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Keywords:

  • capillary malformation;
  • lower lip;
  • lymphatic malformation;
  • venous malformation;
  • face;
  • neck;
  • asymmetry;
  • overgrowth;
  • new syndrome;
  • new association

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. DISCUSSION
  6. REFERENCES

We report on six patients with clinical findings consisting of (1) Capillary malformation (CM) of the lower lip; (2) Lymphatic malformation (LM) of the face/neck; (3) Asymmetry of face and limbs, and (4) Partial/ generalized Overgrowth. This constellation of findings has been observed in six unrelated patients, constituting a likely “new” syndrome/association of capillary-lymphatic-venous malformation and asymmetric overgrowth. © 2008 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. DISCUSSION
  6. REFERENCES

Capillary malformation (CM) usually referred to as a port-wine stain, nevus flammeus or vascular marks, is the most common type of vascular malformation. CM is commonly present at birth and grows in size commensurate with the child. Although some macular stains tend to fade with time, as a congenital malformation of the superficial dermal blood vessels, it usually remains present for life without tendency toward involution [Cohen, 2006].

Some CMs may be associated with other vessel malformations; however most of them appear alone as venular malformations. Recent publications reported on mixed low-flow vascular malformations consisting in combinations of capillary, lymphatic and venous components in variable proportions [López-Gutiérrez and García-Miguel, 2006; Bisdorff et al., 2007]. Non-involuting CMs occur in 0.3% of the population with a similar male to female ratio and involve head and neck in 83% of the cases. They also represent a relevant finding in several combined vascular anomalies such as Sturge–Weber syndrome, Klippel–Trenaunay syndrome (KTS), and Parkes–Weber syndrome.

Overgrown and large for gestational age infants have an increased frequency of vascular marks [Lapunzina et al., 2002; Lapunzina, 2005]. The overgrowth syndromes (OGS) are a heterogeneous group of disorders whose main characteristic is that either weight, height or head circumference are above the 95–97th centile or 2–3 SD above the mean for age and sex. As a result, many OGS has an increased number of cells, hypertrophy and/or an increase in the interstitium [Cohen et al., 2002]. In OGS, vascular malformations or stains are commonly seen in some classical OGS such as Beckwith–Wiedemann syndrome, Bannayan–Riley–Ruvalcaba syndrome and Macrocephaly CM syndrome and also in some partial, localized OGS with asymmetric growth such as KTS and Proteus syndrome. Similarly, vascular malformations are 2–3 times more likely to be observed in large for gestational age infants than in adequate for gestational age infants [Lapunzina et al., 2002], reflecting a close relation between angiogenesis/vasculogenesis and somatic growth. In addition, a number of dysmorphic syndromes have been associated with complex combinations of capillary, lymphatic and venous malformations [VM; Cohen, 2002].

We here report on a series of patients with a common pattern of malformations consisting in: (i) a characteristic CM of the lower lip; (ii) lymphatic malformation (LM) of the face/neck; (iii) asymmetry of face and limbs, and (iv) partial/generalized overgrowth. This constellation of findings has been observed in six unrelated patients, constituting a probably “new” syndrome/association with capillary-lymphaticovenous malformation and asymmetric overgrowth.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. DISCUSSION
  6. REFERENCES

All six patients were evaluated at the Section of Plastic and Reconstructive Surgery, Department of Pediatric Surgery and the Department of Medical and Molecular Genetics, Hospital Universitario La Paz, in Madrid, Spain and all of them were also enrolled in the Spanish Overgrowth Syndrome Registry, also at the same Institution. Authorizations for the inclusion of these patients in this research were obtained by the IRB of Hospital Universitario La Paz (# CEIC-HULP-PI 446).

There were four females and two males (Figs. 1 and 2). CM of the lower lip was observed in all patients coexisting with different degrees of LM and VM of the neck and/or mouth, asymmetric face and/or partial or generalized overgrowth (Table I). VM was observed in only two individuals (Patients 2 and 4). CM of the lower lip showed a constant and similar pattern (midline and almost symmetrical) in all children (Fig. 3). The surface of these lesions was smooth and slightly raised and varied in color from red to bluish or purple. The borders of the CM were well defined in all cases and the size ranged from 2.5 to 11.0 cm (mean 5.4 cm). In two cases, the CM involved the entire lower lip (Patient 2 and 4, Figs. 1 and 3). Mucosal involvement adjacent to or in continuity with cutaneous lesions was also common.

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Figure 1. a: Patient 1; b: Patient 2; c: Patient 3; d: Patient 4; e: Patient 5; f: Patient 6. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Figure 2. a: Patient 3. Asymmetric legs and capillary malformation in the left leg; b: Patient 3's feet. Note asymmetry in wide and size. c: Patient 4. Pectus excavatum. d: Patient 5's neck showing venous malformations in the skin. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Table I. Clinical and Laboratory Findings in Six Patients With CLAPO
 Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6
  • a

    At the time of the patient's birth. (+) denotes severity.

  • CM, capillary malformation; VM, venous malformation; LM, lymphatic malformation; NA, not available.

Age7-month22 years6 years10 months9 years 2 months5 years 4 months10 years
GenderFMFFFM
Parents' agea (M/F)34/4131/3331/3729/3028/3333/34
Birth weight (centile)4,050 g (95)3,950 g (90)3,720 g (75)3,100 g (50)2,900 g (50)3,800 g (75–90)
Birth length (centile)52 cm (90)50 cm (75)51 cm (75–90)50 cm (50–75)49 cm (50)51 cm (50–75)
OFC at birth (centile)NANA32 (50)31 (50)NANA
Gestational age (weeks)393841373737
SiblingsTwo brothersOne younger sisterOne younger sisterOne younger brotherOne younger brother
Weight (centile)8.8 kg (90)72 kg (50)22.15 kg (50)24 kg (50)17 kg (50)44 kg (95)
Height (centile)46 cm (50)172 cm (50)120.5 cm (50)127 cm (75)112 cm (50)146 cm (95)
OFC (centile)46 cm (80)NA51.7 cm (50)53.2 cm (75)50 cm (75)53 cm (p50)
Associated findings Hemorrhoids (surgically removed)Idiopathic endocranial hypertensionPectus excavatum (operated 7 years)  
OvergrowthAsymmetric face slight right arm hypertrophyRight hemihypertophy of leg and arm macrodactyly of right handLeft hemihypertrophy of leg (>15% wide); right hemihypertrophy of arm (10% difference).Increased wide of right armAsymmetric faceGeneralized
CMLower lip +, neck +Lower lip +++++, neck +Lower lip ++Lower lip +++++, Tongue ++Lower lip +++Lower lip ++++, Tongue +
VMNeck +Neck +++Neck ++ 
LMLower lip +, neck ++++Lower lip +Lower lip +, neck ++Lower lip +++++, tongue ++++, neck ++++Lower lip ++++, neck ++Lower lip +++++, tongue +++, neck ++
Karyotype46, XX46, XY46, XX46, XX46, XX46, XY
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Figure 3. Lips and tongue of the patients. a: Patient 1; b: Patient 2; c: Patient 3; d: Patient 4; e: Patient 5; f: Patient 6. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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The LM was microcystic involving the tongue, floor of the mouth, and buccal mucosa in four individuals (Patients 2, 4, 5, and 6; Figs. 4–6). Complaints and morbidity included bleeding, infection, swelling, vesicle formation and malocclusion. The neck and pharynx were involved in five and two patients, respectively. None of them required tracheostomy. Management of the LM included resection in one patient (Patient 4), OK-432 sclerotherapy in two (patients 1 and 4) and CO2 laser photocoagulation in three (Patients 4, 5, and 6). CO2-laser for the tongue lesions was applied to Patients 4 and 5. Although all they achieved normal oral feeding, cosmetic issues remain problematic in most of them. Karyotypes were normal in all patients. Clinical and laboratory findings of all patients are summarized in Table I.

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Figure 4. Histological specimen of the capillary malformation of Patient 4, stained with D2-40 monoclonal antibody. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Figure 5. MRI of Patient 4. Note the vascular malformation of the neck.

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Figure 6. Patient 5. Angiogram of the neck showing capillary malformation of the left vessels (arrows).

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Patient 4 has the most severe CM of the neck and face, leading to an important deformation of the facial shape and dysmorphic facial features (Table I, Figs. 1d and 2c). She also has thin thorax and pectus excavatum. The vascular malformation in this girl was resected at age 1-year. Histological findings showed that most of the malformation comprised endothelial lymphatics (Fig. 4).

The overgrowth was noted at birth in Patients 1–3 and was present in all patients at the moment of consultation. The overgrown segment in patients with localized overgrowth (Patients 1–5) grew proportionally with the patient's growth. Patients 1–5 have partial, localized overgrowth of one or more body segments, however Patient 6 showed generalized overgrowth (weight and height in 95th centile), with no apparent asymmetric limbs/body segments. Neither internal nor visceral abnormalities were observed in any patient. The development and mental status were normal in all patients. No other relatives have similar findings and parents and siblings were apparently normal in all families.

MRIs of the overgrown segments and/or the CM; LM or VM have been performed in all patients. Differentiation between VM and lymphatic malformations (LMs) could be made based on clinical characteristics and MRI post-contrast T1 images (Fig. 5). In VMs the lesions usually enhanced and in LMs showed minimal peripheral enhancement or no enhancement.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. DISCUSSION
  6. REFERENCES

CMs are the most common type of vascular malformation. Vascular marks of the occipital or glabellar regions are common in about 40–50% of BWS and also in some patients with Simpson–Golabi–Behmel or Sotos syndrome. CM of the upper lip is typical and almost pathognomonic of macrocephaly cutis marmorata telangiectatica congenita [Clayton-Smith et al., 1997; Moore et al., 1997; Cohen et al., 2002; Lapunzina et al., 2004; Lapunzina, 2005; Lapunzina and Clayton-Smith, 2007] now correctly renamed as macrocephaly capillary malformation (M-CM) syndrome [Toriello and Mulliken, 2007]. In M-CM, CM of the upper lip is observed in about 75% of patients whereas other areas are involved more infrequently [Lapunzina et al., 2004; Lapunzina and Clayton-Smith, 2007]. However, no patient in the present series showed CM of the upper lip or philtrum and none of them had macrocephaly.

Although CMs around the nape and glabella are usually seen in normal children, true CM of the lower lip is an infrequent finding. Kaplan et al. 1998 reported only 74 children and adolescents with “small superficial capillary hemangiomas” on the lips. Of the 77 lesions they observed, 70% were located on the lower lip and 30% in the upper. However, it is difficult to discriminate in the Kaplan and coworkers' series among vascular malformations and true hemangiomas due to confounding terminology. The problem of nomenclature of vascular lesions leading to confusion has been extensively commented on; Mulliken and Glowacki 1982 and Mulliken 1997 made a distinction and clarification between hemangiomas and vascular malformations based on cellular kinetics and clinical behavior. Hemangiomas have endothelial hyperplasia with rapid post-natal growth followed by slow involution and in contrast, vascular malformations are characterized by flat endothelium and growth of the lesion is commensurate with growth of the child [Mulliken, 1997; Cohen, 2002]. However, CM of the lower lip is rarely or never observed in the known OGS, and to the best of our knowledge, it has not been reported yet associated with LM and/or partial/generalized overgrowth.

The OGS as a group have increased risk of mental retardation and tumors [Cohen et al., 2002; Lapunzina, 2005]. However, no patient in the present series has mental retardation or tumors and none of them has been included in a tumor surveillance program.

In contradistinction to anterior midline lesions of the upper lip that involve typically the upper two thirds of the philtrum with most of them fading within the first year of life, malformations of the lower lip are not transient and progression in thickness and color can be expected. CMs that enlarge the lips (port-wine macrocheilia) are challenging reconstructive problems which, as a result, often go untreated. The CM of the lower lip was observed in all six patients and some of them have macrocheilia (Fig. 3). Thus, the CMs have led to lip hypertrophy in one case. In addition, CM overlying the lower lip may be a marker for an underlying lymphatic anomaly.

Association of lymphatic and capillary involvement has been also described in vascular tumors such as Kaposiform hemangioendothelioma (KHE) and tufted angioma [TA; Arai et al., 2006]. Residual lesions in KHE long term follow-up exhibited three clinical patterns: type I lesions showed a cutaneous red stain, with or without associated red papules. These cutaneous vascular lesions varied in size and appearance over time and were occasionally painful. Type II lesions were telangiectatic streaks and swelling and type III lesions showed a minor, firm, irregular, subcutaneous mass assessed by palpation or deep infiltration evidenced by computed tomography or magnetic resonance imaging. Neither KHE nor TA were observed in our patients.

The concurrence of venous, lymphatic and CMs is also observed in KTS, a partial, localized OGS with vascular component characterized by combined vascular malformations of the capillary, venous and lymphatic types, varicosities of unusual distribution and limb enlargement [Cohen, 2000, 2006]. In KTS lateral venous anomalies are very common, macrodactyly of toes is a usual finding and enlargement of the limb is usually disproportionate; such disproportion is always related to subjacent vascular malformation. However, the partial overgrowth and disproportion of limbs observed in the patients presented herein had no subjacent vascular etiology and resemble those seen in isolated hemihyperplasia, where no vascular anomalies are responsible of the overgrowth and an increment of all tissues in either size or number of cells (or both) is observed.

Recent evidence supports a neural role in both the development and progression of CM and LM. Animal studies show that the sympathetic nervous system influences the composition and functional properties of the vessel wall during development. Immunohistochemical studies of CMs reveal a significantly decreased density of perivascular nervous tissue in affected skin, suggesting that inadequate innervation may be responsible for decreased vascular tone and progressive vascular dilatation. These findings raise the possibility that a lack of neural modulation of vascular flow may be involved in the pathogenesis of port-wine stains.

Inheritance of this syndrome/association is not known. No recurrence of the disorder was observed in six sibs of all six families. There is a slight female preponderance. Somatic mosaicism is a theoretical possibility due to patchy vascular markings of the skin and asymmetric overgrowth.

To summarize, the combination of CM of the lower lip, LM (and in some instances VM) of the face and neck, asymmetry and partial or less frequently generalized overgrowth may constitute a new, non-described association of findings which we heuristically named “CLAPO.” Future reports will probably shed light on the etiopathology, natural history and inheritance of this infrequent disorder.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. DISCUSSION
  6. REFERENCES
  • Arai E, Kuramochi A, Tsuchida T, Tsuneyoshi M, Kage M, Fukunaga M, Ito T, Tada T, Izumi M, Shimizu K, Hirose T, Shimizu M. 2006. Usefulness of D2-40immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma. J Cutan Pathol 33: 492497.
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  • Mulliken JB. 1997. Vascular anomalies. In: AstonSJ, BeasleyRW, ThorneCIIM, editors. Grabb and Smith's plastic surgery. 5th edition. Philadelphia: Lippincott-Raven. p 191203.
  • Mulliken JB, Glowacki J. 1982. Hemangiomas and vascular malformations in infants and children: A classification based on endothelial characteristics. Plast Reconstr Surg 69: 412420.
  • Toriello HV, Mulliken JB. 2007. Accurately renaming macrocephaly-cutis marmorata telangiectatica congenital (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet Part A 143A: 3009.