ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:2944 – 2958 (2007) Newly Delineated Syndrome of Congenital Lipomatous Overgrowth, Vascular Malformations, and Epidermal Nevi (CLOVE Syndrome) in Seven Patients Julie C. Sapp,1 Joyce T. Turner,1 Jiddeke M. van de Kamp,2 Fleur S. van Dijk,2 R. Brian Lowry,3 and Leslie G. Biesecker1* 1 National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 2 VU University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands 3 Department of Medical Genetics, University of Calgary and Alberta Children’s Hospital, Calgary, Alberta, Canada Received 30 June 2007; Accepted 18 July 2007 We present a series of seven patients who were previously contrast to the bony distortion so characteristic of Proteus diagnosed with Proteus syndrome, but who do not meet syndrome, distortion in CLOVE syndrome occurs only published diagnostic criteria for this disorder and whose following major or radical surgery. Here, we contrast natural history is distinct from that of Proteus syndrome. This differences and similarities of CLOVE syndrome to Proteus newly recognized phenotype comprises progressive, com- syndrome. ß 2007 Wiley-Liss, Inc. plex, and mixed truncal vascular malformations, dysregu- lated adipose tissue, varying degrees of scoliosis, and enlarged bony structures without progressive bony over- Key words: overgrowth; asymmetric overgrowth; hemihy- growth. We have named this condition congenital lip- perplasia; bone distortion; Proteus syndrome; hemihyper- omatous overgrowth, vascular malformations, and plasia-multiple lipomatosis syndrome (HHML); Klippel– epidermal nevi (CLOVE syndrome) on a heuristic basis. In Trenaunay syndrome How to cite this article: Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. 2007. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet Part A 143A:2944–2958. INTRODUCTION named this condition congenital lipomatous over- growth, vascular malformations, and epidermal nevi Syndromes with overgrowth as a major manifesta- (CLOVE syndrome) on a heuristic basis (vide infra). tion are clinically and etiologically heterogeneous and incompletely deﬁned. Proper clinical delineation of these syndromes is important both for research and for CASE REPORTS clinical care. Overgrowth or hyperplasia can be non- syndromic or syndromic, the latter including Proteus Patient 1 was a 9-week-old North African male syndrome, Klippel–Trenaunay syndrome, and hemi- who was born at 342/7 weeks’ gestation. An ultra- hyperplasia-multiple lipomatosis syndrome (HHML) sound performed at 26 weeks’ gestation showed [Biesecker et al., 1999]. Here, we present seven patients multiple anomalies including subcutaneous ﬂuid with an overgrowth disorder with manifestations collections with visible septations surrounding the similar to Proteus syndrome, but who do not meet abdomen, thorax, and extremities, multiple sonolu- several speciﬁc criteria for the disorder. Furthermore, cent structures visualized below the kidneys, mild their natural history is distinct from that of Proteus ventriculomegaly, a sonolucent structure in the syndrome. These patients either participated in the midline below the thalamus and the third ventricle, Proteus Syndrome Protocol at the National Institutes of and bilateral pes equinovarus. Fetal MRI showed Health (with some carrying the diagnosis for several years), or were referred to this protocol either for consideration for participation, or an opinion regarding their diagnosis. We propose that the entity Grant sponsor: National Human Genome Research Institute of the National Institutes of Health. we describe here represents a phenotype that is both *Correspondence to: Leslie G. Biesecker, M.D., Building 49, Room recognizable and distinct from Proteus syndrome, 4A80, Bethesda, MD 20892. E-mail: firstname.lastname@example.org HHML, and other overgrowth conditions. We have DOI 10.1002/ajmg.a.32023 American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2945 diffuse polymicrogyria. Amniocentesis showed a normal 46,XY karyotype. At birth, the patient’s weight was 3.0 kg ($95th centile), his length was 50 cm ($25th centile), and his OFC was 36.8 cm (>95th centile). The patient was noted to have a large cranium with an asymmetric face. A large, supple mass with a bluish tinge was present on the right cheek and extended to both sides of the thorax, the upper back, and both sides of the upper portion of his legs. The patient had a pre-auricular pit on the left ear, a small penis, pes equinovarus, and macrodactyly with partial cutaneous syndactyly of the second and third toes bilaterally. He had multiple cutaneous apparent capillary vascular malforma- tions on the head, trunk, and legs, and generalized FIG. 2. Axial MRI image of the chest of Patient 1 showing the axillary masses, hypotonia (Fig. 1). Skeletal surveys and an abdomi- left greater than right. nal ultrasound showed no skeletal abnormalities. MRI of the mediastinum and the abdomen showed adrenal hemorrhage, dislocatable left hip, three cafe-´ multiple subcutaneous ﬂuid collections in the axillae au-lait macules, ‘‘mildly dysmorphic’’ facial features, (Fig. 2). This extended caudally to the left inguinal and broad feet with deviated digits. The patient also region, the left side, and the left medial upper leg. had a small sacral dimple with a tuft of hair consistent One ﬂuid collection showed ﬂow voids. Cranial MRI with spina biﬁda occulta. At about 6 months of age showed a small bleeding site in the left germinal the patient developed a mass on her back, which matrix, polymicrogyria, non-contiguous abnormal- rapidly increased in size and spread to her ﬂank. ities of the gray and white matter, a four-layered Eventual biopsy showed this mass to be a ‘‘cystic cortex, and ventriculomegaly. An EEG showed lymphangioma’’ (more likely a lymphatic vascular epileptic activity. At the age of 8 weeks, the patient malformation). In late infancy and early childhood, experienced severe seizures, which led to his death the patient experienced increasing enlargement of at the age of 9 weeks. this lesion and developed multiple lipomas on her Patient 2 was a 12-year-old Caucasian female who back and abdomen. At age 21 months, the patient was born at 36 weeks’ gestation due to premature was noted to have deep grooves on the soles of her rupture of the membranes. Prenatal ultrasound feet and signiﬁcant muscular overgrowth of her showed slight renal asymmetry, polyhydramnios, lower extremities. She underwent a left inguinal and mildly short femurs. The pregnancy was hernia repair at age 3 years. MRI of the abdomen and complicated by placental chorioangioma with the pelvis performed when the patient was 4 years old placenta weighing 2.5 kg. At birth, the patient’s showed an extensive lesion involving the left length was 51 cm (>þ2SD), she weighed 3.17 kg retroperitoneum, abdomen, and pelvis consistent (þ1–2SD), and her OFC was 33 cm (normal). She with lymphatic vascular malformation. This mass presented with a protruberant abdomen with some continued to enlarge throughout the patient’s child- skin discoloration, inferior vena cava thrombosis, left hood, eventually encompassing much of the patient’s back and buttocks, impairing her ability to walk and causing signiﬁcant back pain (Fig. 3). At age FIG. 3. Abdominal MRI from Patient 2. This scan was performed at 9 years of FIG. 1. Truncal vascular malformation lesions in Patient 1. This patient had age, prior to her surgery to debulk her lipomatous mass of the back. Note the an extensive and complex vascular malformation of the truncal wall that severe increase in fat, both subcutaneously and intraabdominally. Note that extended into the axillae. [Color ﬁgure can be viewed in the online issue, which there is a signiﬁcant inﬁltration of fat into numerous muscles of the trunk and is available at www.interscience.wiley.com.] back. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2946 SAPP ET AL. 11 years, the patient underwent extensive surgery to the pelvis showed a soft tissue mass with both fatty remove this mass, which was said to be a ‘‘lipomatous and non-fatty components consistent with vascular lymphangioma.’’ She required multiple skin grafts malformations involving the pelvic wall and the left and experienced poor wound healing. pelvis with displacement of the psoas muscle. On physical examination, the patient’s height was Radiographs and MRI of the spine showed mild 151.4 cm (25–50th centile), she weighed 45.1 kg thoracolumbar scoliosis and malformed vertebral (50–75th centile), and her OFC was 53.5 cm (25– bodies with large invaginations into the endplates 50th centile). She presented with thoracic asymme- with posterior scalloping and abnormal vertebral try, prominent vessels on her ﬂanks, extremely segmentation noted at T7–T9 and T11 and T12 muscular legs, and a wasted appearance of the (Fig. 5). Spina biﬁda occulta was noted in the sacrum. upper torso and arms. She had broad feet with The patient reportedly did well in regular classes at bilateral plantar soft tissue overgrowth and deep school and the family history was unremarkable. plantar creases not consistent with a cerebriform Patient 3 was a 17-year-old Hispanic male [Eldredge connective tissue nevus (CCTN). She had macro- et al., 1993]. One week prior to birth, an ultrasound dactyly of the third digit on the left foot (Fig. 4). The showed abnormal ureters, bilaterally. At birth, he patient had a protruberant abdomen although no presented with enlarged lower extremities and distinct masses or organomegaly were appreciated. buttocks, right foot postaxial polydactyly, facial MRI of the chest and abdomen showed increased fat asymmetry, birthmarks on his neck, bilateral 2–3 deposition in the left chest wall and around the cutaneous syndactly of the toes, ‘‘ballooning’’ over- paraspinous muscles and a large vascular malforma- growth of both feet, and deformed toes. He also had tion along the left lateral abdominal wall primarily pyloric stenosis, requiring surgical repair. At the age of involving the subcutaneous fat but extending into 8 months, he had orthopedic surgery due to the abdominal musculature and the lower retroper- subluxation of the left hip. At the age of 10 months, itoneum inferior to the kidney. The left kidney was he underwent an ureterostomy for unknown indica- enlarged and its lower pole was displaced anteriorly tions. Between the ages of 2 and 6 years, the patient by the fatty vascular mass. There was also increased underwent several additional surgeries, including fat deposition around the paraspinous muscles and resection of vascular malformations on his right and increased retroperitoneal and intraperitoneal fat, left thighs, amputations of the his second and fourth resulting in small bowel sequestration in the right left toes and his second and third right toes, and mid-abdomen, medial displacement of the descend- ureterostomy reversal. He would eventually undergo ing colon, and right displacement of the abdominal transmetatarsal amputation of all his toes (Fig. 6). On aorta, which was also encased in soft tissue. MRI of physical examination, the patient’s height was 167.1 cm ($10th centile) and he weighed 90.4 kg (95–97th centile). He presented with signiﬁcant facial asymmetry, dental crowding, gingival overgrowth, hamartomas of the buccal mucosa, and tongue asymmetry. A linear epidermal nevus on the right neck extended from the back to the midline. He had thoracic asymmetry, kyphosis, and lordosis in the thoracic spine. He had upper extremity lipoatrophy and diminished muscle mass. He also had an extensive mixed venous and lymphatic vascular malformation with cutaneous involvement on his trunk and buttocks (Fig. 7). The lower extremities showed diminished muscle mass with large amounts of interspersed fat and dysregulated subcutaneous fat. MRI of the chest, abdomen, and pelvis showed cystic masses in the right chest wall, asymmetric subcuta- neous fat distribution in the right posterior chest wall, increased visceral and subcutaneous fat in the pelvis with pelvic wall inﬁltration, and fat extending between the gluteal muscles and very abnormal fat distribution in both thighs (Fig. 8). A skeletal survey showed a convex left upper thoracic curvature (apex about T4, about 1008), convex right lower thoracic FIG. 4. Plain radiographs of the right and left foot, respectively, of Patient 2. curve (apex about T9, about 1008), and a convex left The feet are broad with equinovarus and tibial deviation of digits four and ﬁve lumbar curvature (apex about L2, 608). This was on the left (B), and there is ﬁbular deviation of the hallux on the right (A). Note the normal architecture of the bony elements of the feet, in contrast to the accompanied by deformity and wedging of multiple abnormal structure seen in patients with Proteus syndrome (see Fig. 26). vertebral bodies and irregularity of the endplates American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2947 FIG. 5. A–C: Scoliosis series from Patient 2. Mild lateral thoracic scoliosis is evident in (B). Note that the vertebral bodies show mild wedging. (Fig. 9). Radiographs of the lower extremities showed chest wall. At birth, the patient presented with a deformed pelvis with a shallow right acetabulum, bilateral gigantism of the feet and a large left chest deformed right femoral head and neck that showed wall mass that was treated with a series of nine evidence of superior subluxation and pseudoarthrosis surgeries (Fig. 11A). The mass was found to be a (Fig. 10). The patient had apparently normal cogni- tion. The family history was signiﬁcant for postaxial polydactyly in his mother. Patient 4 was a 19-year-old Caucasian male born at term after a pregnancy complicated by maternal gestational diabetes and hyperemesis [Biesecker et al., 1998, Patient 4; also reported in Jamis-Dow et al., 2004] Prenatal ultrasound performed at 5 months’ gestation showed a large mass on the left FIG. 6. Panels (A,B) are plain radiographs of the right and left foot, respectively, FIG. 7. Lateral view of the trunk of Patient 3 depicting large truncal vascular of Patient 3. These images show multiple bony abnormalities. It is difﬁcult to malformation with extensive cutaneous involvement. [Color ﬁgure can be determine if these abnormalities represent primary or iatrogenic abnormalities. viewed in the online issue, which is available at www.interscience.wiley.com.] American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2948 SAPP ET AL. FIG. 8. MRI of the pelvis for Patient 3 demonstrating massive asymmetric enlargement of the posterior left thigh and abnormal fat distribution of both thighs. The structure in the center bottom of the image is a dependent gluteal mass (see Fig. 10), which is comprised of a heterogeneous mixture of tissue that has signals consistent with fat and non-fat tissue. This lesion is suspected to be a lipomatous-lymphatic vascular malformation. FIG. 10. A,B: Bilateral knee and femur plain radiographs of Patient 3. Note that the dependent gluteal/upper thigh mass is visible in both panels (A,B). complex mixed venous-lymphatic vascular malfor- Both knee joints are relatively normal, although proximal arcing of the ﬁbula is appreciable on the left (B). mation. He had numerous orthopedic surgeries throughout childhood and into adulthood including varus derotational osteotomies of the femurs, bilat- eral femoral-tibial osteotomies, and anterior and posterior spinal fusion from T3 to T11 due to thoracic kyphosis. In addition, the patient had an extradural spinal tumor excised, a large ‘‘cystic hygroma’’ resected, and multiple excisions of the expanding truncal vascular malformation. The patient had chronic renal colic with hematuria, and underwent repeated blood transfusions and hospitalizations for complications associated with this lesion. On physical examination, the patient’s height was 169.7 cm (10–25th centile), and he weighed 96.4 kg (90–95th centile). He presented with a massive, chronically and actively draining mixed vascular FIG. 11. Photograph of the large and complex truncal vascular malformation of Patient 4 at birth (A) and at 14 years of age (B). The patient underwent numerous surgical procedures to debulk this malformation, with limited FIG. 9. A,B: Scoliosis series from Patient 3. Signiﬁcant curvature and wedge- success. [Color ﬁgure can be viewed in the online issue, which is available at shaped vertebrae can be appreciated in both panels. www.interscience.wiley.com.] American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2949 malformation on his trunk, which had signiﬁcant cutaneous involvement (Fig. 11B). He had thoracic asymmetry with several rib exostoses and a 3 cm leg length discrepancy. He had macrodactyly of the ﬁrst through fourth digits on the left foot, and the ﬁrst and second digits on the right foot. There was no evidence of a CCTN. The right testis was absent, which was secondary to surgery to remove a mass on the right groin. Ultrasound disclosed several small cystic lesions present on the scrotum. Plain radio- graphs showed substantial scoliosis of the thoracic spine (Fig. 12). Abdominal and high-resolution chest CT showed marked distortion of the thoracic cage with large fatty/soft tissue overgrowth over the back and chest wall, a cyst on the left kidney, and asymmetric iliac veins. There was no evidence of cystic lung disease. Serial MRI studies showed progressive enlargement of the entire chest wall with fatty, soft tissue, and muscular hyperplasia with cystic elements and a vascular malformation in the right groin, which displaced the bladder (Figs. 13 and 14). The patient graduated from secondary FIG. 13. Abdominal MRI image of Patient 4 at 14 years of age. In this image, school and has taken some college courses. The fatty tissue is dark, showing asymmetric subcutaneous and muscular fatty inﬁltration and subcutaneous signals consistent with a vascular malformation. family history was unremarkable. Patient 5 was a 19-year-old Caucasian male who was born at 36 weeks’ gestation. Birth measurements lesion 11=2 weeks after birth. The patient experienced could not be retrieved. Prenatal ultrasound was difﬁculties with wound healing and required several interpreted to show an abdominal wall defect with skin grafts. The wound remained open until he was possible herniated organs. At birth, the patient had 18–20 months of age. Subsequently, he developed a no abdominal wall defect but instead had a large keloid and constricting scar, which was thought to vascular malformation described as a ‘‘hemangioma- contribute to his eventual scoliosis. At about 1 year of like lesion’’ on the left side of his trunk and wide, age, a mass was found on the patient’s spinal canal overgrown feet. An attempt was made to resect this and he underwent a lumbosacral laminectomy. A FIG. 12. A–C: Scoliosis series from Patient 4. Lateral thoracic scoliosis with ﬁxation rods in place is shown in Panel (B). Mild lumbar scoliosis is shown in panel (C). American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2950 SAPP ET AL. FIG. 14. Chest MRI from Patient 4 at age 19 years. Marked thoracic asymmetry and rotational scoliosis and a large, asymmetric mass comprised of a heterogeneous signal compatible with fat and a complex vascular malformation. FIG. 15. Photograph of Patient 5 demonstrating a large, complex vascular malformation with extensive cutaneous involvement. The scarring is from spinal lipoma was excised and tethered cord numerous surgical procedures to debulk this lesion. [Color ﬁgure can be viewed in the online issue, which is available at www.interscience.wiley.com.] released. Subsequent to this operation, the patient developed progressive, rotational scoliosis. Conse- quently, multiple spinal fusions were performed. In mild overgrowth of the cervical vertebrae with an early childhood, the patient underwent numerous increase in the cephalocaudad height of the vertebral operations including resection of a fatty tumor on the bodies, broad based thoracolumbar scoliosis, and left upper leg, removal of a ﬁbrofatty tumor that evidence of severe osteopenia in the pelvis and developed on the patient’s right trunk, partial lower extremities (Fig. 17). An ultrasound of the right resection of ribs 5–10, removal of the left testis, testicle showed the presence of a varicocele and a multiple shortening osteotomies and a Chiari osteot- probable benign mass. Pulmonary function studies omy for hip dysplasia, although the hip remained showed restrictive lung function, which was dysplastic and in an adducted position. As a child he believed to be due to the patient’s scoliosis and chest also developed knee contractures, which were shape. The patient was not known to have lung cysts treated via several hamstring lengthenings, removal but a high-resolution chest CT was not done. The of pterygia on the backs of both knees, and patient had global developmental delay and had bilateral heel-cord lengthenings. The patient had multiple kidney stones bilaterally with accompany- ing hematuria. On physical examination, the patient’s height was 136 cm (<3rd centile, $50th centile for a 9-year old), he weighed 59.1 kg (10–25th centile), and his OFC was 53.3 cm ($2nd centile). He presented with a linear epidermal nevus on the right side of his posterior neck and signiﬁcant thoracic asymmetry with a palpable subcutaneous soft tissue mass covering almost all of the right side of the back and extending anteriorly to the anterior axillary line. On the left side of his trunk, the patient had a large contracted scar with irregular ﬁbrotic areas with multiple small dark red and raised vascular malfor- mations (Fig. 15). There was reduced muscle mass in both lower extremities with no leg length or width discrepancy. The right hip was pulled into adduction and internally rotated. The patient had a ﬂexion contracture of the left knee and wide feet with normal plantar creases and rocker-bottom soles. He had ﬂexion contractures of his toes, which were FIG. 16. A,B: Plain radiographs of the right and left foot, respectively, of abnormally positioned but were normally sized Patient 5 demonstrating bilateral ﬁbular deviation of the halluces and broaden- (Fig. 16). A skeletal survey showed that there was ing of the forefoot, and, in Panel (B), ﬂexion contractures of several toes. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2951 FIG. 17. A–C: Scoliosis series from Patient 5 demonstrating cervico-thoracic (A,B) and lumbar (C) scoliosis. The patient has undergone spinal fusion and ﬁxation rods are apparent. attended special education high school classes. The overgrowth, which was not a CCTN (Fig. 19). Radio- family history was unremarkable. graphs of his remaining foot and hands revealed Patient 6 was a 27-year-old Caucasian male who multiple bony abnormalities (Fig. 20). MRI and CT of presented at birth after an unremarkable prenatal the chest, abdomen, and pelvis showed a prominent course (no ultrasounds are known to have been left sciatic nerve and a large vascular malformation performed), with bilateral foot overgrowth, macro- involving the left thigh and left hemiscrotum and dactyly of the second and fourth digits of his left increased fat in the right thigh (Fig. 21). This hand, bilateral testicular hydroceles, and a mixed extended superiorly and had extensive soft tissue angiolymphatic vascular malformation on his trunk, inﬁltration. Imaging also disclosed multiple cyst-like which eventually extended throughout his left leg, lesions in the spleen, an enlarged inferior vena cava penis, and scrotum. Throughout childhood, the and iliac veins. The patient died at age 27 years due to patient experienced some overgrowth in his hands complications from his vascular malformations. and developed several lipomatous soft tissue masses Patient 7 was a 55-year-old Caucasian female of the chest, abdomen, and back, which were presenting at birth, after an unremarkable prenatal debulked surgically. These included a hydrocele course, with a ‘‘deformed’’ right foot with signiﬁ- repair, left orchiectomy to remove a complex cantly overgrown digits, an abnormally broad left vascular malformation, amputation of the overgrown foot, and a port-wine vascular malformation on her digits on the left hand, bilateral transmetatarsal back and trunk. In infancy, she underwent surgical amputation of all of his toes, amputation of the left resection of the right second and third toes. In leg above the knee due to progression and compli- childhood, she developed mild scoliosis, dislocated cations of the vascular malformation, and a number of lipoma resections. The patient also experienced frequent rectal bleeding. He was found to have a rectosigmoid arteriovenous malformation, and underwent multiple surgical resections. At age 10 years, the patient developed skin lesions on his trunk that resembled a linear epidermal nevus. As a young adult, the patient reported signiﬁcant orthop- nea. The patient attended regular school, and his family history was unremarkable. On physical examination, the patient’s height was 188 cm (>95th centile), he weighed 67.6 kg (10–25th centile), and his OFC was 60 cm (>90th centile). The patient presented with several skull hyperostoses, extensive mixed vascular/lymphatic malformations, thoracic kyphosis and thoracolumbar scoliosis (Fig. 18). He had a poor dentition and gingival overgrowth. Several epidermal nevi were found on FIG. 18. A,B: Scoliosis series from Patient 6 demonstrating mild thoracic the left thigh. The patient had deeply grooved palmar scoliosis without vertebral anomalies. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2952 SAPP ET AL. FIG. 19. Photograph of the left hand of Patient 6 demonstrating amputated digits and cutaneous and subcutaneous overgrowth. These deep palmar grooves are not consistent with a CCTN (see Fig. 27 for an example of a CCTN in a patient with Proteus syndrome). [Color ﬁgure can be viewed in the online issue, which is available at www.interscience.wiley.com.] FIG. 21. MRI of the upper (A) and lower (B) thighs of Patient 6. He has a complex, admixed lesion comprised of fat, muscle and possible lymphatic patellae, and inguinal hernias. Throughout child- vessels. Again note the inﬁltration of muscle with fatty elements. Panel (A) also hood and into adulthood, she experienced progres- shows that the patient has a complex vascular malformation of the scrotum. sion of the vascular lesion. She had left renal hypoplasia and later developed right kidney disease plenomegaly of unknown cause, focal splenic thought to be consistent with medullary sponge defects/cysts, polycystic ovaries, an ovarian heman- kidney; she developed calculi, which were treated gioma, and was found to have widespread vascular with surgery and lithotripsy. She also had hepatos- malformations throughout her abdominal and pelvic FIG. 20. Panels (A,B) are plain radiographs of the right foot of Patient 6. Panels (C,D) are plain radiograph’s of the patient’s right and left hand, respectively. ‘‘Ballooning’’ soft tissue overgrowth is present in (A) and (B) and bony abnormalities are evident in (A,B,D). The foot abnormalities may be iatrogenic (see Fig. 6). American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2953 FIG. 22. Photograph of the feet of Patient 7 depicting deep plantar grooves that are not consistent with a cerebriform connective tissue nevus. [Color ﬁgure can be viewed in the online issue, which is available at www.interscience. wiley.com.] FIG. 24. Plain radiograph of the right foot of Patient 7 demonstrating enlarged rays and some bony abnormalities, which may be iatrogenic. cavities, and a history of persistent anemia treated On physical examination, the patient’s height was with erythropoeitin. A pelvic mass was removed at 161.2 cm (25–50th centile), she weighed 64.2 kg 32 years of age, described as ‘‘multifocal angioma- (50–75th centile), and her OFC was 54 cm ($50th tosis’’. She had a denervated bladder neck with centile). She presented with facial asymmetry, a incontinence of unknown cause. linear epidermal nevus on the right neck, scoliosis, a FIG. 23. Panels (A–C) are scoliosis series from Patient 7. She has mild scoliosis and mild asymmetry of the vertebral bodies. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2954 SAPP ET AL. FIG. 25. MRI of the spine for Patient 7. Note the signiﬁcant inﬁltration of the back muscles with fatty elements. truncal vascular malformation, and an area of right The patients reported here have a phenotype plantar thickening that, while deeply grooved, was distinct from that of Proteus syndrome, a disorder not a CCTN (Fig. 22). Renal ultrasound showed that is both extremely rare and overdiagnosed enlargement of the right kidney and a small focal [Biesecker, 2005]. Proteus syndrome is a highly lesions consistent with a cyst in the left kidney. Her variable, progressive overgrowth condition charac- creatinine clearance was 50 ml/min. Radiographs of terized by sporadic occurrence, mosaic distribution, the long bones, vertebral column, hands, and feet and a progressive course [Biesecker et al., 1998; disclosed multiple calciﬁcations, particularly in the Biesecker, 2001, 2005, 2006]. Published diagnostic soft tissues of the thorax (presumed phleboliths). criteria delineating the manifestations of Proteus Also present were multiple bony abnormalities syndrome require fulﬁllment of all three general including three enlarged rays in the right foot, attributes mentioned above in addition to a number scoliosis, non-uniformity of the ribs, and non- of speciﬁc criteria [Biesecker, 2006]. Many patients uniformity and asymmetry of the vertebral bodies carrying a diagnosis of Proteus syndrome, on careful (Figs. 23 and 24). MRI of the spine showed fatty examination, do not, in fact, meet diagnostic criteria inﬁltration of the erector spinae muscles posteriorly for the condition, but instead have a phenotype more (Fig. 25). The patient holds an advanced degree and consistent with isolated non-syndromic hemihyper- her family history was unremarkable. plasia (hemihypertrophy), HHML, or an undeﬁned overgrowth condition [Turner et al., 2004]. It is critical for the clinician and researcher to recognize that not DISCUSSION all patients with asymmetric overgrowth, epidermal Signiﬁcant ﬁndings for the present group of seven nevi, and vascular malformations have Proteus patients are summarized in Table I, which also lists syndrome. the diagnostic criteria for Proteus syndrome [Bie- Stringent and speciﬁc delineation of disorders that secker, 2006], a diagnosis carried or considered for all manifest overgrowth serves the dual purposes of seven patients at one time. Other differential deﬁning clinically distinct cohorts to facilitate man- diagnoses considered in this group of patients agement and to advance research into the causes and included Klippel–Trenaunay syndrome1 (Patients 5 treatment of overgrowth. Overgrowth or hyperplasia and 6) and Neuroﬁbromatosis Type I (Patient 7). can be conﬁned to a portion of the body or it may be PTEN mutation analysis for this cohort was negative generalized; it may develop pre- and/or postnatally, for all seven patients. and it may occur as an isolated abnormality or occur as part of a syndrome. Thus, overgrowth has a 1 number of distinct attributes that can be used to Although patients were given the diagnosis of Klippel–Trenaunay– distinguish various clinical presentations of over- Weber syndrome, we do not use this term because this entity probably does not exist. There is a distinction between Klippel–Trenaunay growth. Two attributes have previously been deﬁn- syndrome, on the one hand, and Parkes Weber syndrome, on the other ed: proportionate overgrowth, which is typically [Cohen, 2000]. normal structurally, ‘‘ballooning’’ in appearance, and American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2955 TABLE I. Manifestations in Reported Patients Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Sporadic occurrence a þ þ þ þ þ þ þ Mosaic distribution þ þ þ þ þ þ þ Progressive course b þ þ þ þ þ þ A1. CCTN À À À À À À À B1. Linear epidermal nevus À À þ À þ þ þ B2. Asymmetric, disproportionate overgrowth of B2a. Limbs À À c c À c c B2b. Hyperostosis of the skull À À À À À þ À B2c. Hyperostosis of the external À À À À À À À auditory canal B2d. Megaspondylodysplasia À À À À À À þ B2e. Viscera: (i) spleen, (ii) thymus À À À À À À d B3. Speciﬁc tumors before the second À À À À À À À decade C1. Dysregulated adipose tissue—either C1a. Lipomas À þ þ þ þ þ þ C1b. Regional lipohypoplasia À þ þ þ À À À C2. Vascular malformations: one or þ þ þ þ þ þ þ more C3. Lung cysts À À À À À À À C4. Facial phenotype À À À À À À À Chest/abdominal/pelvic wall vascular þ þ þ þ þ þ þ malformation Facial asymmetry þ À þ À À À þ Broad feet þ þ þ þ þ þ þ Scoliosis À þ þ þ þ þ þ Plantar/palmar overgrowth À þ À À À þ þ Prenatal overgrowth þ þ þ þ þ þ þ Progression of vascular malformations e þ þ þ þ þ þ Testicular cysts b n/a b þ þ b n/a Cutaneous involvement of vascular þ þ þ þ þ þ þ malformation a The features ‘‘Sporadic occurrence’’ through the numbered A, B, C are features that comprise the Proteus syndrome diagnostic criteria. b Unknown or not ascertained. c Patient reports this ﬁnding was present, but there are no objective data to support this. d Spleen enlarged with cysts. e Possible worsening. non-progressive. In contrast, the disproportionate overgrowth typically seen in HHML and other static overgrowth in Proteus syndrome is typically distort- forms of overgrowth. The overgrowth of the cohort ing, progressive, and relentless [Biesecker et al., of patients we present here bears more similarity to 1999; Turner et al., 2004; Cohen, 2005]. Generalized the latter category than to that of Proteus syndrome. overgrowth is part of a number of disorders and is not The nature of the overgrowth of these conditions is considered further because these conditions are also distinct: in HHML and similar disorders, over- clearly distinct from those under discussion here. growth is ‘‘ballooning’’ in appearance. In Proteus Asymmetric overgrowth may be non-syndromic or syndrome, however, overgrowth is ‘‘distorting’’. This comprise a component of a number of disorders, term is used primarily to denote skeletal elements including Proteus syndrome, Klippel–Trenaunay that undergo progressive, and dysplastic, erratic, or syndrome, hemihyperplasia, HHML, encephalocra- deforming postnatal overgrowth. In later years, the niocutaneous lipomatosis, and other ill-deﬁned skeletal elements affected by this process can disorders [Turner et al., 2004]. become so distorted that they are unrecognizable Although all seven patients were referred with a [Jamis-Dow et al., 2004; Biesecker, 2005]. Perhaps the diagnosis of Proteus syndrome (in some cases negative ﬁnding that is most pertinent and worthy of Proteus was a consideration, not a deﬁnite diag- discussion in the patients presented here is the nosis), we came to recognize that their manifesta- attribute of distorting overgrowth. In several instan- tions were distinct from those of Proteus syndrome. ces, our patients’ radiographs do show abnormally Typical Proteus syndrome can be distinguished from formed skeletal elements. However, severely dis- all other forms overgrowth by its postnatal onset, torted skeletal structures are only found in areas of severely deforming and progressive nature, and its the body that have undergone major or radical poor prognosis. This stands in sharp contrast to the surgical procedures. These abnormal skeletal struc- generally non-progressive or mildly progressive tures are not present in these seven patients in American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a 2956 SAPP ET AL. FIG. 28. Lateral view of the legs of a patient (same patient as Fig. 29), showing severe, progressive, distorting overgrowth of the legs, primarily involving the distal femur, proximal tibia, and patella. [Color ﬁgure can be FIG. 26. Plain radiograph of the foot of a patient with Proteus syndrome. viewed in the online issue, which is available at www.interscience.wiley.com.] Dysplastic and disorganized bony structures stand in sharp contrast to the corresponding structures of the seven patients presented here. Note that sulci of the CCTN are visible as well. unoperated areas of the body. This is in marked 6, and 7) to more severe (Patients 3–5). While contrast to the degree of distortion commonly deformed or wedge-shaped vertebrae were present recognized in unoperated parts of the body in in some of these patients, the actual skeletal patients with Proteus syndrome (Fig. 26). Scoliosis disorganization and/or distortion exhibited in these with abnormal vertebral elements is potentially the patients’ vertebral bodies still stands in stark contrast one skeletal manifestation that this group of patients to the effects that Proteus syndrome has on these has in common with Proteus syndrome. The scoliosis same structures, especially over time (Fig. 27). Addi- described in our cohort ranged from mild (Patients 2, tionally, it is interesting to note that arched ﬁbulae can be appreciated in two of these patients, suggesting disproportionate growth of this structure when compared to the tibia. Again, however, these bones are enlarged (lengthened), but not distorted in their basic structure the way they are in Proteus syndrome (Fig. 28). Several of the patients in this report were pre- viously considered by us to have Proteus syndrome. However, we have long been puzzled by the observation that although most patients with Proteus syndrome were normal at birth, a few had massive truncal vascular malformations and overgrown feet. Over the past 12–14 years, we have observed that although this subgroup with congenital overgrowth met the then diagnostic criteria for Proteus syn- drome, their natural history was distinct. That these patients did not develop the relentless, distorting skeletal overgrowth of Proteus syndrome, combined FIG. 27. Cervical (A) and thoracic (B) spine radiographs of a patient with Proteus syndrome. This patient has a profound and progressive scoliosis with with the observations that they did not develop distortion and dysplastic overgrowth of the vertebral bodies. other, more speciﬁc features of Proteus syndrome American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a DELINEATION OF CLOVE SYNDROME 2957 (such as CCTN and lung cysts) [Biesecker, 2001; syndrome, when present. The mature CCTN of Turner et al., 2004; Cohen, 2005], but had instead Proteus syndrome has a ﬁrm, rubbery consistency extensive truncal vascular malformations and sym- and pathologically consists of dense whorls of metrically overgrown feet, leading us to conclude ﬁbrous connective tissue [Twede et al., 2005]. In that this should be considered a distinct entity from addition, the CCTN of Proteus syndrome develops Proteus syndrome. from a multifocal nodular subcutaneous lesion that None of the patients we present here meet current thickens and becomes mostly conﬂuent, with result- diagnostic criteria for Proteus syndrome [Biesecker, ing sulci (Fig. 29). This was not the history reported 2006]. Patient 4 was previously considered to have by these patients; the skin and subcutaneous tissue of Proteus syndrome, although again, ongoing obser- the lesions in the two patients in the present series vation led us to question our previous assessment with these wrinkled lesions was soft and ﬂuctuant, that his overgrowth was progressive [Jamis-Dow consistent with redundant skin overlying a lipoma or et al., 2004]. It is interesting to note that several of the a vascular malformation. Unfortunately, we were patients described here had evidence of plantar or unable to biopsy these lesions in these two patients. palmar overgrowth with wrinkling of the skin. This We believe that the patients presented here have a soft-tissue overgrowth was not consistent with a phenotype that is both recognizable and distinct CCTN, a pathognomonic manifestation of Proteus from Proteus syndrome and other overgrowth conditions. This phenotype comprises progressive, complex, and mixed primarily truncal vascular malformations, dysregulated adipose tissue, varying degrees of scoliosis, and enlarged, yet not severely distorted, bony structures without progressive bony overgrowth. Further characterization of similarly affected patients should allow reﬁnement of this apparently distinct entity, assessment of its unique natural history, and the development of an approach for management for affected patients. We believe that further experience will allow us and our colleagues to deﬁne speciﬁc clinical criteria that distinguish Proteus syndrome from this entity. We suggest that if a clinician is evaluating a patient who seems to have many of the attributes of Proteus syndrome, but has a congenital, complex, vascular malformation (typically, but not always, truncal) and congenital bilateral splaying overgrowth of the feet, this entity should be considered. We propose the name of CLOVE syndrome (congenital lipomatous overgrowth, vascular malformation, epidermal nevus syndrome) on a heuristic basis. We selected this acronym because one of its deﬁnitions is a Middle English word for weight, being about 8 pounds. ACKNOWLEDGMENTS The authors acknowledge Dr. M. Michael Cohen Jr. for being a leader in the ﬁeld of overgrowth syndromes and a strong supporter and stimulating collaborator for more than 10 years on the NIH Proteus syndrome project. We thank Julia Fekecs for assistance with graphics. The authors extend their gratitude to the families who graciously allowed us to participate in their care and for permission to report them in this case series. This work is dedicated to the memory of Christopher Todd Pierini, a courageous and inspiring young man who participated in the FIG. 29. Plantar (A) and lateral (B) image of a CCTN from a patient with National Institutes of Health study. We are indebted Proteus syndrome. Note that the lesion has an abnormal cutaneous surface and has extended laterally around the foot. [Color ﬁgure can be viewed in the online to him and his family for advancing our under- issue, which is available at www.interscience.wiley.com.] standing of this disorder. 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