cell Lesion Syndrome
161
TABLE I. Serum and Urinary Ca and P Response to Intramuscular Parathormone Injection*
P (mg/100 ml)
1
7 AM Blood Ca (mg/100 ml) 7.4
2
7.4
4.5
3
7.5
4.2
Day
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12-Hour urine Ca (mg/12 hr) 7.0 12.0 7.4 3.0 5.4
(7 AM to 7 PM) P (mgil2 hr) 5:28 AM 3:06 PM 4:76 AM 2:60 PM 2:99 AM
On day 2, 150 units were administered intravenously (i.v.) at 7:OO AM and at 7:OO PM.
TABLE 11. Urinary and Plasma Adrenal Steroid Studies* Urine (mg/24 hr)
17 OHCS 1.0 1.5 0.9
17KS 4.0 5.3 1.8
Plasma (pg/lOO ml)
17 OHCS
P‘Triol
Control 0.4 ACTH 0.3 Metgrapone 0.2 *(17 OHCS = 17 hyroxycorticosteroids; 17 KS = 17 ketosteroids; P’Triol units) i.v. for 4 hours. Metyrapone (500 mg) orally q 4 h x six doses.
7.2 26.0 ~
=
~ _ _ _
pregnanetriol). ACTH (40
marized in Table 111,may describe one of the two Noonan pathologists have ascertained the condition by jaw insyndrome patients mentioned by Chuong et al. [19861. volvement and called it either “central giant cell granuOf the 14 cases of this syndrome (Table 1111,eight are loma” or “cherubism.”’ If the patient already carried the females and six are males. Although we have tabulated diagnosis of Noonan syndrome, the condition was somethe available findings in all 14 cases, we have not pro- times called “cherubism with Noonan syndrome” vided numerator and denominator figures (because of (thought to concur by chance). These types of specialty incomplete reporting, which is discussed later in this bias are reinforced by the fact that central giant cell paper). However, impressive manifestations include granuloma, cherubism, and pigmented villonodular short stature, low normal intelligence or development synovitis are specific clinicopathologic entities which do delay, ocular hypertelorism, prominent posteriorly an- accurately diagnose, with histopathologic confirmation, gulated ears, giant cell lesions of bones, joints, and/or the conditions present in the jaws and in the joints, soft tissues, pectus excavatum, and pulmonic stenosis. respectively, when the lesions are limited to those locaTo date, most cases have occurred sporadically. A no- tions. table exception is the family reported by Wendt et al. In the syndrome under discussion, giant cell lesions [19861. An affected father had two affected children, a may occur: 1) in the maxilla and mandible; 2) in the boy and a girl, a finding that is consistent with autoso- joints, sometimes with soft tissue extension andlor eroma1 dominant inheritance. A possibly affected father sive changes of contiguous bone; 3) in bones other than and son were mentioned by Dunlap et al. [19891. Con- the jaws as primary, non-erosive, cyst-like lesions; and firmation is not available. In discussing their case 3, 4) in soft tissue independently of soft tissue extension of Dunlap et al. noted that the proband‘s father “also had synovial involvement. If the patient is seen by an oral cherubism.” Only biopsy material and a panoramic ra- and maxillofacial surgeon or reviewed by an oral padiograph of the jaws were available to Dunlap et al. thologist, the histopathologically confirmed diagnosis is Since the material was examined in a service oral pa- likely to be “central giant cell granuloma, rule out hythology laboratory, neither the proband nor the father perparathyroidism,” as in our case report [Cohen et al., could be examined. 19741, or “cherubism,” as in the four cases reviewed by Dunlap et al. [19891. If the patient is seen by an orthoPROBLEMS IN NOSOLOGY pedic surgeon, the histopathologically confirmed diagWe do not think this syndrome is particularly rare. nosis is likely to be pigmented villonodular synovitis Rather, problems in identifying the condition have re- [Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; sulted from incomplete or truncate ascertainment by Walls and Nogi, 1985;Wendt et al., 19861. It is clear that various specialists. Some pediatricians have labelled cyst-like, giant cell lesions of bones other than the jaws the disorder as “Noonan syndrome.” Some orthopedic may be involved, for example, the short tubular bones, surgeons and some pathologists have ascertained the condition by involvement of the joints and have diagnosed it as “pigmented villonodular synovitis.” Finally, ’Less commonly, it has been called “familial fibrous dysplasia” some oral and maxillofacial surgeons and some oral or even “fibrous dysplasia.”
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a N = normal. bMR = mental retardation, LN = low normal, N = Normal, DL = delayed learning. CLesions of tubular bones and/or long bones and/or ribs. d At the metacarpophalangeal joints. 'At the elbows. 'C = pectus carinatum. g Hypertrophic subaortic stenosis, atrial septa1 defect, and probable aortic regurgitation. hMitral valve prolapse. 'Ventricular septa1 defect. Jocular proptosis, unerupted teeth. kHighly arched palate. 'Lymphedema, highly arched palate. m Widely spaced nipples. nunerupted teeth. ODown-slanting palpebral fissures, eyelid ptosis, cryptorchidism PHigh birth weight, eyelid ptosis, unerupted teeth. qHigh birth weight, epicanthic folds. rOcular proptosis.
Skeletal Giant cell lesions Long and tubular bones, ribs" Jaws Joints with or without soft tissue extension Soft tissue only Hyperextensibility Limitation of motion Pectus excavatum Cubitus valgus Scoliosis Cardiovascular Pulmonic stenosis Other congenital heart defect Genitourinary Incomplete sexual development Double collecting system Other rn
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164
Cohen and Gorlin
particularly phalanges [Cohen et al., 1974; Kaban, 19771, radius [Wagner et al., 19811, humerus [Kaban, 19771, ribs [Dunlap et al., 19891, and even the region around the nasal bones [our case]. Soft tissue giant cell lesions (separate from joint involvement with contiguous soft tissue extension) are illustrated by the fingertip lesions in our case (Fig. 1D,E).3All of the aforementioned are giant cell lesions of similar histologic type regardless of the name used for specific localized forms and regardless of location. In the syndrome under discussion, all the giant cell lesions found have a common pathogenesis. In the literature, there are clues about cherubism, central giant cell granuloma, pigmented villonodular synovitis, and Noonan syndrome that suggest the possibility of the syndrome under discussion. For example, cherubism is an uncommon autosomal dominant condition that affects almost exclusively the maxilla and mandible. However, extremely unusual cases have been noted with additional extra-oral lesions involving the ribs [McClendon et al., 1962,Thompson, 19591,humerus [Bloom et al., 1962; Brannin and Christensen, 1954; Bruce et al., 1953;Thompson, 19621,femur [Bloom et al., 19621, and carpals [Riveros et al., 19501. Bianchi et al. [19871 reported a case of cherubism associated with pulmonic stenosis. Dukart et al. [1974] described a case of cherubism and indicated that the jaw lesions were histologically compatible with either central giant cell granuloma or cherubism. Facial photographs of the patient showed ocular hypertelorism and prominent ears. Salinas et al. [19831 observed a patient (also reported by Dunlap et al. [19891)with cherubism, cyst-like lesions of the ribs, ocular hypertelorism, eyelid ptosis, short neck, cardiovascular defect (? pulmonic stenosis), and cryptorchidism. Finally, we are aware of an unpublished male with cherubism, eyelid ptosis, pulmonic stenosis, and short stature. The mother had short stature, pulmonic stenosis, and a nevus flammeus of the forehead. We have also seen, in an unrelated sporadic instance, a 14-yearold girl with short stature, mental deficiency, ocular hypertelorism, paranasal eminences, cherubism, pulmonic stenosis, and dir dup(18)q12.1-+12.3. Davis and Tideman [1977] reported multiple central giant cell granulomas of the jaws in a patient whose mother had an extensive central giant cell granuloma of the maxilla. The authors did not mention any other findings. Hjprrting-Hansen and Worspre-Petersen [ 19671 observed a woman with giant cell lesions of the jaws, humerus, radius, femur, and phalanges; she had short stature and incomplete development of secondary sexual characteristics. Weldon and Cozzi [ 19821noted multiple giant cell lesions of the jaws associated with pulmonic stenosis. 3Pigmented villonodular synovitis can involve the tendon sheaths of the fingers and results, on occasion, in an overlying soft tissue lesion of the skin of the fingers [Fort and Rodman, 1977; King et al., 19781. Thus, it is conceivable (although unlikely in our view) that the fingertip lesions in our patient represent soft tissue extension of pigmented villonodular tenosynovitis. Such lesions apparently occur in the interphalangeal regions, not on the fingertips.
Pigmented villonodular synovitis is an uncommon disorder that almost always affects a single joint, predominantly the knee. Peak incidence occurs during the third and fourth decades [Johansson et al., 19821. Multiple joint involvement, particularly at relatively young ages, is rare [Leszczynski et al., 1975; Lindenbaum and Hunt, 1977; Wagner et al., 1981; Walls and Nogi, 1985; Wendt et al., 19861. Bobechko and Kostuik [19681 reported two boys and one girl (ages 4, 5, and 10 years, respectively) who developed pigmented villonodular synovitis in one knee. Overlying hemangiomas of the skin were observed at birth in each case. Kelikian and Lewis [19491 briefly mentioned bilateral knee involvement with pigmented villonodular synovitis in two sibs; a third sib was known to have bilateral wrist and knee involvement. It is not stated whether other anomalies were present or not. Hoza (personal communication) observed polyarticular pigmented villonodular synovitis associated with ocular hypertelorism, cavernous hemangioma of the orbit, and pulmonic stenosis. Some cases have been ascertained as Noonan syndrome, for example, those of Dunlap et al. [19891 and Salinas et al. [19831: Other cases have nothing t o do with the syndrome under discussion. For example, Connor et al. [1982] described a case of Noonan syndrome with multiple odontogenic keratocysts. This patient represents an example of the nevoid basal cell carcinoma syndrome. Nelson et al. [1978] observed a case of Noonan syndrome in which xanthomas of the skin and tongue were additional findings. In the final analysis, it is clear that unusual distribution of any of the various types of giant cell lesions suggests that the syndrome under discussion should be considered. Certainly, a full skeletal radiographic survey is indicated in any suspected case. It should also be noted that in this syndrome giant cell lesions evolve with time; they may not be present at any one point, but may appear later.
NAMING THE SYNDROME We have designated the syndrome as the Noonan-like/ multiple giant cell lesion syndrome. We cannot recommend using terms such as Noonan syndrome, pigmented villonodular synovitis, central giant cell granuloma, or cherubism for two reasons. First, each is a specific diagnostic entity sui generis and does not accurately reflect the syndrome under discussion.Second,we strongly suspect that, in the past, the use of these terms-particularly pigmented villonodular synovitis, central giant cell granuloma, and cherubism-has resulted in nosologic blinders that tended to limit the workup of these patients. Nor can we recommend compounding these terms as, for example, in polyarticular pigmented villonodular synovitis/cherubism/Noonan syndrome. We prefer the term Noonan-like/multiple giant cell lesion syndrome because it generalizes the findings in the syndrome; the condition is Noonan-like and has multiple giant cell lesions in various parts of the body. 4The aatient reDorted bv Salinas et al. 119831 is also one of the four patients reported by"Dun1ap et al. [19891.
Noonan-LikelMultipleGiant Cell Lesion Syndrome
165
DIFFERENTIAL DIAGNOSIS Conditions that enter into the differential diagnosis are listed in Table IV. The Noonan-like/multiple giant cell lesion syndrome shares several obvious characteristics in common with the Noonan and LEOPARD syndromes, including short stature, ocular hypertelorism, pectus excavatum, pulmonic stenosis, and delayed development of secondary sexual characteristics. However, neither syndrome has multiple giant cell lesions of bones, jaws, and soft tissues. Pigmented villonodular synovitis, central giant cell granuloma, and cherubism as specific clinicopathologic entities have already been discussed. Advanced hyperparathyroidism with “brown tumors” of bone are histologically identical to central giant cell granulomas of the jaws. In the typical case, hyperparathyroidism is commonly ruled out. In the Noonan-like/multiple giant cell lesion syndrome, there is no evidence of hyperparathyroidism. The Jaffe-Campanacci syndrome consists of caf6-aulait spots, multiple non-ossifying fibromas of bone (including long bones and jaws), and pathological fractures. The lesions are of the giant cell type histologically and are identical to central giant cell granulomas. Other reported changes in some cases have included mental retardation, hypogonadism, cryptorchidism, cardiovascular defects (mitral insufficiencyor aortic stenosis), different types of ocular defects, and miscellaneous anomalies. To date, all cases have been sporadic and no patient has had skin nodules or documented neurofibromas [Campanacci et al., 1983, Mirra et al., 1982, Steinmetz et al., 19881. Ramon syndrome consists of growth deficiency, moderate mental retardation, major seizures, hypertrichosis, gingival fibromatosis, and cherubism. The condition appears to have autosomal recessive inheritance [Ramon et al., 1967, Pina-Net0 et al., 19861. However, some of the patients in the family reported by Pina-Net0 et al. [19861 had juvenile rheumatoid arthritis. They noted palpable subcutaneous nodules around the joints of both hands. Further delineation is necessary to determine if the findings are those of juvenile rheumatoid arthritis or possibly polyarticular pigmented villonodular synovitis. The neurofibromatosis-Noonan syndrome has been reported by a number of authors [Allanson et al., 1985; Kaplan and Rosenblatt, 1985; Mendez, 1985; Opitz and Weaver, 1985; Saul, 1985; Meinecke, 1987; Proud et al., 1987; Quattrin et al., 19871. Opitz and Weaver [1985]
enumerated four possible interpretations: (1) chance concurrence of Noonan syndrome and neurofibromatosis; (2) neurofibromatosis-Noonan syndrome as an unusual variant of Noonan syndrome; (3) neurofibromatosis-Noonan syndrome as an unusual type of neurofibromatosis; and (4) neurofibromatosis-Noonan syndrome as a distinct entity suigeneris. Vertical transmission of complete neurofibromatosis-Noonan syndrome was reported by Quattrin et al. [1987]. Neurofibromatosis-Noonan syndrome has also been reported with classic neurofibromatosis in other relatives [Meinecke,19871or with neurofibromatosis and partial Noonan findings in other relatives [Kaplan and Rosenblatt, 1985; Proud et al., 1987; Abuelo and Meryash, 19881.Sporadic instances have been observed [Allanson et al., 1985; Mendez, 1985; Saul, 19851. The cardio-facial-cutaneous (CFC) syndrome is characterized by high forehead with bitemporal constriction, hypoplastic supraorbital ridges, ptosis of the eyelids, downslanting palpebral fissures, posteriorly angulated ears with prominent helices, and neck webbing in some instances. The facial appearance is reminiscent of that observed in Noonan syndrome. Other manifestations include growth deficiency, mental retardation, cardiovascular defects, and dry hyperkeratotic skin. Most cases have been sporadic to date [Reynolds et al., 1986; Mucklow, 19891, but dominant inheritance has been suggested in one family [Verloes et al., 19881. The patient with Noonan-like/multiple giant cell lesion syndrome reported by Walls and Nogi [19851 and later examined by Falace [19891 was originally diagnosed erroneously as having fetal hydantoin syndrome at birth, presumably because of ocular hypertelorism, broad nasal bridge, highly arched palate, and pulmonic stenosis, all of which were present in the patient.
TABLE IV. Differential Diagnosis
Abuelo DN, Meryash DL (1988): Neurofibromatosis with fully expressed Noonan syndrome. Am J Med Genet 29:937-941. Allanson J E , Hall JG, Van Allen MI (1985):Noonan phenotype associated with neurofibromatosis. Am J Med Genet 21:457-462. Bianchi SD, Boccardi A, Mela F, Romagnoli R (1987): The computed tomographic appearance of cherubism. Skeletal Radio1 16:6-10. Bloom J, Chacker FM, Thomas KH (1962): Multiple giant-cell lesions of bone; report of a case. Oral Surg 15 [Suppl 21:74-83. Bobechko WP, Kostuik JP (1968): Childhood villonodular synovitis. Cana J Surg 11:480-486. Brannin DE, Christensen RO (1954):Bilateral giant cell tumors of the mandible in siblings; report of cases. J Oral Surg 12:247-251.
Noonan syndrome LEOPARD syndrome Pigmented villonodular synovitis Cherubism Central giant cell granuloma Hyperparathyroidism Jaffe-Campanacci syndrome Ramon syndrome Neurofibromatosis-Noonan syndrome Cardio-facio-cutaneous (CFC) syndrome
CONCLUSIONS We have defined a syndrome of short stature, low normal intelligence or developmental delay, ocular hypertelorism, prominent posteriorly angulated ears, giant cell lesions of bones,joints, andlor soft tissues, pectus excavatum, and pulmonic stenosis. To date, most cases have occurred sporadically, although one affected family is consistent with autosomal dominant inheritance. The syndrome is probably not rare but is incompletely understood, for the most part, because of ascertainment by various specialties in the past. The Noonan-like/multiple giant cell lesion syndrome needs to be further delineated. REFERENCES
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