Newly delineated syndrome of congenital lipomatous overgrowth

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					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: leslieb@helix.nih.gov
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. This work was supported
                                                                 American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

2958                                                            SAPP ET AL.

by intramural research funds of the National Human                     Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr,
Genome Research Institute of the National Institutes                      Viljoen DL, Cohen MM Jr. 1999. Proteus syndrome: Diagnostic
of Health (JCS and LGB).                                                  criteria, differential diagnosis, and patient evaluation. Am J
                                                                          Med Genet 84:389–395.
                                                                       Cohen MM Jr. 2000. Klippel–Trenaunay syndrome. Am J Med
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   syndrome. JAMA 285:2240–2243.                                       Eldredge PMS, Munoz GS, Ruiz S. 1993. Sindrome de Proteus. A
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Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N,         Proteus syndrome literature: Application of diagnostic criteria
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Description: Newly delineated syndrome of congenital lipomatous overgrowth