The Misnomer “Macrocephaly–Cutis Marmorata Telangiectatica Congenita Syndrome”: Title and subTitle BreakReport of 12 New Cases and Support for Revising the Name to Macrocephaly–Capillary Malformations FREE

The syndrome macrocephaly–cutis marmorata telangiectatica congenita (M-CMTC) is characterized by macrocephaly (>95th percentile) and cutaneous vascular anomalies that have been called “cutis marmorata telangiectatica congenita (CMTC),”^{1 - 2} in association with several minor features.^{3 - 4} Making a definitive diagnosis has been difficult owing to the lack of clear criteria, especially precise recognition of the associated cutaneous vascular findings.

We now describe 12 new patients with a diagnosis of M-CMTC syndrome. We have also reviewed 100 previously reported cases of M-CMTC and examined all published photographs of these cases. Based on our own experiences with patients with this condition and review of previously reported cases, we have observed that the vascular anomalies are not true CMTC but rather capillary malformations in the form of reticulated port-wine stains (PWS) of the torso and extremities and centrofacial capillary malformations (eg, persistent salmon patches). Recently, Toriello and Mulliken⁵ proposed that this condition be renamed macrocephaly–capillary malformations (M-CM) based on similar observations. We provide further support for a change in the name of this syndrome from M-CMTC to M-CM to more accurately describe the associated vascular anomalies. Furthermore, we suggest revised clinical criteria based on these 112 patients for establishing a diagnosis of M-CM (Table 1).

This study was approved by the institutional review board of Children's Memorial Hospital, Chicago, Illinois (CMH). All possible new cases, as well as those reviewed in the literature, were screened for having M-CMTC if the patients had the major findings of macrocephaly and a vascular malformation (CTMC or capillary malformation/PWS). In addition to these 2 major criteria, patients were required to have at least 2 additional minor characteristics as set forth by Franceschini et al⁶ and Robertson et al⁷ (Table 1). At CMH, the medical charts of all patients with a diagnosis of vascular malformation (International Classification of Diseases, Ninth Revision [ICD-9] code 709.1), PWS (ICD-9 code 757.32) and CMTC (also ICD-9 code757.32) in the electronic database were reviewed; in addition, all patients with a Kodachrome (Eastman Kodak, Rochester, New York) or electronic photograph of PWS or CMTC were screened. When information about head circumference was not available in a patient's medical chart, the pediatrician was contacted to determine the presence or absence of macrocephaly. Other features were tallied if both a vascular malformation and macrocephaly were confirmed. Two patients were identified based on these measures. At sites other than CMH, patients’ conditions were evaluated based on author recall (6 patients). Patients included from the M-CMTC support group Web site were evaluated based on information from the parents (telephone conversation) and pediatrician (medical records), as well as photographs (4 patients).

Photographs of all cases were reviewed by 3 of us D.R.W., I.J.F., and A.S.P.) to characterize the vascular anomalies. An international literature search was performed using the National Library of Medicine PubMed database of the National Institutes of Health (covering the period 1966 through fall 2006) using the terms “macrocephaly–cutis marmorata telangiectatica congenita,” “macrocephaly AND cutis marmorata telangiectatica congenita,” “macrocephaly AND cutis marmorata telangiectatica congenita syndrome,” “M-CMTC,” “macrocephaly AND CMTC,” and “macrocephaly AND cutis marmorata.”^{1 - 2 ,4 ,6 - 34}

The clinical findings present in our 12 patients are outlined in Table 1. All of our patients had capillary malformations (PWS) on their trunk and extremities; none had CMTC. More than half (58%) also had a capillary malformation on the lip, philtrum, and glabella (Figure 1). Most of the nonfacial stains showed a reticulated pattern (Figure 2), but confluent staining was concurrently noted in some patients. For example, patients 5 and 9 showed both a reticulated pattern of staining and nearby sites of confluent PWS (Figure 3A and B). Patient 6 had widespread PWS on her trunk and upper extremities but a pattern more reminiscent of persistent cutis marmorata on her distal lower extremities. No patient, however, showed as coarse a reticulated pattern as seen in true CMTC (Figure 3C).

At least 7 (58%) of our cases had notable fading of the PWS by 2 to 3 years of age. In patient 6, the PWS on her upper body faded considerably by 2 years of age. In 2 patients (patients 4 and 9), marked fading was noted as early as 8 months of age. Interestingly, patient 4 was born with a large tufted angioma on the posterior aspect of the left shoulder. His course was complicated by Kasabach-Merritt syndrome, necessitating systemic corticosteroid therapy and partial excision at 6½ months of age (Figure 1).

All 12 patients had macrocephaly and asymmetry caused by hemihypertrophy of the body and/or head. Ten of the 12 (83%) had developmental delay, including mild to moderate motor (9 of 12), speech (5 of 12), and/or cognitive (2 of 12) developmental delay; more than 1 type of delay was noted in 6 patients.

Of the 100 previously described patients with M-CMTC in the literature,^{1 - 2 ,4 ,6 - 34} only 34^{1 - 2 ,6 - 7 ,11 ,13 ,16 ,18 ,20 ,22 ,33} had accompanying photographs that allowed review of the cutaneous vascular pattern. None of the photographs showed CMTC. The vascular malformations in these photographs appeared to represent either PWS (reticulated more often than confluent) or persistent cutis marmorata.

Cutis marmorata telangiectatica congenita is a low-flow vascular malformation that is characterized by its distinctive violaceous coarsely reticulated marbled (“marmorata”) pattern (Figure 3C).³⁵ It is generally present at birth, may become more vivid within the first few weeks, and typically slowly fades thereafter, particularly during the first years of life.^{7 ,14 ,28} Cutis marmorata telangiectatica congenita may be accentuated by cold or crying,²⁸ but its persistence with warming and its deeper, broader, coarser vasculature distinguish CMTC from cutis marmorata, a common infantile physiologic response to a cool environment. Persistent cutis marmorata has been reported in Down syndrome, trisomy 18, and Cornelia de Lange syndrome.^{36 - 38} It may be associated with ipsilateral limb hypotrophy as well as skin atrophy and ulceration at lesional sites; glaucoma and developmental delay have rarely been described in association with CMTC.^{14 ,22 ,25 ,28 ,35}

The appearance of the vascular malformation of all of our cases, together with those critically analyzed from the previously reported cases, suggests that the vascular anomalies characteristic of this syndrome are not CMTC but rather capillary malformations (PWS). The PWS were typically finely reticulated, but some patients showed variability, with finely reticulated PWS in some areas, more confluent PWS in other areas, and sometimes coarser PWS in yet other areas. Furthermore, none of our patients with true CMTC showed macrocephaly and other defining criteria. Thus, we have modified a major criterion that defines the syndrome to be capillary malformation rather than the original criterion of CMTC.⁷ We have also modified the terms “angiomata” as used by Franceschini et al⁶ and “midline facial naevus flammeus” as used by Robertson et al⁷ to the term “midline capillary malformation” to more accurately describe the persistent centrofacial salmon patches that 7 of our 12 patients demonstrated. Prominent persistent salmon patches are also a feature of Beckwith-Wiedemann syndrome, another overgrowth syndrome that is easily distinguished from M-CM (Table 2).

The confusion that led previously to use of the name M-CMTC to describe the syndrome likely resulted from the reticulated appearance of many of the PWS in affected patients and the tendency to fade during infancy and early childhood. Most PWS have a more uniform color with confluent vascular staining, but they may show a more reticulated pattern. Most commonly confluent PWS tend to persist throughout life, often darkening with increasing age. Interestingly, many of our patients had considerable fading of their vascular stains during the first years of life. Some evolved into a finer, more telangiectatic pattern. Others faded overall, becoming barely perceptible or disappearing completely in some areas. The pathomechanism for the fading is unclear. In contrast to true CMTC, the reticulated PWS in our patients showed no ulceration or cutaneous atrophy, nor was ipsilateral limb atrophy present.

Macrocephaly, a key feature of M-CM syndrome, is typically noted at birth and can be progressive. The macrocephaly may be associated with several neurologic structural anomalies, but the severity of structural brain abnormalities may not correlate with the degree of macrocephaly.²³ Similarly, the extent of the PWS does not correlate with the severity or number of associated anomalies. Among the described structural abnormalities are cerebral asymmetry, ventriculomegaly (usually nonobstructive), Chiari type I malformation, acquired cerebellar tonsillar herniation, cortical dysplasia, and polymicrogyria.^{2 ,7 - 8 ,10 - 11 ,13 ,20} Conway et al¹¹ recently reviewed the neurologic and imaging findings of M-CM in depth and emphasized the potentially progressive nature of central nervous system disease. Clinical signs that should cause concern are a rapidly enlarging head; acute or progressive paresis; focal neurologic signs; seizures; apnea, swallowing problems, oculomotor difficulties, and other brainstem signs; or lethargy, irritability, headache, or other symptoms of increased intracranial pressure. Conway et al¹¹ recommended baseline brain magnetic resonance imaging scans at the time of diagnosis with follow-up studies every 6 months until age 2 years with an interval assessment at 3 years. Developmental delay in M-CM is usually mild to moderate, but early intervention with speech or physical therapy may be helpful. Although cardiac arrhythmias are rare in patients with M-CM, a baseline electrocardiograph is appropriate. Serial limb length measurements are also necessary to address the orthopedic aspects of the condition. Because the vascular stains often fade, decisions regarding laser therapy should be individualized based on their location, extent, and patient and parental preferences.

Two of the 112 patients, including 1 of our cases, developed Wilms tumor,⁴ in comparison to a risk in the general population of 1 in 10 000. This risk is considerably higher than in Klippel-Trénaunay (KT) syndrome,^{40 - 41} in which 1 case occurred in 1363 patients in the literature and in none of the 8614 patients in the National Wilms Tumor Study Group. The risk in M-CM is only slightly less than the 3.3% occurrence in patients with Beckwith-Weidemann syndrome in the first 4 years of life (giving a relative risk of Wilms tumor of 816).⁴² We would recommend serial abdominal sonography (every 3-6 months through the first 7 years of life) in patients with M-CM syndrome and hemihypertrophy.

Features of M-CM syndrome may overlap with manifestations of other overgrowth syndromes with vascular malformations, particularly KT syndrome, and less commonly with Proteus, Bannayan-Riley-Ruvalcaba, and CLOVE (congenital lipomatous overgrowth, vascular malformations, and epidermal nevi)³⁹ syndromes (Table 2). In our case series, most patients were initially misdiagnosed as having KT syndrome. The presence of macrocephaly, syndactyly, or polydactyly; developmental delay; and joint and skin laxity may help to distinguish M-CM syndrome from KT syndrome. In contrast, the venous varicosities and lymphangiectasia may help to distinguish KT syndrome from M-CM syndrome but may not be evident until later in life.

The genetic basis for M-CM syndrome is unknown. Although Lapuzina et al⁴ noted that only 44% of the 75 cases reviewed were female, suggesting a slight male predominance, only 42% of our patients were male, refuting that supposition. Despite the lack of evidence of the molecular mechanism, a lethal mutation with survival by somatic mosaicism has been proposed to underlie the vascular malformations.^{13 ,43} Until the molecular basis of M-CM syndrome and others, particularly KT syndrome, is understood, classification must rely on clinical features.

In conclusion, our 12 cases, together with those 100 previously reported in the literature, convincingly demonstrate that the vascular anomalies associated with M-CMTC are not true CMTC but rather PWS (often reticulated) and persistent central facial vascular stains (salmon patches). The term M-CM is accurate and should be adapted to decrease confusion and aid in the diagnosis.

Correspondence: Amy S. Paller, MD, Department of Dermatology, 676 N St Clair St, Ste 1600, Chicago, IL 60611-2997 (apaller@northwestern.edu).

Accepted for Publication: May 3, 2008.

Author Contributions: Dr Wright had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wright, Frieden, Orlow, Chamlin, and Paller. Acquisition of data: Wright, Frieden, Orlow, Shin, Chamlin, Schaffer, and Paller. Analysis and interpretation of data: Wright, Frieden, and Paller. Drafting of the manuscript: Wright and Paller. Critical revision of the manuscript for important intellectual content: Wright, Frieden, Orlow, Shin, Chamlin, and Schaffer. Administrative, technical, and material support: Wright. Study supervision: Wright, Frieden, Shin, Chamlin, and Paller.

Financial Disclosure: None reported

Additional Contributions: John Gregory, MD, pediatric hematologist/oncologist in Morristown, New Jersey, provided information and pictures for patient 4. We would like to thank the families of children with this syndrome for sharing clinical information for this article.