Cutis marmorata telangiectatica congenita: a literature review

Background Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterised by persistent reticulated marbled erythema. It tends to be associated with cutaneous atrophy, ulcerations and body asymmetry. CMTC is usually reported to be a benign condition; however, associated anomalies are not rare. Here, we have compiled information on published CMTC patients with the aim to evaluate the proposed diagnostic criteria by Kienast et al. and address the clinical manifestations, associated anomalies, differential diagnoses, management and prognosis. Our review is based on a search of the PubMed database which retrieved studies between 1922 and April 2019. The search yielded 148 original articles with a total of 485 patients. Results Of the identified patients, 24.5% had generalised CMTC, 66.8% had localised and 8.7% had a non-specified distribution of CMTC. Associated anomalies were observed in 42.5% of patients, predominantly body asymmetry and neurological defects like seizure and developmental delay. Fewer patients (10.1%) had ophthalmological defects, usually glaucoma. The major criterium “absence of venectasia” was not met in 20.4% of patients. Conclusion We suggest that children with CMTC should be referred to an ophthalmologist for regular follow-up, and children with CMTC affecting the legs should be monitored for leg length discrepancy throughout the growth period. Furthermore, we suggest reconsideration of the major criterium “absence of venectasia” from the proposed diagnostic criteria, and instead include body asymmetry.


Background
Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital vascular anomaly, classified as a simple vascular malformation and subclassified as a capillary malformation (CM) by the International Society for the Study of Vascular Anomalies (ISSVA) [1]. CMTC is described as a persistent reticulated marbled erythema, which blanches with pressure and does not resolve with heating [2,3]. As it affects capillaries and venules, CMTC is characterised as a slow-flow vascular lesion [4][5][6]. The affected cutaneous areas may develop cutaneous atrophy and ulcerations, and may also be associated with body asymmetry. The condition has often been reported as benign; however, associated anomalies such as congenital glaucoma, limb asymmetry and central nervous system involvement are frequently observed, which require the attention of medical professionals [7][8][9][10]. CMTC was first described by the Dutch paediatrician Cato van Lohuizen, who named the condition CMTC [11]. Since then, it has been referred to in the literature under several different terms including congenital generalised phlebectasia [12], naevus vascularis reticularis [13], congenital phlebectasia [14], congenital livedo reticularis [15] and van Lohuizen syndrome [16]. CMTC patients with co-existing Mongolian spots ("blue spots" or dermal melanocytosis) have been described as having phacomatosis pigmentovascularis type V (PPV type V) or phacomatosis cesiomarmorata [17][18][19].
Although the aetiology of CMTC remains unknown, two genetic theories were suggested by Rudolf Happle in 2002, who described the concept of an autosomal lethal mutation surviving by mosaicism and the theory of paradominant inheritance [20]. More recent studies identified GNA11 mutations in skin biopsies from CMTC-affected skin areas [21][22][23]. In two of these studies, the mutation was either not detectable in blood [23] or found at a low level of 0.3% in blood [22]. CMTC is, however, still a clinical diagnosis [7][8][9][10]. Kienast et al. proposed a set of diagnostic criteria, where the presence of three major and two minor criteria out of five was considered indicative of CMTC [3]. The major criteria include: congenital reticulate (marmorated) erythema, absence of venectasia within the affected region at 1 year orof age, and unresponsiveness to local warming. Minor criteria are: fading of erythema within 2 years, telangiectasia within the CMTC-affected area, port-wine stain outside the CMTC-affected areas, ulceration, and cutaneous atrophy. However, these diagnostic criteria have not been validated. Histopathology does not play a role in the diagnosis of CMTC due to unspecific and inconsistent findings in skin biopsies [7,[24][25][26].
In this literature review, we evaluate the proposed criteria of Kienast et al. [3] and address the clinical manifestations, associated anomalies, differential diagnosis, management and prognosis of CMTC.

Methods
A literature search was performed in PubMed using the following keywords: cutis marmorata telangiectatica congenita, Van Lohuizen's syndrome, CMTC, congenital phlebectasia, naevus vascularis reticularis, congenital livedo reticularis, and phacomatosis cesiomarmorata. The MeSH search function in PubMed was also applied. The search retrieved 731 unfiltered articles. All abstracts for the unfiltered articles were reviewed in terms of their relevance to the subject, including synonyms for CMTC. We included articles written in English, German, French, Norwegian, Swedish, Danish and Turkish (Fig. 1).
A total of 193 articles were identified for full-text review. In addition, we searched the reference lists of the identified articles for additional sources, leading to a total of 204 articles for full-text review. A total of 168 articles were deemed relevant for the subject, including In those articles with multiple cases consisting of both true CMTC patients and other capillary malformations such as macrocephaly-capillary malformation (M-CMTC, M-CM or M-CAP), Sturge Weber syndrome etc. only the true CMTC cases were included in the count. All uncertain cases were discussed in the study group, so only true CMTC cases were included in our study.
For each original article, the following variables were registered: gender, ethnicity, presence of the proposed diagnostic criteria of Kienast et al., distribution of skin lesions, associated anomalies, histopathology, family history, treatment, and prognosis.

Patients
We identified 485 CMTC patients with skin lesions described from birth, within the first months of life or with an unspecified duration. Of these patients, 43.2% were male, 51.4% were female and 5.4% were an unspecified gender. The female:male ratio was 1.2:1. The patients represented different ethnicities including Caucasian, Hispanic, Asian, African and Middle Eastern. A total of seven CMTC cases were assumed to be familial [27][28][29][30][31][32].
We found that 24.5% of patients had generalised CMTC, 26.9% of whom had CMTC involving the face. A larger proportion of patients (66.8%) had localised CMTC, and 7.1% of these had CMTC erythema involving the face. Overall, the lower extremities were affected in 60.5% of patients, upper extremities in 25.9%, trunk in 27.5% and hands or feet in 4.9% (Table 2).

Associated anomalies
A total of 206 patients (42.5%) had associated anomalies, 146 patients had no associated anomalies, and for the remaining 133 patients this information was not available. The most frequent anomaly was body asymmetry, seen in 37.7%. This includes asymmetry of the limbs, trunk and face as a result of either hypertrophy or hypotrophy. In addition, 10.1% had neurological defects, where the most frequent symptoms were seizures and developmental delay. The third most frequent anomaly was ophthalmological complications, seen in 9.9% of patients, half of which were congenital glaucoma. Furthermore, 5.2% had cardiovascular defects, 4.5% had Mongolian spots, 3.3% had dysmorphic features, 2.5% had genitourinary defects and 1.0% had endocrinological defects (Table 3).

Glaucoma
Twenty-four (4.9%) of all 485 published CMTC patients had glaucoma. Patients with generalised CMTC had a higher tendency for glaucoma, which was present in 16 (13.4%) out of 119 patients with generalised CMTC. Of the patients with localised CMTC, eight patients (2.5%) had glaucoma out of 324 patients with localised CMTC. Patients with CMTC on the face had the highest frequency of glaucoma, comprising 13 (24%) out of 55 patients with CMTC on the face (Fig. 2).

Leg length discrepancy
Body asymmetry was observed in 37.7% of CMTC patients, and of those, 36.1% had a leg length discrepancy. Of all of the 485 CMTC patients, 13.6% (Fig. 3) had a leg length discrepancy ranging from 1 to 6.8 cm.

Discussion
We applied the proposed diagnostic criteria of Kienast et al. [3] to assess CMTC. One of the major criteria is the absence of venectasia; however, we found that phlebectasia was present in 20.4% of the published CMTC patients, suggesting that this major criteria should be reconsidered.
Evaluating the diagnostic criteria of Kienast et al. in terms of validity is a challenge due to both the retrospective nature of this review and the amount of missing information for the published patients, ranging from 66.0-88.2%. Improvement in the marbled skin appearance over time was described in 143 (29.5%) patients (Table 1), whereas 4.5% did not show improvement, and this information was lacking in the remaining 66.0% of patients. There was a wide age span for when improvement was seen. The literature reported that patients between the ages of 6 weeks to 26 years showed improvement of the skin condition [2,33]; however, many articles did not  specify the exact age at improvement. In several articles, improvement was described after 2 years of age [7,[34][35][36][37]. Patients with no improvement of CMTC were also described [15,17,[38][39][40][41][42][43], but some of these patients had a short follow-up [44][45][46]. Adults with persistent erythema were also reported [27,47,48]. Another issue in the literature was the short follow-up or no follow-up, which makes it challenging to describe the precise prognosis of CMTC. In the literature, asymmetry was found to be the most frequent anomaly, comprising 37.7%, while the minor criteria "improvement of erythema" should be further investigated as a part of CMTC in future prospective studies.

Associated anomalies
The definition of associated anomalies varies in the literature. Some authors regard cutaneous atrophy, ulcerations and port-wine stains as associated anomalies rather than integral parts of the syndrome, therefore the percentage of CMCT patients reported to have associated anomalies ranges from 18.8 to 80% [3,7,8,10,24,29,49]. In this study, we defined associated anomalies as those not included in the proposed diagnostic criteria (Table 3), and found that 42.5% of the CMTC patients had associated anomalies. However, this finding might be an overestimation due to publication bias, and it might not reflect the true nature of CMTC. We recognise that many findings of associated anomalies listed in Table 3 may be coincidental findings.

Glaucoma
There was a relatively high presence of glaucoma, reported in 4.9% of patients. In patients with generalised CMTC, the proportion increased to 13.4%, and in patients with skin lesions on the face, the proportion was 24%. Even though glaucoma is not the most frequent anomaly, it can have severe consequences including decreased vision and, in the worst case, blindness, which may occur if it is not discovered in time. Most CMTC patients were diagnosed with glaucoma in early infancy [50][51][52][53][54]; however, two patients were described to have late-onset glaucoma at the age of 3 and 9 years despite earlier ophthalmological check-ups [55,56]. The nature of this rare condition and the consequences of overlooked glaucoma suggest that CMTC patients should be referred to and followed up by an ophthalmologist.

Leg length discrepancy
Body asymmetry was the most frequent associated anomaly, and 13.6% of all reported patients had a leg length discrepancy. This defect can have functional consequences if not treated timely. One patient was described to have a leg length discrepancy that resolved spontaneously within the first 9 months of life [46]. Another patient, however, had a leg length discrepancy which progressed over time at 6 and 9 months of followup [57]. In another patient, growth retardation of one leg was first noticed at 6 months of age [58]. This suggests that children with CMTC affecting the lower extremities should be monitored for leg length discrepancy during childhood.
A large study from 2014 including a total of 29 patients with CMTC and leg length discrepancy suggested a treatment algorithm where leg length discrepancy greater than 2 cm should be treated with epiphysiodesis [9].

Differential diagnosis
The characteristic marbled erythema of CMTC can also be seen in other conditions such as those listed in Table 4. Some of these differential diagnoses have a more severe prognosis and require different treatment approaches, such as Klippel-Trenaunay syndrome and macrocephalycapillary malformation, which highlights the importance of a correct diagnosis.

Genetics
The recent genetic finding of GNA11 mutation in affected skin [21][22][23] confirms that CMTC is possibly a postzygotic mosaic condition. This explains the low incidence of familial cases. Two other studies have reported autosomal recessive inherited homozygous mutations in the ARL6IP6 gene in patients with CMTC and stroke [38,63]. The consequence of the ARL6IP6 gene mutation remains unknown, although it is thought to be a genetic susceptibility factor for younger patients with ischemic stroke [64].

Treatment and follow-up
When suspicion of CMTC is raised, it is recommended to perform a careful evaluation of the patient for associated anomalies, ideally in a multidisciplinary team with a paediatrician, dermatologist, ophthalmologist and, eventually, an orthopaedic surgeon.
Two reports described effective laser therapy for erythema and ulceration [23,65], while other reports stated no effect of laser treatment [25,66]. A single case of Klippel-Trenaunay syndrome [1] Soft tissue and bone hypertrophy with port-wine stain, lymphangioma, and/or varicosities typically involving one extremity. Associated with PIK3CA mutation.
Sturge-Weber syndrome [1] Facial port-wine stain, vascular malformation in eyes and meninges, and calcium deposits in the brain. Many of the patients have mutations in the GNAQ gene.
Adams-Oliver syndrome [61] Cardiac malformations, limb defects, aplasia cutis congenita of the scalp and abnormalities of the cranium.
ineffective left brachial sympathectomy can also be found in the literature [27]. Finally, another patient received sympathetic nerve blockade combined with vasodilator treatment with good efficacy for pain in CMTCaffected areas [67]. Due to the limited number of studies, we cannot recommend a treatment strategy for skin lesions in CMTC.

Conclusion
CMTC is a relatively benign disorder on its own, which does not usually require treatment. However, health care professionals should be aware of the frequently associated anomalies, such as glaucoma and leg length discrepancy, which may have serious consequences if not recognised and treated. We suggest that children with CMTC should be referred to an ophthalmologist after birth for regular check-ups for glaucoma, and that children with CMCT on the legs should be regularly monitored for leg length discrepancy during childhood until the end of the growth period (Fig. 4). Furthermore, we suggest reconsideration of the major criteria "absence of venectasia" from the proposed diagnostic criteria, and propose that body asymmetry should be taken into consideration. Finally, the genetic research in this area is evolving, most recently with the identification of mutations in the GNA11 gene. Further studies should clarify whether molecular genetics should be part of the diagnostic process in the future.