American Journal of Medical Genetics 43:662-668 (1992)
Encephalocraniocutaneous Lipomatosis and the Proteus Syndrome: Distinct Entities With Overlapping Manifestations Sherman McCall, Magda I. Ramzy, Joel K. Cure’, G.S.Pai The Division of Genetics, Department of Pediatrics (S.M., G.S.P.), the Division of Craniofacial Genetics, Department of Pediatric Dentistry (M.Z.R3, the Department of Radiology (J.K.C.), Medical University of South Carolina, Charleston, and the Department of Human Genetics, National Research Center, Cairo, Egypt (M.Z.R.)
We have studied three children with cutaneous (epidermal nevi),subcutaneous (lipomas, plantar skin thickening),vascular (hemangioma, lymphangioma),skeletal (osteoma,exostosis, localized hypertrophy), and neurological (hydrocephaly, lissencephaly, partial agenesis of the corpus callosum)developmental defects associated with the Proteus syndrome and related hamartoneoplastic conditions. We compared our fmdings in these three patients with those of 50 others with Proteus syndrome and nine with encephalocraniocutaneous lipomatosis (ECCL) reported in the literature. We found that Proteus syndrome and ECCL have distinct identities even though some clinical manifestations are shared by both and a few patients have manifestations of both conditions. o 1992 Wiley-Liss,
entation were Proteus syndrome, Klippel-TrenaunayWeber syndrome and encephalocraniocutaneous lipomatosis (ECCL) or organoid nevus syndrome, respectively. Over a period of observation ranging from 6 months to 7 years, two of them have evolved clearly into Proteus syndrome while the third has ECCL with additional manifestations more commonly seen in Proteus syndrome. Proteus syndrome is a sporadic disorder defined originally on the basis of partial gigantism of hands and feet, variable skin abnormalities, subcutaneous and bony tumors, and tissue hypertrophy [Wiedemann et al., 19831. The accumulated experience with 50 cases has now expanded the spectrum of abnormalities noted in this syndrome [Clark et al., 1987; Gorlin et al., 1990; Hotamisligil and Ertogan, 19901. ECCL, also known as the Fishman syndrome [Brumback and Leech, 19871, was originally described by Haberland and Perou [19701 Inc. as a new example of ectomesodermal dysgenesis characterized by profound mental retardation, early onset of seizures, unilateral temporo-frontal lipomatosis, ipKEY WORDS: Proteus syndrome, encephalosilateral cerebral and leptomeningeal lipomatosis, cerecraniocutaneous lipomatosis, bral malformation and calcification, and lipomas of the mesoectodermal dysgenesis, skull, eye, and heart. At least nine patients have been congenital lipomatosis, organreported with ECCL [Fishman et al., 1978; Sanchez et oid nevus syndrome, neuroal., 1981; Miyao et al., 1984; Savage et al., 1985; Fishcutaneous syndrome man, 19871. While Wiedemann and Burgio [1986] have hypothesized that ECCL is a more circumscript form of the Proteus syndrome, Gorlin et al. 119903 have mainINTRODUCTION tained them as separate entities. The legitimacy of The congenital hamartomatous neurocutaneous dis- ECCL as a clinical entity distinguishable from Proteus orders constitute a large group of clinically defined syn- syndrome is discussed in the light of our experience. dromes with overlapping manifestations. Since the complete phenotype of these syndromes often evolves over a CLINICAL REPORTS period of time, diagnosis may remain uncertain in some Patient 1 young patients. We have followed the clinical course of BR, a 7-year-old boy with Roteus syndrome, is the three children in whom the diagnoses at initial presthird child of a 40-year-old father and 39-year-old mother. He was born a t term by spontaneous vaginal Fteceived for publication June 20, 1991; revision received October delivery. His birth weight (3,750 gm), length (53 cm), neonatal course, growth, and development throughout 4, 1991. Address reprint requests to Dr. G.S.Pai, Director, Division of infancy were normal. At approximately 10 months, two Genetics, Medical University of South Carolina, 171 Ashley Ave- lipomatous swellings were excised from the anterior aspect of his chest. He was referred for genetic evaluanue, Charleston, S.C. 29425.
0 1992 Wiley-Liss, Inc.
Proteus Syndrome tion when additional lipomas appeared over his trunk. An inguinoscrotal mass initially thought to be a hernia turned out to be a lipoma without pelvic extension. Asymmetric growth of his fingers and toes, clinodactyly, a linear nevus on the left side of his neck extending from the body of the mandible t o the clavicle, palpable osteomas over the skull, and right supraorbital ridge were found during the examination and suggested a diagnosis of Proteus syndrome. His height and weight were at the 50th centile until age 5 years. By age 7 years, his height increased to the 95th centile while his weight remained at the 50th. In conjunction with this rapid acceleration of his linear growth, asymmetry of his face and chest became more obvious and the right supraorbital and temporal osteomas became cosmetically significant. An osteoma in his right external ear canal led to impaired hearing. His fingers continued asymmetric growth with mild limitation of movement of several small joints. He also had significant leg length discrepancy and mild scoliosis.Figures 1 and 2 show the clinical manifestations of Proteus syndrome in this child. Results of routine laboratory studies including urinalysis, serum chemistry, alpha fetoprotein, carcinoembryonic antigen levels, and G-banded karyotype were normal. A skeletal survey showed overgrowth of the phalanges of the clinically hypertrophied digits, hyperostosis of the right supraorbital ridge, asymmetric mandible, and mild ephiphyseal dysplasia throughout the skeleton but most noticeable in the right femoral capital epiphysis. The right tibia was shorter and broader than the left and there was mild thoracolumbar scoliosis.
663
subsequent clinical course has suggested an alternate diagnosis of Proteus syndrome. JC was born at term, by C section because of breech presentation. At birth he had two large lymphangio-hemangiomas, which covered most of his left flank and left half of the back from the iliac crest to the scapula. These were excised in two separate operations. An MRI scan of the trunk at that time showed subcutaneous masses consistent with hemangiomas with no intraabdominal parenchymal abnormality. By 10 months, multiple subcutaneous lipomas had appeared on his chest and back. His right leg was shorter than left secondary to congenital hip dysplasia which could not be treated successfully. When first seen by us at 18 months, the child had a right inguinoscrotal mass which was surgically explored and found to be a thrombosed hemangioma of the spermatic cord. He also had severe failure to thrive, severe muscle atrophy, virtual absence of subcutaneous fat, and a huge lipoma that covered his entire back (Fig. 3). He had mildly delayed gross motor, speech, and language development. When last seen a t 27 months, JC’s growth failure was quite striking with height and weight at the 50th centile for an 18-month-oldchild and his OFC of 44.5 cm at the 50th centile for an 8-month-old infant. His face was heart shaped with absence of subcutaneous fat and diminution of the buccal fat pad. He did not have specific abnormalities of any facial, intraoral, or ocular structures (Fig. 4).A strawberry hemangioma covered the lateral aspect of his left gluteal region and flank (Fig. 5). His feet were short and wide with excessive space between the toes, especially the first and the second. He had pes cavus deformity on both sides and plantar skin thickening that was more striking on the Patient 2 right than the left (Fig. 6). A small deeply pigmented J C is a 27-month-old white boy who was diagnosed at nevus was noted on the posterior aspect of his right birth to have Klippel-Trenaunay-Weber syndrome. His ankle. New lipomas developed over his arms, but linear
Fig. 1. Patient 1, at age 3 years, showing epidermal nevus on the left side of his neck, left sided hemihypertrophy and scoliosis.
864
McCall et al.
Fig. 3. Patient 2, a t age 22 months, showing a huge lipoma that covered his entire back.
Fig. 2. Patient 1,at age 3 years, showing localized overgrowth and clinodactyly of several fingers and toes, and a subcutaneous lipoma over his right great toe.
sebaceous nevi, osteomas, and lateral body asymmetry were not present except for the previously noted mild leg length discrepancy resulting from congenital hip dysplasia. Skeletal radiographs showed no other abnormalities. His chromosomes were not examined.
Patient 3 J M was the 3900 gm product of a 36-week gestation of a 19-year-old primigravid mother who had inherited autosomal dominant paraparesis from her father. Fetal hydrocephalus had been diagnosed by ultrasound in the sixth month of gestation and the karyotype of cultured amniotic fluid cells was 46,XX. At birth J M was large for gestational age and had an OFC of 41.5 cm and a length of 53 cm. She was markedly hypotonic, lethargic, and minimally responsive to stimuli. In addition she had a yellowish-brown linear nevus on the left side of her forehead and a large lipoma that covered the left half of her face. Computed tomography of her head showed cerebral dysgenesis, hydrocephalus, and a cystic intracerebral lesion consistent with a lipoma. A ventriculo-peritonea1 shunt was placed. The organoid nevus syndrome and ECCL were considered among the most likely diagnoses. Complex generalized seizures that began on the first day of life could not be treated effectively with anticonvulsants. When first seen by us a t 4 months, JM had developed
Fig. 4. Patient 2, at age 22 months, showing loss of subcutaneous fat, muscle atrophy.
linear sebaceousnevi on the left side of her abdomen and the dorsal aspect of her left forearm and below the tip of the left scapula. She had macrocephaly with hydrocephalus, frontal bossing, left occipital exostosis, and hemihypertrophy of the left half of her cranium and face. A large lipoma covered the left half of her face causing considerable facial distortion (Fig. 7). Uni-
Proteus Syndrome
665
Fig. 5. Patient 2 a t age 27 months. Notice hemangioma in left flank, surgical scar from previous excision of hemangioma, generalized subcutaneous fat loss, lipomas over right forearm and upper arm, and variable muscle atrophy.
Fig. 6. Plantar skin thickening in patient 2 at age 27 months. Note excessive space between first and second toes.
lateral ocular abnormalities included an enlarged left orbit, megalopapilla, poor foveal reflex, absence of retinal pigment, abnormal extraocular movements, and a fleshy scleral tumor (choristoma). She had a dysplastic, malrotated right auricle that was much smaller than the left. A sacral tuft of hair and mild scoliosis were other abnormalities. Syndactyly between the first and second toes was noted on both of her feet. This was reportedly inherited from her father who was not available for examination.
Radiographs showed a narrow rib cage with dysplastic 5th, 6th, 7th, and 8th ribs bilaterally and diffuse osseous hypomineralization. Cranial roentgenograms and ultrasound and computed tomography showed large head, asymmetric and deformed orbits, dilated lateral and third ventricles (right greater than left), lissencephaly of the entire left cerebral hemisphere, a large abnormal left Sylvian fissure, partial absence of the corpus callosum, and an area of increased echogenicity in the left frontal lobe (Fig. 8). Cerebral calcificationswere present
666
McCall et al.
Fig. 7. Patient 3 a t age 4 months. Note epidermal nevus in the midline and on the left side of forehead, facial lipoma, and subtle hemihypertrophy of left side of the body.
in her left frontal and left parietal regions. EEG showed left-sided hypsarrhythmia. It was noteworthy that most of her extracranial abnormalities except for the malformed right pinna and sacral hair tuft were left sided. She had mild hemi-
Fig. 8. Axial CT scan at the level of the foramina of Munro demonstrating left sided hemimegalencephaly with pachygyria, hypodense gliotic white matter, ventricular dilatation, and an abnormal anteriorly pointed configuration of the left anterior horn.
hypertrophy of the entire left side of her body. Severe failure to thrive and uncontrollable seizures led to her death a t age 6 months. An autopsy was not performed.
DISCUSSION Our patients highlight several interesting issues pertaining to the ongoing controversy for lumping and splitting of syndromes with overlapping manifestations. The strict adherence to the originally described minimal diagnostic criteria of a syndrome limit the inevitable expansion of the boundaries of newly recognized syndromes that follow from observations of new cases and leave many cases undiagnosed. On the other hand, too loose a definition that becomes all inclusive and defeats some of the important purposes of syndrome delineation, i.e., to discern subtle differences between superficially similar entities to obtain clues to the cause, pathogenesis, prognosis, and improved clinical care of affected individuals. Our patient 1 has five of seven manifestations, i.e., partial gigantism of hand and feet, pigmented nevi, hemihypertrophy, lipomas and osteomas, asymmetric skull with osseous protuberances, used by Wiedemann et al. [19831 to define the Proteus syndrome. Patient 2 has only two of these, i.e., subcutaneous tumors (lipomas and hemangiomas) and a pigmented nevus that is not typical of Proteus syndrome. However, he has several additional findings now generally accepted as part of the expanded Proteus syndrome phenotype. These include thickening of the plantar skin, short wide feet with excessive space between first and second toes, striking muscle atrophy, and virtual absence of subcutaneous fat [Clark et al., 19871. Furthermore, the multiple small lipomas and the massive one on his back (Fig, 3) clearly exclude the diagnosis of K1ippel-Trenaunay-Webersyndrome in this child.
Proteus Syndrome
Our patient 3 presents the most interesting challenge. This infant died at 6 months. Therefore, we will not know what additional manifestations would have appeared to clarify the nature of the syndrome(s1 that killed her. This infant’s clinical manifestations include a large lipoma over her left cheek, a scleral tumor in her left eye, and ipsilateral cerebral dysgenesis, including lissencephaly, cortical calcifications, hydrocephaly, and uncontrollable seizures. These findings are virtually identical to the original description of ECCL by Haberland and Perou [1970], except that their patient had porencephalic cyst, fleshy cutaneous tumors, and the post mortem finding of lipomatous infiltration of the meninges and the heart. Later cases of ECCL have expanded the phenotype to include intracranial vascular aneurysm, subcutaneous scalp tumor, alopecia, and extracranial lipomas and other skin tumors [Fishman, 1987; Schlak and Skopnik, 19851. The additional findings in our patient that suggest a diagnosis of Proteus syndrome are the lipomas over her back and chest, epidermal nevi over her forehead and arm, hemihypertrophy, severe muscle atrophy, and absence of subcutaneous fat. In this regard she most closely resembles the patients reported by Malamitsi-Puchner et al. [1986] and Mayatepek et al. [1989]. Wiedemann and Burgio [ 19861have suggested on the basis of Zuntova’s report [19831 that ECCL may represent a circumscript form of Proteus syndrome. Did our patient have Proteus syndrome with severe central nervous system involvement, expanded ECCL syndrome, or both syndromes limited mostly to the left side of her body? Clearly this question cannot be answered with certainty in the present state of our knowledge of the pathogenesis of these syndromes. To get at least a partial answer to the question we analyzed the clinical manifestations of 50 patients with Proteus syndrome and 9 with ECCL reported in the literature [Bialer et al., 1989; Bitoun and Gellis, 1981; Clark et al., 1986; Fishman et al., 1978; Fishman, 1987; Gorlin et al., 1990; Haberland and Perou, 1970; Hotamisligil, 1990; Hotamisligil and Ertogan, 1990; Miyao et al., 1984; Sanchez et al., 1981; Savage et al., 1985; Viljoen et al., Wiedemann et al., 19831. Proteus syndrome clearly has a wide range of manifestations, but only a few of these are common among the 50 reported cases. Similarly, ECCL has a fairly characteristic phenotype in which developmental defects of the central nervous system, cranial and facial involvement, and scleral tumor are common. When subcutaneous soft tissue tumors are present, usually over the scalp, they are diffuse, do not have the cerebroid-gyriform aspect to them. and there is usually aloDecia. an uncommon finding in Proteus syndrome.”Alsiof importance is the fact that ECCL is primarily unilateral. In contrast, Proteus syndrome is typically bilateral, asymmetric, and involves the trunk and limbs. Table I shows the clinical manifestations of our 3 patients compared with those most frequently seen in Proteus syndrome and ECCL. Judging by the frequencies of the listed manifestations, our patients 1 and 3 clearly have Proteus syndrome and ECCL, respectively. If we apply the scoring system proposed by Hotamisligil
667
TABLE I. Comparison of Proteus syndrome, ECCL and Present Cases*
BR Patient Manifestations of Proteus syndrome present in >50% of patients Partial gigantism of hands and/or feet Epidermal nevi and/or skin thickening Hemihypertrophy Subcutaneous tumors (extracranial) Skull anomalies including buckelschadel Manifestations of ECCL present in >50% of patients Unilateral cranial and facial subcutaneous tumors Unilateral choristoma (scleral hamartoma) Ipsilateral cerebral dysgenesis Cerebral cortical calcification Mental retardation -
JC 2
JM 3
-
-
+
+
-
*
-
-
+
-
-
+
-
-
+ +
1
+ + + + +
-
+-
+-
? *Derived from Bialer et al. [1989], Clark et al. [19871, Gorlin et al. [1990], Hotamisligil and Ertogan [19901, Viljoen et al. [19871, Wiedemann et al. [1983], Haberland and Perou [19701, Fishman [19871. + , present; - , absent; ?, uncertain; ?, unknown.
+
t19901, patients 1and 3 will both be diagnosed to have Proteus syndrome. Both methods exclude patient 2 from either diagnosis. Our argument for the diagnosis of Proteus syndrome in patient 2 is based on his overall gestalt as presented above. Only three patients with Proteus syndrome have been reported, besides our patient 3, with severe central nervous system involvement [Malamitsi-Puchner et al., 1986; Mayatepek et al., 1989; Zuntova, 19831. Even though Wiedemann and Burgio [19861 astutely suggested on the basis of one of these patients (Zuntova, 19831, and another with ECCL [Schlak and Skopnik, 19851,that the two entities may be one, we feel that it is premature to expand the definition of Proteus syndrome to encompass ECCL as suggested by Kouseff and Viljoen [1990].When the causeb) and pathogenesis of the hamartoneoplastic syndromes are better understood, ECCL may very well turn out to be a more circumscript or milder expression of Proteus syndrome. We may even speculate that deletions or mutations in a family of contiguous or functionally related genes may be responsible for both Proteus syndrome and ECCL. In fact, a variety of clinically defined syndromes in this group may well have common cause and pathogenesis.
ACKNOWLEDGMENTS This work was supported in part by a grant from the Children’s Fund, Health Sciences Foundation, Medical University of South Carolina. Dr. Ramzy was supported by the Peace Fellowship of the Agency for International Development. REFERENCES Bialer MG, Riedy MJ, Wilson WG (1988): Proteus syndrome versus Bannayan-Zonana syndrome: A problem in differential diagnosis. Eur J Pediatr 148:122-125.
668
McCall et al.
Bitoun P, Gellis S (1982): Picture of the month: Encephalocraniocutaneous lipomatosis. Am J Dis Child 136:1085-1086. Brumback RA, Leech RW (1987): Fishman’s syndrome (encephalocraniocutaneous lipomatosis): A field defect of ectomesoderm. J Child Neurol 2:168-169. J, Baraitser M (1g87):Roteus Clark RD, Donnai D, %gers J, cooper syndrome: An exDanded uhenotvue. Am J Med Genet 27:99-117. “Fishman MA, Chang CS, Miller J E (1978):Encephalocraniocutaneous lipomatosis. Pediatrics 61580-582. Fishman MA (1987): Encephalocraniocutaneous lipomatosis. J Child Neurol 2:186-193. Gorlin R J, Cohen MM Jr., Levin LS (1990):“Syndromes of the Head and Neck.” 3rd ED. Oxford: Oxford University Press, pp 361-362,403406. Haberland C, Perou M (1970):Encephalocraniocutaneous lipomatosis: A new example of ectomesodermal dysgenesis. Arch Neurol 22:144-155. Hotamisligil GS (1990):Proteus syndrome and hamartoses with overgrowth. Dysmorph Clin Genet 4:87-102. Hotamisligil GS, Ertogan F (1990):The Proteus syndrome: Association with nephrogenic diabetes insipidus. Clin Genet 38:139-144. Kouseff BG, Viljoen DL (1990): Proteus syndrome. In Buyse ML (ed): “Birth Defects Encyclopedia.” Cambridge: Blackwell Scientific Publications, for Center for Birth Defects Information Services, Inc., pp 1418-1420. Malamitsi-Puchner A, Kitsiou S, Bartsocas cs (1987):severe ProteuS syndrome in an 18-month-old boy. Am J Med Genet 27:119-125.
Mayatepek E, Kurczynski Tw, Ruppert ES, HennessY JR, B r i n k RA, French BN (1989): Expanding the phenotype of the Proteus syndrome: A severely affected patient with new findings. Am J Med Genet 32:402-406, Miyao M, Saito T, Yamamoto Y, Kamoshita S (1984): Enceuhabcraniocutaneous lipomatosis: A recently described nekoBrain 11:280-284. cutaneous syndrome’ Sanchez NP, Rhodes AR, Mandell F, Mihm MC (1981): Encephalocraniocutaneous lipomatosis: A new neurocutaneous syndrome. Br J Dermatol 104239-96. Savage MG, Heldt L, Dann JJ, Bump RL (1985): Encephalocraniocutaneous lipomatosis and mixed odontogenic tumors. J Oral Maxillofac Surg 43:617-620. Schlack HG, Skopnik H (1985): Encephalocraniocutane Lipomatose und linearer Naevus sebaceus. Mschr Kinderheilk 133:235-237. Viljoen DL, Nelson MM, de Jong G, Beighton P (1987): Proteus syndrome in South Africa: Natural history and clinical manifestations in six individuals. Am J Med Genet 27:87-97. Wiedemann H-R, Burgio GR, Aldenoff P, Kaufmann HJ,Schirg E (1983):The Proteus syndrome: Partial gigantism ofthe hands and/ or feet, nevi, hemihypertrophy, subcutaneous tumors, macroceDhalv or other skull anomalies and Dossible accelerated erowth a i d vikeral affections. Eur J Pediatr-l40:5-12. lipoWiedemann H-R, ~~~~i~GR (1986): ~ncepha~ocraniocutaneous J ~ e Genet d 25:403-404. matosis and Roteussyn&.ome. Zuntova A (1983): Asymmetrical osteocutaneous lipomatosis in a three-year-old boy associated with defective development of the brain. cs &diatr 38:724-727,
-
Encephalocraniocutaneous Lipomatosis and the Proteus Syndrome: Distinct Entities With Overlapping Manifestations Sherman McCall, Magda I. Ramzy, Joel K. Cure’, G.S.Pai The Division of Genetics, Department of Pediatrics (S.M., G.S.P.), the Division of Craniofacial Genetics, Department of Pediatric Dentistry (M.Z.R3, the Department of Radiology (J.K.C.), Medical University of South Carolina, Charleston, and the Department of Human Genetics, National Research Center, Cairo, Egypt (M.Z.R.)
We have studied three children with cutaneous (epidermal nevi),subcutaneous (lipomas, plantar skin thickening),vascular (hemangioma, lymphangioma),skeletal (osteoma,exostosis, localized hypertrophy), and neurological (hydrocephaly, lissencephaly, partial agenesis of the corpus callosum)developmental defects associated with the Proteus syndrome and related hamartoneoplastic conditions. We compared our fmdings in these three patients with those of 50 others with Proteus syndrome and nine with encephalocraniocutaneous lipomatosis (ECCL) reported in the literature. We found that Proteus syndrome and ECCL have distinct identities even though some clinical manifestations are shared by both and a few patients have manifestations of both conditions. o 1992 Wiley-Liss,
entation were Proteus syndrome, Klippel-TrenaunayWeber syndrome and encephalocraniocutaneous lipomatosis (ECCL) or organoid nevus syndrome, respectively. Over a period of observation ranging from 6 months to 7 years, two of them have evolved clearly into Proteus syndrome while the third has ECCL with additional manifestations more commonly seen in Proteus syndrome. Proteus syndrome is a sporadic disorder defined originally on the basis of partial gigantism of hands and feet, variable skin abnormalities, subcutaneous and bony tumors, and tissue hypertrophy [Wiedemann et al., 19831. The accumulated experience with 50 cases has now expanded the spectrum of abnormalities noted in this syndrome [Clark et al., 1987; Gorlin et al., 1990; Hotamisligil and Ertogan, 19901. ECCL, also known as the Fishman syndrome [Brumback and Leech, 19871, was originally described by Haberland and Perou [19701 Inc. as a new example of ectomesodermal dysgenesis characterized by profound mental retardation, early onset of seizures, unilateral temporo-frontal lipomatosis, ipKEY WORDS: Proteus syndrome, encephalosilateral cerebral and leptomeningeal lipomatosis, cerecraniocutaneous lipomatosis, bral malformation and calcification, and lipomas of the mesoectodermal dysgenesis, skull, eye, and heart. At least nine patients have been congenital lipomatosis, organreported with ECCL [Fishman et al., 1978; Sanchez et oid nevus syndrome, neuroal., 1981; Miyao et al., 1984; Savage et al., 1985; Fishcutaneous syndrome man, 19871. While Wiedemann and Burgio [1986] have hypothesized that ECCL is a more circumscript form of the Proteus syndrome, Gorlin et al. 119903 have mainINTRODUCTION tained them as separate entities. The legitimacy of The congenital hamartomatous neurocutaneous dis- ECCL as a clinical entity distinguishable from Proteus orders constitute a large group of clinically defined syn- syndrome is discussed in the light of our experience. dromes with overlapping manifestations. Since the complete phenotype of these syndromes often evolves over a CLINICAL REPORTS period of time, diagnosis may remain uncertain in some Patient 1 young patients. We have followed the clinical course of BR, a 7-year-old boy with Roteus syndrome, is the three children in whom the diagnoses at initial presthird child of a 40-year-old father and 39-year-old mother. He was born a t term by spontaneous vaginal Fteceived for publication June 20, 1991; revision received October delivery. His birth weight (3,750 gm), length (53 cm), neonatal course, growth, and development throughout 4, 1991. Address reprint requests to Dr. G.S.Pai, Director, Division of infancy were normal. At approximately 10 months, two Genetics, Medical University of South Carolina, 171 Ashley Ave- lipomatous swellings were excised from the anterior aspect of his chest. He was referred for genetic evaluanue, Charleston, S.C. 29425.
0 1992 Wiley-Liss, Inc.
Proteus Syndrome tion when additional lipomas appeared over his trunk. An inguinoscrotal mass initially thought to be a hernia turned out to be a lipoma without pelvic extension. Asymmetric growth of his fingers and toes, clinodactyly, a linear nevus on the left side of his neck extending from the body of the mandible t o the clavicle, palpable osteomas over the skull, and right supraorbital ridge were found during the examination and suggested a diagnosis of Proteus syndrome. His height and weight were at the 50th centile until age 5 years. By age 7 years, his height increased to the 95th centile while his weight remained at the 50th. In conjunction with this rapid acceleration of his linear growth, asymmetry of his face and chest became more obvious and the right supraorbital and temporal osteomas became cosmetically significant. An osteoma in his right external ear canal led to impaired hearing. His fingers continued asymmetric growth with mild limitation of movement of several small joints. He also had significant leg length discrepancy and mild scoliosis.Figures 1 and 2 show the clinical manifestations of Proteus syndrome in this child. Results of routine laboratory studies including urinalysis, serum chemistry, alpha fetoprotein, carcinoembryonic antigen levels, and G-banded karyotype were normal. A skeletal survey showed overgrowth of the phalanges of the clinically hypertrophied digits, hyperostosis of the right supraorbital ridge, asymmetric mandible, and mild ephiphyseal dysplasia throughout the skeleton but most noticeable in the right femoral capital epiphysis. The right tibia was shorter and broader than the left and there was mild thoracolumbar scoliosis.
663
subsequent clinical course has suggested an alternate diagnosis of Proteus syndrome. JC was born at term, by C section because of breech presentation. At birth he had two large lymphangio-hemangiomas, which covered most of his left flank and left half of the back from the iliac crest to the scapula. These were excised in two separate operations. An MRI scan of the trunk at that time showed subcutaneous masses consistent with hemangiomas with no intraabdominal parenchymal abnormality. By 10 months, multiple subcutaneous lipomas had appeared on his chest and back. His right leg was shorter than left secondary to congenital hip dysplasia which could not be treated successfully. When first seen by us at 18 months, the child had a right inguinoscrotal mass which was surgically explored and found to be a thrombosed hemangioma of the spermatic cord. He also had severe failure to thrive, severe muscle atrophy, virtual absence of subcutaneous fat, and a huge lipoma that covered his entire back (Fig. 3). He had mildly delayed gross motor, speech, and language development. When last seen a t 27 months, JC’s growth failure was quite striking with height and weight at the 50th centile for an 18-month-oldchild and his OFC of 44.5 cm at the 50th centile for an 8-month-old infant. His face was heart shaped with absence of subcutaneous fat and diminution of the buccal fat pad. He did not have specific abnormalities of any facial, intraoral, or ocular structures (Fig. 4).A strawberry hemangioma covered the lateral aspect of his left gluteal region and flank (Fig. 5). His feet were short and wide with excessive space between the toes, especially the first and the second. He had pes cavus deformity on both sides and plantar skin thickening that was more striking on the Patient 2 right than the left (Fig. 6). A small deeply pigmented J C is a 27-month-old white boy who was diagnosed at nevus was noted on the posterior aspect of his right birth to have Klippel-Trenaunay-Weber syndrome. His ankle. New lipomas developed over his arms, but linear
Fig. 1. Patient 1, at age 3 years, showing epidermal nevus on the left side of his neck, left sided hemihypertrophy and scoliosis.
864
McCall et al.
Fig. 3. Patient 2, a t age 22 months, showing a huge lipoma that covered his entire back.
Fig. 2. Patient 1,at age 3 years, showing localized overgrowth and clinodactyly of several fingers and toes, and a subcutaneous lipoma over his right great toe.
sebaceous nevi, osteomas, and lateral body asymmetry were not present except for the previously noted mild leg length discrepancy resulting from congenital hip dysplasia. Skeletal radiographs showed no other abnormalities. His chromosomes were not examined.
Patient 3 J M was the 3900 gm product of a 36-week gestation of a 19-year-old primigravid mother who had inherited autosomal dominant paraparesis from her father. Fetal hydrocephalus had been diagnosed by ultrasound in the sixth month of gestation and the karyotype of cultured amniotic fluid cells was 46,XX. At birth J M was large for gestational age and had an OFC of 41.5 cm and a length of 53 cm. She was markedly hypotonic, lethargic, and minimally responsive to stimuli. In addition she had a yellowish-brown linear nevus on the left side of her forehead and a large lipoma that covered the left half of her face. Computed tomography of her head showed cerebral dysgenesis, hydrocephalus, and a cystic intracerebral lesion consistent with a lipoma. A ventriculo-peritonea1 shunt was placed. The organoid nevus syndrome and ECCL were considered among the most likely diagnoses. Complex generalized seizures that began on the first day of life could not be treated effectively with anticonvulsants. When first seen by us a t 4 months, JM had developed
Fig. 4. Patient 2, at age 22 months, showing loss of subcutaneous fat, muscle atrophy.
linear sebaceousnevi on the left side of her abdomen and the dorsal aspect of her left forearm and below the tip of the left scapula. She had macrocephaly with hydrocephalus, frontal bossing, left occipital exostosis, and hemihypertrophy of the left half of her cranium and face. A large lipoma covered the left half of her face causing considerable facial distortion (Fig. 7). Uni-
Proteus Syndrome
665
Fig. 5. Patient 2 a t age 27 months. Notice hemangioma in left flank, surgical scar from previous excision of hemangioma, generalized subcutaneous fat loss, lipomas over right forearm and upper arm, and variable muscle atrophy.
Fig. 6. Plantar skin thickening in patient 2 at age 27 months. Note excessive space between first and second toes.
lateral ocular abnormalities included an enlarged left orbit, megalopapilla, poor foveal reflex, absence of retinal pigment, abnormal extraocular movements, and a fleshy scleral tumor (choristoma). She had a dysplastic, malrotated right auricle that was much smaller than the left. A sacral tuft of hair and mild scoliosis were other abnormalities. Syndactyly between the first and second toes was noted on both of her feet. This was reportedly inherited from her father who was not available for examination.
Radiographs showed a narrow rib cage with dysplastic 5th, 6th, 7th, and 8th ribs bilaterally and diffuse osseous hypomineralization. Cranial roentgenograms and ultrasound and computed tomography showed large head, asymmetric and deformed orbits, dilated lateral and third ventricles (right greater than left), lissencephaly of the entire left cerebral hemisphere, a large abnormal left Sylvian fissure, partial absence of the corpus callosum, and an area of increased echogenicity in the left frontal lobe (Fig. 8). Cerebral calcificationswere present
666
McCall et al.
Fig. 7. Patient 3 a t age 4 months. Note epidermal nevus in the midline and on the left side of forehead, facial lipoma, and subtle hemihypertrophy of left side of the body.
in her left frontal and left parietal regions. EEG showed left-sided hypsarrhythmia. It was noteworthy that most of her extracranial abnormalities except for the malformed right pinna and sacral hair tuft were left sided. She had mild hemi-
Fig. 8. Axial CT scan at the level of the foramina of Munro demonstrating left sided hemimegalencephaly with pachygyria, hypodense gliotic white matter, ventricular dilatation, and an abnormal anteriorly pointed configuration of the left anterior horn.
hypertrophy of the entire left side of her body. Severe failure to thrive and uncontrollable seizures led to her death a t age 6 months. An autopsy was not performed.
DISCUSSION Our patients highlight several interesting issues pertaining to the ongoing controversy for lumping and splitting of syndromes with overlapping manifestations. The strict adherence to the originally described minimal diagnostic criteria of a syndrome limit the inevitable expansion of the boundaries of newly recognized syndromes that follow from observations of new cases and leave many cases undiagnosed. On the other hand, too loose a definition that becomes all inclusive and defeats some of the important purposes of syndrome delineation, i.e., to discern subtle differences between superficially similar entities to obtain clues to the cause, pathogenesis, prognosis, and improved clinical care of affected individuals. Our patient 1 has five of seven manifestations, i.e., partial gigantism of hand and feet, pigmented nevi, hemihypertrophy, lipomas and osteomas, asymmetric skull with osseous protuberances, used by Wiedemann et al. [19831 to define the Proteus syndrome. Patient 2 has only two of these, i.e., subcutaneous tumors (lipomas and hemangiomas) and a pigmented nevus that is not typical of Proteus syndrome. However, he has several additional findings now generally accepted as part of the expanded Proteus syndrome phenotype. These include thickening of the plantar skin, short wide feet with excessive space between first and second toes, striking muscle atrophy, and virtual absence of subcutaneous fat [Clark et al., 19871. Furthermore, the multiple small lipomas and the massive one on his back (Fig, 3) clearly exclude the diagnosis of K1ippel-Trenaunay-Webersyndrome in this child.
Proteus Syndrome
Our patient 3 presents the most interesting challenge. This infant died at 6 months. Therefore, we will not know what additional manifestations would have appeared to clarify the nature of the syndrome(s1 that killed her. This infant’s clinical manifestations include a large lipoma over her left cheek, a scleral tumor in her left eye, and ipsilateral cerebral dysgenesis, including lissencephaly, cortical calcifications, hydrocephaly, and uncontrollable seizures. These findings are virtually identical to the original description of ECCL by Haberland and Perou [1970], except that their patient had porencephalic cyst, fleshy cutaneous tumors, and the post mortem finding of lipomatous infiltration of the meninges and the heart. Later cases of ECCL have expanded the phenotype to include intracranial vascular aneurysm, subcutaneous scalp tumor, alopecia, and extracranial lipomas and other skin tumors [Fishman, 1987; Schlak and Skopnik, 19851. The additional findings in our patient that suggest a diagnosis of Proteus syndrome are the lipomas over her back and chest, epidermal nevi over her forehead and arm, hemihypertrophy, severe muscle atrophy, and absence of subcutaneous fat. In this regard she most closely resembles the patients reported by Malamitsi-Puchner et al. [1986] and Mayatepek et al. [1989]. Wiedemann and Burgio [ 19861have suggested on the basis of Zuntova’s report [19831 that ECCL may represent a circumscript form of Proteus syndrome. Did our patient have Proteus syndrome with severe central nervous system involvement, expanded ECCL syndrome, or both syndromes limited mostly to the left side of her body? Clearly this question cannot be answered with certainty in the present state of our knowledge of the pathogenesis of these syndromes. To get at least a partial answer to the question we analyzed the clinical manifestations of 50 patients with Proteus syndrome and 9 with ECCL reported in the literature [Bialer et al., 1989; Bitoun and Gellis, 1981; Clark et al., 1986; Fishman et al., 1978; Fishman, 1987; Gorlin et al., 1990; Haberland and Perou, 1970; Hotamisligil, 1990; Hotamisligil and Ertogan, 1990; Miyao et al., 1984; Sanchez et al., 1981; Savage et al., 1985; Viljoen et al., Wiedemann et al., 19831. Proteus syndrome clearly has a wide range of manifestations, but only a few of these are common among the 50 reported cases. Similarly, ECCL has a fairly characteristic phenotype in which developmental defects of the central nervous system, cranial and facial involvement, and scleral tumor are common. When subcutaneous soft tissue tumors are present, usually over the scalp, they are diffuse, do not have the cerebroid-gyriform aspect to them. and there is usually aloDecia. an uncommon finding in Proteus syndrome.”Alsiof importance is the fact that ECCL is primarily unilateral. In contrast, Proteus syndrome is typically bilateral, asymmetric, and involves the trunk and limbs. Table I shows the clinical manifestations of our 3 patients compared with those most frequently seen in Proteus syndrome and ECCL. Judging by the frequencies of the listed manifestations, our patients 1 and 3 clearly have Proteus syndrome and ECCL, respectively. If we apply the scoring system proposed by Hotamisligil
667
TABLE I. Comparison of Proteus syndrome, ECCL and Present Cases*
BR Patient Manifestations of Proteus syndrome present in >50% of patients Partial gigantism of hands and/or feet Epidermal nevi and/or skin thickening Hemihypertrophy Subcutaneous tumors (extracranial) Skull anomalies including buckelschadel Manifestations of ECCL present in >50% of patients Unilateral cranial and facial subcutaneous tumors Unilateral choristoma (scleral hamartoma) Ipsilateral cerebral dysgenesis Cerebral cortical calcification Mental retardation -
JC 2
JM 3
-
-
+
+
-
*
-
-
+
-
-
+
-
-
+ +
1
+ + + + +
-
+-
+-
? *Derived from Bialer et al. [1989], Clark et al. [19871, Gorlin et al. [1990], Hotamisligil and Ertogan [19901, Viljoen et al. [19871, Wiedemann et al. [1983], Haberland and Perou [19701, Fishman [19871. + , present; - , absent; ?, uncertain; ?, unknown.
+
t19901, patients 1and 3 will both be diagnosed to have Proteus syndrome. Both methods exclude patient 2 from either diagnosis. Our argument for the diagnosis of Proteus syndrome in patient 2 is based on his overall gestalt as presented above. Only three patients with Proteus syndrome have been reported, besides our patient 3, with severe central nervous system involvement [Malamitsi-Puchner et al., 1986; Mayatepek et al., 1989; Zuntova, 19831. Even though Wiedemann and Burgio [19861 astutely suggested on the basis of one of these patients (Zuntova, 19831, and another with ECCL [Schlak and Skopnik, 19851,that the two entities may be one, we feel that it is premature to expand the definition of Proteus syndrome to encompass ECCL as suggested by Kouseff and Viljoen [1990].When the causeb) and pathogenesis of the hamartoneoplastic syndromes are better understood, ECCL may very well turn out to be a more circumscript or milder expression of Proteus syndrome. We may even speculate that deletions or mutations in a family of contiguous or functionally related genes may be responsible for both Proteus syndrome and ECCL. In fact, a variety of clinically defined syndromes in this group may well have common cause and pathogenesis.
ACKNOWLEDGMENTS This work was supported in part by a grant from the Children’s Fund, Health Sciences Foundation, Medical University of South Carolina. Dr. Ramzy was supported by the Peace Fellowship of the Agency for International Development. REFERENCES Bialer MG, Riedy MJ, Wilson WG (1988): Proteus syndrome versus Bannayan-Zonana syndrome: A problem in differential diagnosis. Eur J Pediatr 148:122-125.
668
McCall et al.
Bitoun P, Gellis S (1982): Picture of the month: Encephalocraniocutaneous lipomatosis. Am J Dis Child 136:1085-1086. Brumback RA, Leech RW (1987): Fishman’s syndrome (encephalocraniocutaneous lipomatosis): A field defect of ectomesoderm. J Child Neurol 2:168-169. J, Baraitser M (1g87):Roteus Clark RD, Donnai D, %gers J, cooper syndrome: An exDanded uhenotvue. Am J Med Genet 27:99-117. “Fishman MA, Chang CS, Miller J E (1978):Encephalocraniocutaneous lipomatosis. Pediatrics 61580-582. Fishman MA (1987): Encephalocraniocutaneous lipomatosis. J Child Neurol 2:186-193. Gorlin R J, Cohen MM Jr., Levin LS (1990):“Syndromes of the Head and Neck.” 3rd ED. Oxford: Oxford University Press, pp 361-362,403406. Haberland C, Perou M (1970):Encephalocraniocutaneous lipomatosis: A new example of ectomesodermal dysgenesis. Arch Neurol 22:144-155. Hotamisligil GS (1990):Proteus syndrome and hamartoses with overgrowth. Dysmorph Clin Genet 4:87-102. Hotamisligil GS, Ertogan F (1990):The Proteus syndrome: Association with nephrogenic diabetes insipidus. Clin Genet 38:139-144. Kouseff BG, Viljoen DL (1990): Proteus syndrome. In Buyse ML (ed): “Birth Defects Encyclopedia.” Cambridge: Blackwell Scientific Publications, for Center for Birth Defects Information Services, Inc., pp 1418-1420. Malamitsi-Puchner A, Kitsiou S, Bartsocas cs (1987):severe ProteuS syndrome in an 18-month-old boy. Am J Med Genet 27:119-125.
Mayatepek E, Kurczynski Tw, Ruppert ES, HennessY JR, B r i n k RA, French BN (1989): Expanding the phenotype of the Proteus syndrome: A severely affected patient with new findings. Am J Med Genet 32:402-406, Miyao M, Saito T, Yamamoto Y, Kamoshita S (1984): Enceuhabcraniocutaneous lipomatosis: A recently described nekoBrain 11:280-284. cutaneous syndrome’ Sanchez NP, Rhodes AR, Mandell F, Mihm MC (1981): Encephalocraniocutaneous lipomatosis: A new neurocutaneous syndrome. Br J Dermatol 104239-96. Savage MG, Heldt L, Dann JJ, Bump RL (1985): Encephalocraniocutaneous lipomatosis and mixed odontogenic tumors. J Oral Maxillofac Surg 43:617-620. Schlack HG, Skopnik H (1985): Encephalocraniocutane Lipomatose und linearer Naevus sebaceus. Mschr Kinderheilk 133:235-237. Viljoen DL, Nelson MM, de Jong G, Beighton P (1987): Proteus syndrome in South Africa: Natural history and clinical manifestations in six individuals. Am J Med Genet 27:87-97. Wiedemann H-R, Burgio GR, Aldenoff P, Kaufmann HJ,Schirg E (1983):The Proteus syndrome: Partial gigantism ofthe hands and/ or feet, nevi, hemihypertrophy, subcutaneous tumors, macroceDhalv or other skull anomalies and Dossible accelerated erowth a i d vikeral affections. Eur J Pediatr-l40:5-12. lipoWiedemann H-R, ~~~~i~GR (1986): ~ncepha~ocraniocutaneous J ~ e Genet d 25:403-404. matosis and Roteussyn&.ome. Zuntova A (1983): Asymmetrical osteocutaneous lipomatosis in a three-year-old boy associated with defective development of the brain. cs &diatr 38:724-727,
-
