Macrocephaly–Cutis Marmorata Telangiectatica Congenita Syndrome” Report of 12 New Cases and Support for Revising the Name to Macrocephaly–Capillary Malformations

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OBSERVATION The Misnomer “Macrocephaly–Cutis Marmorata Telangiectatica Congenita Syndrome” Report of 12 New Cases and Support for Revising the Name to Macrocephaly–Capillary Malformations

Dakara Rucker Wright, MD; Ilona J. Frieden, MD; Seth J. Orlow, MD, PhD; Helen T. Shin, MD; Sarah Chamlin, MD; Julie V. Schaffer, MD; Amy S. Paller, MD

Background: The condition known as macrocephaly– stains (PWS), not CMTC. Seven of the 12 patients also cutis marmorata telangiectatica congenita syndrome had centrofacial capillary malformations. In our com- (M-CMTC) is a rare congenital syndrome of unknown prehensive review of 100 previously reported cases, only etiology characterized by macrocephaly and vascular le- 34 were accompanied by photographs that were suffi- sions that have been described as either cutis marmo- ciently clear to review for diagnostic purposes. None had rata or cutis marmorata telangiectatica congenita (CMTC). true CMTC, with most having reticulated PWS or per- Most patients also exhibit facial and limb asymmetry; so- sistent cutis marmorata. matic overgrowth; developmental delay; capillary malformations of the nose, philtrum, and/or upper lip; neu- Conclusions: Reticulated or confluent PWS and persis- rologic abnormalities; syndactyly or polydactyly; tent capillary malformations of the central face, rather craniofacial abnormalities; and joint laxity or soft skin. than CMTC, are the most characteristic cutaneous vascular anomalies seen in so-called M-CMTC syndrome. Observations: We describe 12 patients with this con- The name macrocephaly–capillary malformations (M-CM) dition from tertiary care medical centers (8 cases) and more accurately reflects the features of this syndrome. accrued via an M-CMTC support group Web site (4 cases). All patients showed reticulated or confluent port-wine Arch Dermatol. 2009;145(3):287-293

HE SYNDROME MACRO- Recently, Toriello and Mulliken5 pro- cephaly–cutis marmorata posed that this condition be renamed telangiectatica congenita macrocephaly–capillary malformations (M-CMTC) is character- (M-CM) based on similar observations. We ized by macrocephaly provide further support for a change in the (TϾ95th percentile) and cutaneous vascu- name of this syndrome from M-CMTC to lar anomalies that have been called “cutis M-CM to more accurately describe the as- marmorata telangiectatica congenita sociated vascular anomalies. Further- (CMTC),”1,2 in association with several mi- more, we suggest revised clinical criteria Author Affiliations: nor features.3,4 Making a definitive diag- based on these 112 patients for establish- Department of Dermatology, nosis has been difficult owing to the lack ing a diagnosis of M-CM (Table 1). Henry Ford Hospital, Detroit, of clear criteria, especially precise recog- Michigan (Dr Wright); nition of the associated cutaneous vascu- METHODS Department of Dermatology lar findings. and Pediatrics, University of California, San Francisco We now describe 12 new patients with This study was approved by the institutional re- (Dr Frieden); Department of a diagnosis of M-CMTC syndrome. We view board of Children’s Memorial Hospital, Chi- Dermatology, New York have also reviewed 100 previously re- cago, Illinois (CMH). All possible new cases, as University Medical Center, ported cases of M-CMTC and examined well as those reviewed in the literature, were New York (Drs Orlow and all published photographs of these cases. screened for having M-CMTC if the patients had Schaffer); Department of Based on our own experiences with pa- the major findings of macrocephaly and a vas- Pediatric Dermatology, tients with this condition and review of cular malformation (CTMC or capillary malfor- Hackensack University Medical previously reported cases, we have ob- mation/PWS). In addition to these 2 major cri- Center, Hackensack, New Jersey served that the vascular anomalies are not teria, patients were required to have at least 2 (Dr Shin); and Departments of additional minor characteristics as set forth by Dermatology and Pediatrics, true CMTC but rather capillary malfor- Franceschini et al6 and Robertson et al7 (Table 1). Northwestern University mations in the form of reticulated port- At CMH, the medical charts of all patients with Feinberg School of Medicine, wine stains (PWS) of the torso and a diagnosis of vascular malformation (Interna- Chicago, Illinois (Drs Wright, extremities and centrofacial capillary mal- tional Classification of Diseases, Ninth Revision Chamlin, and Paller). formations (eg, persistent salmon patches). [ICD-9] code 709.1), PWS (ICD-9 code 757.32)

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Major and Minor Clinical Criteria Modified for the Diagnosis of M-CM Present in Our 12 Reported Cases

Patient No./Sex/Age

Criteria 1/M/12 y 2/F/19 mo 3/M/4 y 4/M/15 mo 5/M/4 mo 6/F/2 y Major Criteria (Requires Both) Macrocephaly (Ͼ95th percentile) ϩϩ ϩ ϩϩϩ Capillary malformation (PWS) ϩϩ ϩ ϩϩϩ Minor Criteria (at Least 2) Asymmetry or overgrowth ϩϩ ϩ ϩϩϩ Developmental delay ϩϩ ϩ ϩ−− Midline facial capillary ϩϩ − ϩϩ− malformations Neonatal hypotonia − ϩ −−−− Syndactyly or polydactyly − ϩϩ− ϩϩ Frontal bossing − ϩ −−−− Joint hypermobility, − ϩ −−−− hyperelastic skin Hydrocephalus − − − − − − Additional Findings in Our Patients Upturned Mild Dental malocclusion; Kasabach-Merritt None Macrodactyly nose and ventriculomegaly Wilms tumor, syndrome of L foot, upper lip, with possible hypertrophy of R second associated with a hypertelorism, angelic Chiari type I and third toes, thickened tufted angioma, full lips facies, malformation; skin and prominent wide space headaches doughy ears, creases on plantar between first and hypertelorism surfaces, lipomas on R second toes, wide-spaced toes dorsal foot, macrodactyly, dermatomyofibroma, full lips negative PTEN testing

Patient No./Sex/Age Total No.a Criteria 7/F/4 y 8/F/10 y 9/F/8 mo 10/M/4 y 11/F/3 y 12/F/5 y (%) Major Criteria (Requires Both) Macrocephaly (Ͼ95th percentile) ϩϩϩϩϩϩ12 (100) Capillary malformation (PWS) ϩϩϩϩϩϩ12 (100) Minor Criteria (at Least 2) Asymmetry or overgrowth ϩϩϩϩϩϩ12 (100) Developmental delay ϩϩϩϩϩϩ10 (83) Midline facial capillary − ϩϩ−−ϩ 7 (58) malformations Neonatal hypotonia ϩϩϩϩ− ϩ 6 (50) Syndactyly or polydactyly − ϩ − − − − 5 (42) Frontal bossing ϩϩϩϩ− − 5 (42) Joint hypermobility, −−ϩϩ− ϩ 4 (33) hyperelastic skin Hydrocephalus ϩϩ−−−ϩ 3 (25) Additional Findings in Our Patients Ventriculomegaly, Seizures, Hypertelorism, Twin B; seizures, None Wide space preventricular Arnold-Chiari type low-set ears, syringomyelia between first and contractions and I malformation, wide space with tethered second toes, atrial septal defect syringomyelia, between first cord, wide space macrodactyly of (resolved), spinal lipoma, and second between first and second toes scoliosis, leg macroglossia, high toes, R cheek second toes, cramping, wide arched palate, fuller than L, macrodactyly of space between first hypertelorism, flat flat nasal first 3 toes, and second toes, nasal bridge, flat bridge, PTEN tracheobronchial hypertelorism, full feet, bilateral negative abnormality, high face and lips supernumerary arched palate, digits, scoliosis carotid artery thrill

Abbreviations: L, left; M-CM, macrocephaly–capillary malformation; PWS, port-wine stain; R, right; ϩ and − signs, the presence or absence of a feature, respectively. aMeans total number in which the feature was present.

and CMTC (also ICD-9 code757.32) in the electronic database PWS or CMTC were screened. When information about head cir- were reviewed; in addition, all patients with a Kodachrome (East- cumference was not available in a patient’s medical chart, the pe- man Kodak, Rochester, New York) or electronic photograph of diatrician was contacted to determine the presence or absence of

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Figure 1. Patient 4 at 10 days old, showing a midfacial capillary malformation of the lip, philtrum, and glabella (A). The reticulated port-wine stain (PWS) is extensive on the trunk and extremities. Note the presence of a large tufted angioma on left shoulder (arrow), making the right hemihypertrophy difficult to appreciate. B, By 8 months, the midfacial capillary malformation of the lip, philtrum, and glabella of the patient remain, but the reticulated PWS has considerably faded. The tufted angioma has now been partially excised, allowing one to better appreciate the right hemihypertrophy.

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 (tele- phone 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 interna- tional literature search was performed using the National Li- brary 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 Figure 2. Patient 1 demonstrates the reticulated or telangiectatic port-wine “macrocephaly AND cutis marmorata.”1,2,4,6-34 stain and asymmetry caused by left-sided hemihypertrophy in the macrocephaly–capillary malformation syndrome. RESULTS ing and nearby sites of confluent PWS (Figure 3A and The clinical findings present in our 12 patients are out- B). Patient 6 had widespread PWS on her trunk and up- lined in Table 1. All of our patients had capillary mal- per extremities but a pattern more reminiscent of per- formations (PWS) on their trunk and extremities; none sistent cutis marmorata on her distal lower extremities. had CMTC. More than half (58%) also had a capillary No patient, however, showed as coarse a reticulated pat- malformation on the lip, philtrum, and glabella tern as seen in true CMTC (Figure 3C). (Figure 1). Most of the nonfacial stains showed a re- At least 7 (58%) of our cases had notable fading of the ticulated pattern (Figure 2), but confluent staining was PWS by 2 to 3 years of age. In patient 6, the PWS on her concurrently noted in some patients. For example, pa- upper body faded considerably by 2 years of age. In 2 patients 5 and 9 showed both a reticulated pattern of stain- tients (patients 4 and 9), marked fading was noted as early

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Figure 3. Patient 5 showing the reticulated port-wine stain (PWS) on his arm with its pink to red, fine reticular vascular pattern (A). B, A more confluent PWS is on the trunk. C, For comparison, an example of a true cutis marmorata telangiectatica congenita on the arm of an infant. None of our patients nor previously reported cases of macrocephaly–capillary malformation syndrome showed this dark violaceous, coarse, broad reticular vascular pattern.

as 8 months of age. Interestingly, patient 4 was born with COMMENT a large tufted angioma on the posterior aspect of the left shoulder. His course was complicated by Kasabach- Cutis marmorata telangiectatica congenita is a low-flow Merritt syndrome, necessitating systemic corticosteroid vascular malformation that is characterized by its dis- 1 therapy and partial excision at 6 /2 months of age (Figure 1). tinctive violaceous coarsely reticulated marbled (“mar- All 12 patients had macrocephaly and asymmetry morata”) pattern (Figure 3C).35 It is generally present at caused by hemihypertrophy of the body and/or head. Ten birth, may become more vivid within the first few weeks, of the 12 (83%) had developmental delay, including mild and typically slowly fades thereafter, particularly dur- to moderate motor (9 of 12), speech (5 of 12), and/or ing the first years of life.7,14,28 Cutis marmorata telangi- cognitive (2 of 12) developmental delay; more than 1 type ectatica congenita may be accentuated by cold or cry- of delay was noted in 6 patients. ing,28 but its persistence with warming and its deeper, broader, coarser vasculature distinguish CMTC from cu- REVIEW OF PHOTOGRAPHS tis marmorata, a common infantile physiologic re- OF PREVIOUSLY REPORTED CASES sponse to a cool environment. Persistent cutis marmorata has been reported in Down syndrome, trisomy 18, Of the 100 previously described patients with M-CMTC and Cornelia de Lange syndrome.36-38 It may be associ- in the literature,1,2,4,6-34 only 34* had accompanying pho- ated with ipsilateral limb hypotrophy as well as skin at- tographs that allowed review of the cutaneous vascular rophy and ulceration at lesional sites; glaucoma and de- pattern. None of the photographs showed CMTC. The velopmental delay have rarely been described in vascular malformations in these photographs appeared association with CMTC.14,22,25,28,35 to represent either PWS (reticulated more often than con- The appearance of the vascular malformation of all of fluent) or persistent cutis marmorata. our cases, together with those critically analyzed from the previously reported cases, suggests that the vascular *References 1, 2, 6, 7, 11, 13, 16, 18, 20, 22, 33. anomalies characteristic of this syndrome are not CMTC

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Beckwith- Klippel-Tre´naunay Wiedemann Proteus CLOVE PTEN Hamartoma M-CM CMTC Syndrome Syndrome Syndrome Syndromea Syndrome/BRR Cutaneous Faint, finely Isolated area of PWS usually limited Capillary malformation Occasional Capillary, venous, Occasional capillary reticulated or broad, reticulated to extremity on forehead capillary, and mixed malformations, confluent PWS violaceous malformations vascular venous capillary malformations malformations malformation, typically on extremity Centrofacial Skin and soft-tissue Lymphedema, Linear earlobe crease Epidermal nevi Epidermal nevi Pigmented penile or capillary atrophy with or lymphangiectasis labial macules malformation without ulceration Skin laxity (variable) PWS Venous varicosities, Circular depression on Lipomas, Lipomas Lipomas, other venous helix cerebriform hamartomas malformations hyperplasia/ connective tissue nevi Overgrowth Macrocephaly, No overgrowth; Usually Macroglossia, Progressive severe Hemihypertrophy, Megalencephaly, GI asymmetry, more typically hemihypertrophy macrosomia asymmetric milder polyps, thyroid hemihypertrophy, ipsilateral limb of limb with overgrowth, overgrowth than neoplasms macrosomia atrophy vascular especially of Proteus malformation; distal extremities syndrome more rare is hemiatrophy (Servelle- Martorelle syndrome variant) Extracutaneous Neonatal hypotonia; Localized CMTC, Neonatal syndactyly or rarely has hypoglycemia, polydactyly, extracutaneous omphalocele; hydrocephalus, anomalies; in tumors: Wilms progressive more widespread tumor, adrenal tonsillar CMTC, reported carcinoma, herniation, and anomalies nephroblastoma, other structural include hepatoblastoma, brain glaucoma, and abnormalities, cardiac defects, rhabdomyosarcoma joint laxity, Wilms arterial tumor anomalies, neurologic defects, dystrophic teeth, and spinal cord defects

Abbreviations: BRR, Bannayan-Riley-Ruvalcaba; CLOVE, congenital lipomatous overgrowth, vascular malformations, and epidermal nevi; CMTC, cutis marmorata telangiectatica congenita; GI, gastrointestinal; M-CM, macrocephaly capillary malformations; PWS, port-wine stains. a See article by Sapp et al.39

but rather capillary malformations (PWS). The PWS were ertson et al7 to the term “midline capillary malforma- typically finely reticulated, but some patients showed vari- tion” to more accurately describe the persistent centro- ability, with finely reticulated PWS in some areas, more facial salmon patches that 7 of our 12 patients confluent PWS in other areas, and sometimes coarser PWS demonstrated. Prominent persistent salmon patches are in yet other areas. Furthermore, none of our patients with also a feature of Beckwith-Wiedemann syndrome, an- true CMTC showed macrocephaly and other defining cri- other overgrowth syndrome that is easily distinguished teria. Thus, we have modified a major criterion that de- from M-CM (Table 2). fines the syndrome to be capillary malformation rather The confusion that led previously to use of the name than the original criterion of CMTC.7 We have also modi- M-CMTC to describe the syndrome likely resulted from fied the terms “angiomata” as used by Franceschini et al6 the reticulated appearance of many of the PWS in affected and “midline facial naevus flammeus” as used by Rob- patients and the tendency to fade during infancy and early

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 childhood. Most PWS have a more uniform color with con- CLOVE (congenital lipomatous overgrowth, vascular mal- fluent vascular staining, but they may show a more reticu- formations, and epidermal nevi)39 syndromes (Table 2). lated pattern. Most commonly confluent PWS tend to per- In our case series, most patients were initially misdiag- sist throughout life, often darkening with increasing age. nosed as having KT syndrome. The presence of macro- Interestingly, many of our patients had considerable fad- cephaly, syndactyly, or polydactyly; developmental de- ing of their vascular stains during the first years of life. Some lay; and joint and skin laxity may help to distinguish evolved into a finer, more telangiectatic pattern. Others faded M-CM syndrome from KT syndrome. In contrast, the ve- overall, becoming barely perceptible or disappearing com- nous varicosities and lymphangiectasia may help to dis- pletely in some areas. The pathomechanism for the fading tinguish KT syndrome from M-CM syndrome but may is unclear. In contrast to true CMTC, the reticulated PWS not be evident until later in life. in our patients showed no ulceration or cutaneous atro- The genetic basis for M-CM syndrome is unknown. phy, nor was ipsilateral limb atrophy present. Although Lapuzina et al4 noted that only 44% of the 75 Macrocephaly, a key feature of M-CM syndrome, is cases reviewed were female, suggesting a slight male pre- typically noted at birth and can be progressive. The mac- dominance, only 42% of our patients were male, refut- rocephaly may be associated with several neurologic struc- ing that supposition. Despite the lack of evidence of the tural anomalies, but the severity of structural brain ab- molecular mechanism, a lethal mutation with survival by normalities may not correlate with the degree of somatic mosaicism has been proposed to underlie the vas- macrocephaly.23 Similarly, the extent of the PWS does not cular malformations.13,43 Until the molecular basis of correlate with the severity or number of associated anoma- M-CM syndrome and others, particularly KT syn- lies. Among the described structural abnormalities are drome, is understood, classification must rely on clini- cerebral asymmetry, ventriculomegaly (usually nonob- cal features. structive), Chiari type I malformation, acquired cerebel- In conclusion, our 12 cases, together with those 100 lar tonsillar herniation, cortical dysplasia, and polymi- previously reported in the literature, convincingly dem- crogyria.2,7,8,10,11,13,20 Conway et al11 recently reviewed the onstrate that the vascular anomalies associated with M- neurologic and imaging findings of M-CM in depth and CMTC are not true CMTC but rather PWS (often reticu- emphasized the potentially progressive nature of cen- lated) and persistent central facial vascular stains (salmon tral nervous system disease. Clinical signs that should patches). The term M-CM is accurate and should be cause concern are a rapidly enlarging head; acute or pro- adapted to decrease confusion and aid in the diagnosis. gressive paresis; focal neurologic signs; seizures; apnea, swallowing problems, oculomotor difficulties, and other Accepted for Publication: May 3, 2008. brainstem signs; or lethargy, irritability, headache, or other Correspondence: Amy S. Paller, MD, Department of Der- symptoms of increased intracranial pressure. Conway et matology, 676 N St Clair St, Ste 1600, Chicago, IL 60611- 11 al recommended baseline brain magnetic resonance 2997 ([email protected]). imaging scans at the time of diagnosis with follow-up stud- Author Contributions: Dr Wright had full access to all ies every 6 months until age 2 years with an interval as- the data in the study and takes responsibility for the in- sessment at 3 years. Developmental delay in M-CM is usu- tegrity of the data and the accuracy of the data analysis. ally mild to moderate, but early intervention with speech Study concept and design: Wright, Frieden, Orlow, or physical therapy may be helpful. Although cardiac ar- Chamlin, and Paller. Acquisition of data: Wright, Frieden, rhythmias are rare in patients with M-CM, a baseline elec- Orlow, Shin, Chamlin, Schaffer, and Paller. Analysis and trocardiograph is appropriate. Serial limb length mea- interpretation of data: Wright, Frieden, and Paller. Draft- surements are also necessary to address the orthopedic ing of the manuscript: Wright and Paller. Critical revision aspects of the condition. Because the vascular stains of- of the manuscript for important intellectual content: Wright, ten fade, decisions regarding laser therapy should be in- Frieden, Orlow, Shin, Chamlin, and Schaffer. Adminis- dividualized based on their location, extent, and patient trative, technical, and material support: Wright. Study su- and parental preferences. pervision: Wright, Frieden, Shin, Chamlin, and Paller. Two of the 112 patients, including 1 of our cases, de- Financial Disclosure: None reported 4 veloped Wilms tumor, in comparison to a risk in the gen- Additional Contributions: John Gregory, MD, pediat- eral population of 1 in 10 000. This risk is considerably ric hematologist/oncologist in Morristown, New Jersey, 40,41 higher than in Klippel-Tre´naunay (KT) syndrome, in provided information and pictures for patient 4. We would which 1 case occurred in 1363 patients in the literature and like to thank the families of children with this syn- in none of the 8614 patients in the National Wilms Tu- drome for sharing clinical information for this article. mor Study Group. 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