Pathogenesis

The etiology of CM is not fully understood, however recent reports of mutations in GNAQ in both syndromic and non-syndromic CMs point to an underlying genetic basis.⁹ Another familial form of CM occurring with AVM has been reported in the CM-AVM syndrome.

Cutaneous findings

PWS are pink or red patches that typically grow proportionately with the child’s somatic growth, and persist throughout the patient’s life. They consist of ectatic dermal capillaries and may occur anywhere on the body (Fig. 22.2A). PWS may appear to lighten over the first 3–6 months of life, but this should not be taken as a sign of resolution. Rather, this physiologic lightening is due to the decrease in blood hemoglobin concentration corresponding to the change from fetal to adult type hemoglobin (Fig 22.2B).¹⁰ Capillary malformations can occur anywhere on the body. They may or may not be associated with overgrowth of the affected area (Fig. 22.2). Port-wine stains on the face tend to follow a dermatomal pattern, respecting the trigeminal nerve V1-V3 distribution or comprising multiple dermatomes (Fig. 22.3). The natural history of port-wine stains over a lifetime is often one of gradual darkening from pink-red to a crimson or deep purple hue. Skin thickening and soft tissue and/or bony hypertrophy may also develop. Eczematous changes can occur in PWS and salmon patches, either with or without treatment. Nodular vascular lesions (pyogenic granulomas) may appear within PWS during childhood or adult life and may require surgical intervention.¹¹ The association of PWS with pigmentary anomalies such as extensive Mongolian spots, nevus spilus, or nevoid hyperpigmentation is a feature of phakomatosis pigmentovascularis (see further discussion of this entity below, Fig. 22.4, Table 22.2).

Extracutaneous findings

Progressive soft tissue and bony overgrowth may occur during childhood, especially with V2 PWS, and subtle changes are sometimes noted even in the neonatal period.¹² Asymmetric maxillary hypertrophy associated with distortion of the facial features requires multidisciplinary management with orthodontic follow-up and treatment. Some patients require procedures to correct skeletal overgrowth in late childhood. Gingival hypertrophy may also develop. Port-wine stains are also a manifestation of several different syndromes with other extracutaneous features discussed later in the chapter (see ‘Syndromes associated with vascular malformations’, below).

Management

The gradual thickening and nodularity of PWS provide a medical rationale for treatment during infancy and childhood.¹¹ The flashlamp-pumped pulsed dye laser (PDL) is the gold standard treatment for PWS and poses a very low risk of scarring, even in young infants. It has been used for longer than 15 years and advances such as the development of a cooling system have improved efficacy. Most PDL units have a wavelength of 595 nm. Settings of 0.45–1.5 ms pulse duration, 6–10 J/cm² fluences, and 7–10 mm spot size along with the coolant system (dynamic cooling device) are used in the majority of cases. Although only 15–20% of PWS clear completely with PDL, the majority of treated lesions lighten significantly.^13,14 Response to laser treatment varies by area and skin type: outcomes are better on the face and neck, albeit with less improvement in V2 than other facial sites, and are also better in patients with type I–II skin.¹⁴ The extremities do not respond as well.^13–15 Controversy exists regarding the age at which treatment should begin. Some authors have noted a better therapeutic response with fewer treatments when treatment was initiated in early infancy,¹⁶ but others have found no difference.¹⁷ Treating earlier (in infancy or early childhood) can be helpful in reducing stigmatization and may help prevent thickening of the skin.¹⁸ Treating early in infancy may enable the physician to treat with topical anesthesia, as small infants can be swaddled and held during a brief treatment and local anesthetic can be applied prior to the procedure. In older children with large stains, general anesthesia may be required. In most cases, re-darkening occurs with time and touch-up treatments are often needed in later childhood or teen years.¹⁹

In treatment-resistant CM, other laser modalities have recently been studied in an attempt to decrease thickness, color, and nodularity. These include the long-pulsed neodymium : yttrium-aluminum-garnet (Nd : YAG) laser, the combined PDL and Nd : YAG laser, and the alexandrite laser.^20–24

Other novel therapies show some initial promise, including intense pulsed light (IPL), photodynamic therapy (PDT), and application of topical anti-angiogenic factors (imiquimod and rapamycin) in conjunction with laser ablation.^25–35

In cases where there is soft tissue or bony overgrowth, or in syndromic CM, a multidisciplinary approach to management is often necessary. Patients may require orthodontic work, maxillofacial reconstruction or soft tissue debulking. Ideally, follow-up in a multidisciplinary vascular anomalies center is beneficial.

Pathogenesis

VMs are sporadic in the majority of cases, but, familial cases of both VM and (more often) GVM occur. The genetic basis for familial VMs (VMCM syndrome, see below) and GVM are now known. The mutated gene in familial VMCM syndrome maps to chromosome 9p17; and is an activating mutation in the kinase domain of the receptor tyrosine kinase Tie2.³⁶ Sporadic Tie2 mutations are also found in 50% of sporadic VMs.³⁷ GVM can be either a sporadic or an autosomal dominant condition, linked to mutations in the glomulin gene (mapping to 1p21–p22). Unlike VMs, far more cases of GVM are familial (approx. 64%).^38,39

Cutaneous findings

At birth, the majority of VM are subtle, bluish, ill-defined, compressible plaques or nodules. Rarely, a bulky venous mass is observed in the neonatal period (Fig. 22.5). VMs may be diffuse or localized. Affected skin and mucous membranes are typically blue with normal skin temperature, without a thrill or bruit. Lesions swell when dependent or with crying. In many cases, the blue-hued cutaneous component heralds involvement of deeper structures. Local venous thromboses can lead to the formation of phleboliths, which can be tender when palpated and are visible on radiographs as round calcifications.

Glomuvenous malformations (GVM; formerly called ‘glomangioma’) may be solitary or multiple, and may be localized or involve a larger territory of skin (Fig. 22.6). They are often bluish to purple, cobblestoned or plaque-like in appearance. During childhood, they typically acquire a deeper blue hue and thicken, and become tender when palpated. Congenital plaque-like GVMs are usually pink at birth, with noticeable thickening and change in color to blue-purple during childhood. These plaque-like GVMs may arise sporadically, or occur as a manifestation of autosomal dominant GVM. Other family members may have smaller, blue vascular lesions scattered over the skin, increasing in number with age.³⁸

Extracutaneous findings

In addition to skin and mucosal involvement, VM can also involve deeper soft tissues, muscles, joints, and in severe cases, visceral sites such as the abdomen and pelvis. A majority of patients with extensive VMs develop a chronic localized intravascular coagulopathy (LIC), which is distinct from Kasabach–Merritt phenomenon (KMP). VM associated LIC can result in either thrombosis (with pain and phlebolith formation) or bleeding, and persists throughout life. It differs from KMP because the primary process is one of ongoing clotting, with consumption of clotting factors, low fibrinogen and elevated d-dimers, but without the marked thrombocytopenia of KMP.^40,41 Large and intramuscular VMs are more likely to have associated VM-LIC. Pain is a common complaint either due to phlebolith formation or often in larger extremity lesions.⁴² ‘Blue rubber bleb nevus’ syndrome, the association of multiple cutaneous venous malformations with gastrointestinal and other internal lesions, is discussed later in this chapter. Some patients with VM experience worsening of symptoms during puberty or in pregnancy. In contrast to VMs, GVMs are typically localized to the skin and soft tissues without mucosal or intramuscular involvement. GVMs are not associated with LIC.

Diagnosis

The diagnosis is usually established on the basis of clinical features. Imaging modalities including ultrasonography, Doppler, MRI, and CT scans are useful for evaluating the extent of involvement.⁴³ The finding of associated LIC and specifically elevated d-dimer levels, can help confirm the diagnosis of VM in uncertain cases.⁴⁴ Apart from helping to confirm the diagnosis, the decision to image early in infancy depends on whether functional problems are present or early treatments are planned. Many VMs, however, especially larger ones, eventually do require imaging studies, and MRI with contrast is the best study to delineate disease. A number of radiologic classification schema have been proposed and may predict response to treatment, with smaller and more localized lesions being more amenable to sclerotherapy.⁴⁵ In individuals with craniofacial VMs, it is advisable to image the brain: developmental venous anomalies (DVA) in the brain are more common in patients with craniofacial VMs than in the general population (25% vs 0.5%).⁴⁶ DVAs are uncommon trajectories of the brain’s venous drainage and pose little risk of cerebral hemorrhage, but documenting their presence can help avoid misdiagnosis of a more worrisome condition later in life. Histopathology can also help to confirm the diagnosis when uncertainty is present and/or to distinguish between VM and GVM.

Differential diagnosis

Extensive VMs in a leg or an arm and adjacent trunk must be differentiated from Klippel–Trenaunay and other overgrowth syndromes, as management and prognosis is variable (see Table 22.4). Sinus pericranii should be considered in the differential diagnosis of a VM located on the central forehead. This presents as a bluish, nonpulsating mass that is usually congenital and quickly expands when the patient puts their head in a dependent position or with crying. Sinus pericranii represents a direct communication between superficial veins and intracranial venous sinuses through a bony defect. It is best imaged using CT with bone windows.

Course

Venous malformations tend to enlarge and become more symptomatic with time. Their clinical course and complications depend on anatomic location, with differing problems in the craniofacial area, trunk, and limbs.⁴¹ The cheek, lip and tongue are common locations for craniofacial VMs, and there is sometimes deep extension to the temporal and orbital areas. Swelling is noted with dependency and activity. Over time, the VM may progressively distort the facial features and mold the underlying developing bones, which can result in deformities such as an open bite or enlargement of the orbit. Extensive retropharyngeal involvement can result in obstructive sleep apnea, occasionally even in young children. VMs located on the trunk and limbs may involve skin, skeletal muscles, joints, and bones, often causing pain. During infancy and early childhood, the skin component of the VM expands and becomes deep blue. However, the deeper component may remain undiagnosed until it becomes symptomatic. Swelling, functional impairment, and limited joint motion occur when the child becomes older and more active, especially if playing sports. VM-LIC associated with large and intramuscular VM can manifest as early as the neonatal period.

Management

Due to the heterogeneity of VMs and the clinical and radiologic diagnostic overlap with other vascular anomalies, multidisciplinary management is recommended. VMs are reported to comprise up to 40% of referrals to vascular anomalies centers.⁴⁷ VMs can be treated with many different modalities including sclerotherapy, excision, endovenous laser ablation, cutaneous laser ablation or a combination of these modalities. Sclerotherapy has emerged as the mainstay of treatment for VMs, followed by surgical excision. The decision regarding when to treat is usually based on whether there is significant functional impairment or disfigurement. Sclerotherapy involves the introduction of an endothelial-cell cidal sclerosant into the vascular spaces of the malformation.⁴⁸

Several different sclerosants can be used, including ethanol or sodium tetradecyl sulfate. Complications of sclerotherapy include tissue necrosis, nerve palsies, hemoglobinuria and oliguria.⁴⁹ Surgical management can be most helpful in small or localized lesions. A combination of sclerotherapy followed by surgical debulking is often used in large or complex cases. In craniofacial lesions, therapy is aimed at preventing distortion of facial anatomy, limiting bone deformity, open bite or shift of the dental midline, lip expansion, and displacement of the lip commissures.^50,51 MRI and ultrasound features may be especially helpful in determining optimal management.⁵¹ Multiple treatments are often required over years. Laser or radiofrequency ablation are occasionally helpful. Conservative therapy with compression should be initiated early on and is even encouraged from infancy in diffuse extremity VMs. Comp­ression increases comfort, limits swelling, and improves co­agulopathy. Compression is less useful for intramuscular VMs and may exacerbate pain.

Evaluation of large VMs includes assessment for, and possibly treatment of, VM-LIC. d-dimer levels should be obtained periodically to assess the extent of coagulopathy. Treatment with low-dose aspirin can be a helpful adjunct to conservative therapy in some cases. Low molecular weight heparin (LMWH) has been found to be useful in patients with chronic VM-LIC during episodes of exacerbation (thrombosis, pain) or before and after planned procedures such as sclerotherapy or surgical excision, to prevent thrombosis and/or control intraoperative hemorrhage.⁵² In patients with a history of thromboembolic events or in those with high risk, large and/or combined malformations, placement of an inferior or superior vena cava filter may help prevent pulmonary embolus.⁵³

Pathogenesis

The etiology of LMs is still unknown. LMs arise in a sporadic manner and no associated genetic basis has yet been discovered. This may suggest that a genetic cause is likely related to somatic mutations, which, if occurring within the germline, would be incompatible with life.⁵⁴ This is in contrast to primary lymphedema, where several genetic mutations leading to specific lymphedema syndromes have been discovered and have improved our understanding of the molecular pathways involved in lymphangiogenesis.⁵⁵ In primary lymphedema, defective lymphatic drainage leads to accumulation of lymphatic fluid in the interstitial space (Fig. 22.7).

Several forms of lymphedema are known, including familial congenital lymphedema, Nonne–Milroy syndrome, Meige disease, and Hennekam syndrome, summarized in Table 22.3.

Cutaneous findings

Macrocystic LMs are usually visible at birth and are commonly diagnosed by prenatal ultrasound investigation. They occur more commonly in the neck and axilla, where they are often referred to as cystic hygroma (Fig. 22.8).⁵⁶ The detection in utero of some huge LMs of the neck, axilla, and thoracic area may lead to a discussion about terminating the pregnancy, as the prognosis is poor. Microcystic LMs can infiltrate diffusely throughout the dermis. Clear or hemorrhagic vesicles (so-called ‘lymphangioma circumscriptum’), which may intermittently leak lymphatic fluid, may be visible on the surface of the lesion. Severe combined LMs may also occur on the trunk and limbs.⁵⁷

Extracutaneous findings

Cervicofacial LMs involving the tongue and floor of the mouth will interfere with normal development of the jaw and create an open bite deformity. The most severe forms of combined micro/macrocystic LMs, which are more common on the head and neck, can cause life-threatening airway disease and other functional problems in the neonate (Fig. 22.9). Intraoral involvement also causes drainage of serosanguineous lymphatic fluid, aggressive caries, and loss of teeth. Involvement of the mandible with ensuing overgrowth is present in about 40% of these patients.^58,59 Extra- and intraconal orbital LM occurs in association with eyelid LM; this uncommon location causes severe complications including disfigurement, bleeding, infection, proptosis, and visual loss.⁶⁰ Severe cervicofacial LMs, usually the combined micro/macrocystic type, involving the hypopharynx and larynx, the tongue and the floor of the mouth, can cause airway and esophageal obstruction requiring nasogastric tube feeding and emergency tracheotomy in the newborn.⁶¹ Of 31 cases with such severe involvement, 58% required tracheostomy in infancy and one-third could not be decannulated.⁵⁹ Visceral LMs, intrathoracic or abdominal, are less common, representing about one-tenth of cases. LMs are more susceptible to bacterial infections, and recurrent cellulitis can be a complication.

Diagnosis

The diagnosis is established either clinically or using CT, MRI, or ultrasound. Fluid aspiration and analysis may be helpful because a number of neonatal growths, including some malignant tumors, can present with large cyst-like swellings.⁶² Histologically, lymphatic vessels or cysts have thin walls and lumina appear empty. Several positive immunohistochemical markers of lymphatic vessels have been identified, including LYVE-1, VEGFR-3 and D2-40, and can help to differentiate LM from other vascular anomalies.

Treatment

Lymphatic malformations are benign and treatment is usually directed at managing complications or attempting to restore anatomy. Conservative measures include observation, prophylactic antibiotics when infection is a concern, and in the case of primary lymphedema, compression. Sclerotherapy has emerged as an important treatment for LMs, and can be done early, even in the neonatal period. A variety of sclerosing agents have been used, including doxycycline, ethanol, bleomycin, OK-432 and STS. Macrocystic LMs respond very well to sclerotherapy. Surgical resection is another therapeutic option for macrocystic LMs, as well as for microcystic and combined types, but recurrences and complications such as seroma or chronic lymphatic leakage may occur.^{58–60,63,64} Radiofrequency ablation can be helpful in the management of LMs, most commonly for the lips and tongue to help decrease chronic leakage and bleeding.^65,66

A multidisciplinary approach is required for complex LMs.⁵⁹

Pathogenesis

Arteriovenous malformations arise due to errors in vascular development, which occur during embryogenesis. AVMs represent direct shunting from the arterial to the venous system due to the absence of an intervening capillary bed. Recently, the genetic basis for familial types of AVM has been discovered. Mutations in RASA1 have been found in individuals with AVM of the extremity (Parkes Weber syndrome) and in CM AVM syndrome (see below for further discussion on Parkes Weber syndrome), vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies caused by RASA1 mutations.⁹ Other mutations associated with AVMs or AVM variants include endoglin, which gives rise to hereditary hemorrhagic telangiectasia syndrome (HHT) and PTEN as seen in high flow lesions of the PTEN hamartoma tumor syndrome (see below).

Cutaneous findings

Most commonly, AVMs present as a pink vascular stain on the skin, mimicking port-wine stain. They are often located on the head and neck, the nose and central face/lip are common locations as is the ear (Fig. 22.10). As mentioned above, lesions are warm and may have a thrill or a bruit. AVMs may develop pyogenic granulomas within them that bleed and may need to be excised or treated with laser ablation.⁶⁷ Any patient who presents with small, multifocal lesions that resemble PWS but demonstrate high flow on Doppler examination should receive a workup for CM AVM syndrome (see below). Lesions may become thicker, more nodular and darker in color with time. AVMs often progress during puberty or with trauma.

Extracutaneous findings

AVMs can be life-threatening lesions that worsen over time. Complications include disfigurement, pain, bony erosion, hemorrhage, and even death. Large AVMs may have associated high-output heart failure at birth or later in life, requiring intervention.

Diagnosis

Most AVMs can be diagnosed based on their natural history and physical examination characteristics. They may not be obvious at birth, most commonly lesions mimic port-wine stain, but unlike PWS, AVMs expand through childhood. In general, AVMs are warm, a bruit may be audible, and a thrill may be palpable. An actual vascular mass with tense draining veins, a thrill, and a bruit is uncommon for AVM in a newborn, and may represent a congenital hemangioma (see Chapter 21). The Schobinger Classification of AVMs divides the presentation into four stages based on severity and associated findings: Stage I, lesions are quiescent; Stage II, AVMs have expanded and a thrill or bruit is palpable; Stage III, AVM destruction occurs and lesions can lead to ulceration, bleeding and pain; and Stage IV AVMs are associated with cardiac compromise.⁶⁸

Color Doppler ultrasonography as well as MR with MR angio­graphy may be helpful in diagnosis, as well as delineating the extent of disease. Angiography is sometimes done to aid in diagnosis or in preparation for embolization or resection. In contrast to VMs, AVMs are not known to be associated with LIC.

Management

Early on, conservative observation may be the best course for Stage I and II AVMs, as interventions may lead to enlargement or worsening of the lesions secondary to trauma. In more advanced malformations, where there are complications or functional compromise, embolization is usually the first-line treatment. Embolization can also be done prior to a planned surgical resection.⁶⁹ Embolization involves the delivery of an embolic agent, usually ethanol, onyx, polyvinyl alcohol or coils, into the AVM in an attempt to block the blood flow and reduce shunting.⁷⁰ Embolization is considered a palliative measure, as there is no cure for AVMs. Surgical management of AVMs should be performed with caution as exacerbation or recurrences are common and any resulting deformity may not be cosmetically acceptable.⁷⁰

Macrocephaly capillary malformation syndrome (megalencephaly capillary malformation polymicrogyria syndrome)

Macrocephaly capillary malformation syndrome (MCM/MCAP) was formerly known as macrocephaly CMTC. However, the most commonly associated vascular anomalies are a persistent nevus simplex or typical CM/PWS (not CMTC) and the diagnostic criteria for this condition were revised to reflect this.^78,79 MCM/MCAP is associated with megalencephaly, developmental delay, brain and body asymmetry, capillary malformations, digital anomalies (syndactyly, polydactyly), and brain malformations; characteristically, polymicrogyria. Other features include seizures, developmental delay, hydrocephalus, and joint laxity. Recently, the genetic basis for this condition has been identified. Affected individuals were found to harbor mutations in the AKT3, PIK3CA or PIK3R2 genes.⁸⁰ MCM/MCAP is a heterogeneous overgrowth syndrome, most commonly patients present with macrocephaly and cutaneous CMs. The associated capillary stain is most commonly located on the central face (philtrum and glabella) but can be seen on any area of the body. As in all overgrowth syndromes, there is a possibility of increased risk for Wilms tumor – many experts recommend serial abdominal ultrasounds in infancy and early childhood.

Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is a pediatric overgrowth disorder that carries an increased risk for malignancy, specifically Wilms tumor. BWS can present antenatally with visceromegaly on prenatal ultrasonography. It is associated with persistent nevus simplex or capillary malformation of the mid-forehead. Other findings include overgrowth of tissues and organs, macroglossia, and abdominal wall defects, usually omphalocele. High birthweight, hemihypertrophy, and neonatal hypoglycemia are also reported. Intelligence is usually not impaired.

The genetic basis of BWS is complex and several different modes of inheritance are possible. Inheritance can be via autosomal dominant, contiguous gene duplication or genomic imprinting. Chromosome 11p is implicated in several of these inheritance modes.⁸¹

Nova syndrome

Nova syndrome is a familial disorder in which a congenital glabellar capillary stain occurs in association with neurologic malformations, including Dandy–Walker malformation, hydrocephalus, cerebellar vermis agenesis, and mega cisterna magna.

Phakomatosis pigmentovascularis

Phakomatosis pigmentovascularis (PPV) is a term used to describe the association of cutaneous pigmentary and vascular anomalies. Five types with two subtypes per group are classically described. An alternate classification uses descriptive terminology to highlight the cutaneous features (Table 22.2, Fig. 22.4). Capillary malformations are described in types I–IV and cutis marmorata telangiectatica congenita in type V. The pigmentary anomalies include blue-gray macules/patches (dermal melanocytosis), nevus spilus and epidermal nevi which are darkly pigmented. Nevus anemicus is also reported. PPV has been described in association with other vascular anomalies including Klippel–Trenaunay syndrome and Sturge–Weber syndrome.^82,83

Maffucci syndrome

Maffucci syndrome (MS) is a rare sporadic syndrome characterized by vascular lesions of the skin and multiple bone tumors. This form of enchondromatosis is associated with spindle cell hemangioma, begins in childhood and worsens with maturity. Congenital forms occur and disease presents in 25% of cases by the first year of life.⁸⁷ The skin lesions clinically resemble venous malformations, are nodular, develop slowly, and are rare in infancy. Although they have features of slow-flow venous anomalies – phleboliths, hypersignal on signal-enhanced T₂ sequences with MRI – histologic examination reveals a spindle cell hemangioma, in addition to malformed venous channels.⁴ Enchondromas are benign cartilage-forming tumors within the medullary cavity of the bone. These tumors are identical to those present in another form of multiple enchondromatosis, Ollier disease. They involve both the metaphyses and the diaphyses, and may cause bony distortion, fragility, and shortening of an affected limb. The hands and feet are involved in 90% of patients. Cranial enchondromas result in severe neuro-ophthalmologic consequences. Over time, enchondromas may develop malignant transformation. Somatic mosaic IDH1 and IDH2 mutations are associated with the lesions in both Ollier disease and MS.⁸⁸

Cutis marmorata telangiectatica congenita

Cutis marmorata telangiectatica congenita (CMTC) is a form of vascular malformation with a distinctive reticulated pattern. Most cases are sporadic. A female predominance is reported in some cases series, while others show no difference in incidence among genders.^89,90 CMTC can be confined to a small area, have a regional distribution, or more diffuse skin involvement. At birth, a reticulated purple network is noted. The skin is streaked with linear and patchy vascular lesions intermingled with telangiectasia. Within affected areas there are often focal areas of atrophy and/or ulceration, even during the neonatal period (Fig. 22.12). These changes are often most prominent over the limbs. This conspicuous atrophic reticulate pattern differs from physiologic cutis marmorata, a normal finding in newborns, in that the pattern is coarse and less regular. CMTC may be associated with port-wine stains, which can become more apparent with maturity as the reticulate lesions fade. CMTC may improve with age, but rarely disappears completely with areas of atrophy often persisting. Ulcerations may continue to arise during infancy and childhood, particularly in areas overlying the joints, resulting in scaly areas of scarring.

Localized or regional CMTC with involvement of one or two areas of skin (most often the extremities) is more common than the diffuse type, but because of its generally benign course is likely less frequently reported in the literature. A difference in limb girth is common, and the affected limb may have a thinner, pseudo-‘athletic’ appearance compared with the normal extremity as a result of having less fat or diminished muscles and bones. Subsequent growth is usually proportional to the original degree of limb asymmetry.⁹¹ Multiple abnormalities have been reported in association with CMTC, however, care should be taken when reviewing older case series, since cases of macrocephaly CM syndrome associated with a reticulated capillary malformation and not true CMTC, may have been included. The most frequently described associated anomaly in many case series is body asymmetry. Other reported associated anomalies include musculoskeletal anomalies, vascular abnormalities including co-existing capillary malformations/PWS, arterial stenosis and cardiac defects. CMTC, syndactyly, cardiac defects and alopecia are features of Adams Oliver syndrome.⁹² Less frequently reported anomalies include brain and spinal cord defects, glaucoma and other ocular anomalies, imperforate anus, abnormal genitalia, dystrophic teeth, congenital hypothyroidism, stenosing tendonitis, and others.^{89,91,93–96,90}

The differential diagnosis of CMTC includes macrocephaly CM syndrome, which is discussed above, and persistent true cutis marmorata. Neonatal lupus can be associated with extensive livedo reticularis, telangiectasia, and atrophic striae, and mimics CMTC.⁹⁷ Less generalized PWS with a blotchy reticulated quality are also sometimes mistaken for CMTC. The residual, persistent, reticulate vascular lesions of CMTC respond poorly to pulsed dye laser treatments and can be associated with a greater risk of scarring than is usually associated with this mode of therapy. Associated port-wine stains, however, are amenable to PDL therapy. Management of extracutaneous associated abnormalities is directed at specific signs or symptoms. Infants with CMTC located in a distribution similar to the port-wine stain of Sturge–Weber syndrome are at higher risk for CNS and ophthalmologic complications and require evaluation.

Verrucous hemangioma and angiokeratoma circumscriptum

Verrucous hemangioma (VH) is a rare congenital vascular anomaly which has historically been classified as a vascular malformation but shows immunohistochemical features of both a vascular tumor and vascular malformation.^98,99 VH presents in infancy and is typically located on the lower extremities but may arise at other sites (Fig. 22.13). It may be a single lesion or grouped. Initially, there are blue to purple soft compressible lesions that develop overlying hyperkeratosis and bleeding over time. In its early stages VH may mimic an infantile hemangioma, venous malformation or combined venous lymphatic malformation. The lesions persist and do not involute. As hyperkeratosis develops, the lesion may mimic angiokeratoma, and capillary-lymphatic–venous malformation or even a pigmented/melanocytic lesion.

Angiokeratoma circumscriptum is another rare congenital vascular anomaly which often occurs on the lower extremities. At birth, it may present as pink-red patches and become increasingly hyperkeratotic with age.^99–101 Histopathologic evaluation of VH reveals verrucous hyperplasia of the epidermis overlying a vascular lesion composed of small sized vessels separated by fibrous and adipose tissue. There is extension into the subcutis and in some cases the fascia. This is particularly important when undertaking removal, since wide excision is required in order to prevent recurrence. These features help to differentiate them from angiokeratoma, which may be congenital or appear later in childhood and are usually small and superficial. Immunohistochemical analysis can reveal focal immunoreactivity for GLUT1 (a marker that is typically seen in infantile hemangiomas)⁹⁹ and negative for staining for lymphatic differentiation and Wilms Tumor 1 transcription factor (WT1). WT1 is typically positive in vascular tumors and negative in vascular malformations.^102,103 The diagnosis of this rare vascular anomaly is best established with clinicopathologic correlation.

Wyburn–Mason, Bonnet–Dechaume–Blanc, and Brégeat syndromes

These rare syndromes are characterized by arteriovenous malformations in the craniofacial area with fast-flow vascular anomalies in the skin (midline or hemifacial), orbit, retina, and brain (thalamus, hypothalamus and optic chiasm). These eponyms are now considered to be synonymous. In infancy, the cutaneous AVM commonly mimics a facial port-wine stain, although it is usually fainter and less well-demarcated than PWS (Fig. 22.10). It is warm on palpation and is sometimes associated with an abnormally increased skin thickness at birth. MR is a helpful noninvasive tool that may be used in infants for the detection of the enlarged tortuous vessels and AV shunting. These findings are more clearly delineated later in life with conventional arteriography. Lesions slowly enlarge over years and may cause distortion of facial features, visual loss, and cerebral hemorrhage.¹⁰⁶

Cobb syndrome

Cobb syndrome (cutaneomeningospinal angiomatosis) is the association of a dermatomal skin vascular malformation (trunk and arm or leg), a fast-flow intramedullary spinal AVM, and a vertebral vascular anomaly in the same segment. This metameric angiomatosis is the truncal counterpart of the syndromic cephalic AVMs. In infancy, this syndrome may be undiagnosed because the cutaneous vascular signs are subtle or are diagnosed as skin capillary malformation. Patients may present with neurologic symptoms in childhood or later in life. Hyperpigmentation has also been described overlying the spinal AVM.^107,108 The diagnosis is often established later, when an abnormal vertebra is incidentally imaged or if neurologic symptoms of spinal cord compression occur. The existing literature on Cobb syndrome in infants needs to be interpreted with caution, given that some case reports of Cobb syndrome in infants actually represent segmental infantile hemangiomas associated with intraspinal hemangiomas or tethered cord.

Hereditary hemorrhagic telangiectasia

Also known as Osler–Weber–Rendu syndrome, hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder with various phenotypes corresponding to at least three distinct genotypes.¹⁰⁹ Genetic testing makes early diagnosis available to relatives in a given affected family. HHT is characterized by skin and mucosal telangiectasia, spontaneous epistaxis and a risk of arteriovenous malformations in lungs, brain, and liver.¹¹⁰ Telangiectasia of the skin, lips, and mouth are not visible during infancy and mucosal and visceral hemorrhages are typically uncommon during this period. However, it is important to note that there are reports of infants of parents with known HHT presenting with intracranial hemorrhage in the neonatal period.¹¹¹

Ataxia–telangiectasia

This is a rare autosomal recessive disease characterized by progressive cerebellar ataxia, telangiectasia, elevated α-fetoprotein levels, B- and T-cell immunodeficiency with sinopulmonary infections, cancer susceptibility (especially hematologic malignancies and breast cancer), sensitivity to ionizing radiation and radiomimetic drugs, and premature aging.¹¹² The onset of telangiectasia in the newborn period is rare, however ocular telangiectasia may be noted in children as young as 1 year of age. In a group of 48 patients, the median age of onset of gait abnormalities was 15 months, and 72 months for telangiectasias. The median age of diagnosis was 78 months, shortly after the appearance of telangiectasia in two-thirds of patients.¹¹³ The mutated gene (ATM) maps to 11q22–23, and more than 400 mutations have been documented in affected individuals.

Hennekam syndrome

Hennekam syndrome, also known as generalized lymphatic dysplasia, is a rare diffuse lymphatic anomaly that is typically characterized by lymphedema of the extremities, which may be progressive and asymmetric, intestinal lymphangiectasia resulting in protein-losing enteropathy, developmental delay and abnormal fascias. Involvement of the pleura, pericardium, kidney and thyroid is reported.^118–120 Autosomal recessive inheritance is suspected and in some cases it has been linked to mutations in the CCBE1 gene.¹²¹ The expansion of the phenotype raises the question of more than one gene defect.

Hereditary cholestasis with lymphedema (Aagenaes syndrome)

Hereditary cholestasis with lymphedema is an autosomal recessive disease that occurs mostly in infants of Norwegian ancestry. Significant leg lymphedema due to lymph vessel hypoplasia that is congenital or develops later in life, requires lifelong treatment. Cholestasis and obstructive jaundice are present at birth and may improve in adulthood, but in childhood, they may be lethal. Children have severe bleeding if vitamin K supplementation is not provided. They also complain of itching, and have growth retardation.

Parkes Weber syndrome

Parkes Weber syndrome (PKWS) is the association of vascular stain, limb overgrowth (length and girth), and a fast-flow vascular anomaly with multiple arteriovenous shunts (Fig. 22.16). It is important to differentiate this disorder from KTS, as the prognosis is different. In rare instances, PKWS is complicated at birth by high-output cardiac failure. In the neonatal period, noninvasive assessment of PKWS is best done using ultrasound/color Doppler and MR angiography. Arteriography is usually not performed in the neonatal period, unless endovascular arterial embolization of the AVFs is mandatory to reduce the arterial overload accountable for congestive heart failure. Thus, KTS is a slow-flow vascular anomaly, whereas PKWS is a fast-flow vascular anomaly, but both can result in hypertrophy of the affected limb. Parkes Weber syndrome may occur as a manifestation of CM-AVM syndrome, therefore it is essential that a complete family history be obtained from affected individuals and genetic testing for RASA1 mutations is recommended.

CLOVES syndrome

CLOVES syndrome refers to congenital lipomatous overgrowth, vascular malformations, epidermal nevi and skeletal anomalies/scoliosis. It is a newly described overgrowth syndrome resulting from post-zygotic activation mutations in the PIK3CA gene.¹³⁰ In CLOVES, the large lipomatous masses are usually present on the trunk and lead to scoliosis of the spine. Other skeletal anomalies include macrodactyly and a widened space between the first and second toes, known as a sandal-gap deformity. Most patients with CLOVES syndrome have vascular malformations, most commonly CM or CLVM, however fast-flow lesions (spinal AVMs) are also described.¹³¹ In the past, patients with CLOVES were often misdiagnosed as having KT or Proteus syndrome, as there is considerable clinical overlap (Fig. 22.17). The identification of similar gene mutations in CLOVES, Proteus and MCAP (see above) suggests a common lineage, where each syndrome results from a mutation within the same molecular pathway (Fig. 22.18). Like many of the complex overgrowth syndromes, screening for Wilms tumor is also recommended.

Proteus syndrome

Proteus syndrome, first described by Wiedemann and colleagues,¹³² is characterized by asymmetric localized overgrowth of various body parts, affecting soft tissues and bones. It is caused by mutations in the AKT1 gene.¹³³ The syndrome may be evident at birth, but a progressive course and mosaic distribution of the lesions are characteristic and necessary for diagnosis.^134,135 The most characteristic features are the asymmetric, disproportionate growth with regional gigantism and cutaneous manifestations, including connective tissue nevus (cerebriform dermal thickening of soles and palms), epidermal nevi, lipomas, café-au-lait spots, and vascular malformations of the slow-flow type, such as extensive CLVMs.^134,135 Visceral benign tumors, mainly lipomas, but tumors in the endocrine glands or CNS, and visceral vascular malformations are also observed. Intelligence is normal in most patients, but learning disabilities are present in one-third. Ophthalmologic and neurologic alterations or seizures have been reported. Surgical reconstruction is the primary treatment for these children. A multidisciplinary approach, including orthopedic management is essential because of discrepancies in limb and foot growth. Excision of lipomas or laser treatment of vascular lesions is sometimes indicated. The differential diagnosis for Proteus syndrome includes KTS, CLOVES, SOLAMEN and MCM/MCAP. Recent advances have led to the discovery of the specific genetic mutations of each of these conditions, where affected genes are involved in the same molecular signaling pathway (AKT1/PIK3CA). AKT1 is activated by loss of function mutations in PTEN, which helps to explain why patients with PTEN mutations (SOLAMEN, Cowden) have some overlapping yet distinct features (Table 22.3, Fig. 22.18).

PTEN hamartoma tumor syndrome

The PTEN gene encodes for a tumor suppressor phosphatase that has been implicated in familial cancer syndromes. The PTEN hamartoma tumor syndrome is the name given recently to this group of familial syndromes, which includes Cowden and Bannayan–Riley–Ruvalcaba syndromes (BRRS). Cowden syndrome is associated with a high risk for the development of cutaneous hamartomas and internal malignancies such as breast, thyroid and endometrial carcinoma. BRRS is an auto­somal dominant disorder characterized by macrocephaly, developmental delay and penile lentigines. Both syndromes are due to mutations in the PTEN gene, which suggests a similar risk for the development of malignancy.¹³⁶ In both syndromes, associated vascular malformations are frequently described and usually consist of high flow, intramuscular vascular anomalies associated with increased adipose tissue. These vascular malformations have been found to be quite specific to PTEN hamartoma tumor syndromes and should prompt investigation, workup and continued monitoring for early-onset malignancies in suspected cases.¹³⁷ See Chapter 29 for further discussion on selected genetic overgrowth syndromes.

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