Ophthalmic Genetics

ISSN: 1381-6810 (Print) 1744-5094 (Online) Journal homepage: https://www.tandfonline.com/loi/iopg20

Cutis marmorata telangiectatica congenita: a

focus on its diagnosis, ophthalmic anomalies, and
possible etiologic factors

Matthew S. Elitt, Joan E. Tamburro, Rocio T. Moran & Elias Traboulsi

To cite this article: Matthew S. Elitt, Joan E. Tamburro, Rocio T. Moran & Elias Traboulsi (2020):
Cutis marmorata telangiectatica congenita: a focus on its diagnosis, ophthalmic anomalies, and
possible etiologic factors, Ophthalmic Genetics, DOI: 10.1080/13816810.2020.1744018

To link to this article: https://doi.org/10.1080/13816810.2020.1744018

Published online: 31 Mar 2020.

Submit your article to this journal

Article views: 14

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iopg20
OPHTHALMIC GENETICS
https://doi.org/10.1080/13816810.2020.1744018

REVIEW

Cutis marmorata telangiectatica congenita: a focus on its diagnosis, ophthalmic

anomalies, and possible etiologic factors
a
Matthew S. Elitt , Joan E. Tamburrob,c, Rocio T. Morand, and Elias Traboulsi e

a
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; bDepartment of
Pediatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA; cDepartment of Dermatology, Cleveland Clinic Foundation, Cleveland, Ohio, USA;
d
Division of Genetics and Genomics, The MetroHealth System, Cleveland, Ohio, USA; eCole Eye Institute, Cleveland Clinic Foundation, Cleveland,
Ohio, USA

ABSTRACT ARTICLE HISTORY

Purpose: Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder typified by Received August 26, 2019
localized or generalized cutaneous vascular anomalies, which dissipate over time. We review the Revised January 28, 2020
diagnostic approach to CMTC and present a comprehensive examination of its ocular manifestations. Accepted March 3, 2020
Additionally, we offer recommendations for the ophthalmologic workup for patients with CMTC. Finally, KEYWORDS
we examine the possible causes of CMTC and summarize the current efforts to establish an etiologic Cutis marmorata
mechanism for this disease. telangiectatica congenita;
Methods: Thirty-three published cases of CMTC with ocular anomalies are examined in detail. CMTC; ophthalmic; review;
Results: CMTC is diagnosed based on a specific set of congenital cutaneous symptoms, principally ocular; glaucoma;
congenital reticular erythema that is unresponsive to local warming and absence of venectasia within ophthalmology; retina;
the skin lesions. Ocular findings are not currently employed in this diagnostic process, likely due to an posterior segment; genetic
incomplete understanding into their presentation, frequency, and natural history. We show that the
majority of ophthalmic manifestations are congenital, with glaucoma and posterior segment anomalies,
consisting of retinal perfusion defects and vascular abnormalities, as the most frequently reported
findings. Typical ophthalmic medical and surgical interventions appear to be effective for management
of these CMTC-related pathology. Unfortunately, the etiology and pathophysiology of CMTC remains
unknown, which obfuscates efforts to identify, examine, and initiate treatment in patients.
Conclusions: While the ophthalmic community has traditionally viewed glaucoma as the classic ocular
anomaly of CMTC, this dataset advocates for the prompt investigation of posterior segment abnormal-
ities as well. However, our understanding of CMTC’s ocular anomalies is complicated by a lack of
reporting and/or incomplete (or nonexistent) ophthalmic examinations, and we strongly encourage
comprehensive ophthalmic examinations for all CMTC patients at the time of diagnosis, followed by
appropriate screening and surveillance throughout life. We believe these recommendations will spur
additional data and disease insights that may be useful for future refinements to CMTC diagnostic
algorithms.

Introduction
Cutis marmorata telangiectatica congenita (CMTC, OMIM
#219250) is a sporadic, congenital disorder characterized by
cutaneous vascular abnormalities that typically occur in
a localized distribution (1). The first case was documented
in 1922 by the Dutch female pediatrician Cato van Lohuizen
(2), but only ~300 cases have been described since that time
(3,4). The precise etiology of CMTC remains elusive, and
various genetic and non-genetic mechanisms have been sug-
gested (5). No defining histopathological features have been
identified (6,7), and the diagnosis is currently based on its
cutaneous clinical features (4,5). Unfortunately overlap of
CMTC’s clinical signs with several other disorders, including
Klippel-Trenaunay syndrome, and Sturge-Weber syndrome,
present challenges for the diagnosing clinician (3,5).
Additionally CMTC is quite rare, further complicating the
development of a comprehensive profile of its clinical fea-
tures – including its ocular abnormalities.
In this review we will discuss the current diagnostic
approach for CMTC and delineate conditions mimicking
this disorder. We will also detail the ocular manifestations
that have been reported in patients with CMTC and present
recommendations to standardize the ophthalmologic workup
for these patients. Finally we will evaluate the possible causes
of CMTC and provide information on current genetic
research studies for this condition.
Diagnostic approach to CMTC
CMTC is diagnosed clinically, typically at birth or in the early
postnatal period based on the pentad of cutis marmorata
(Figure 1), telangiectasia, phlebectasia, ulceration, and gradual
symptom improvement (2,8). In 2009 Kienast and Hoeger
further refined these criteria using a cohort of 27 CMTC
patients as well as previously published CMTC cases (4).
They proposed a diagnosis of CMTC based a collection of

CONTACT Elias Traboulsi traboue@ccf.org Cole Eye Institute, Cleveland Clinic Foundation, I32, 9500 Euclid Avenue, Cleveland, OH 44106
© 2020 Taylor & Francis Group, LLC
2 M. S. ELITT ET AL.

unclear if these descriptions merely represent misclassified

disease or bona fide CMTC variants (3–5).
Several disorders can possess CMTC-like features, including
Trisomy 21, Trisomy 18, Cornelia de Lange syndrome, and Divry-
Van Bogaert syndrome (9). While these syndromes display unam-
biguous, disease-defining features that allow for straightforward
identification and diagnosis, several other disorders can exhibit
considerable symptom overlap with CMTC, including Adams-
Oliver syndrome, Bockenheimer’s syndrome, Klippel-Trenaunay
syndrome, megalencephaly–capillary malformations, neonatal
lupus erythematous, phacomatosis pigmentovascularis type V,
physiologic cutis marmorata, and Sturge-Weber syndrome.
Correct discrimination of these various disorders from CMTC
necessitates careful adherence to disease-specific diagnostic cri-
teria, including disease-defining genetic and clinical features
(Table 2). A more holistic description of CMTC’s clinical findings,
Figure 1. A photo of a patient with CMTC highlighting the characteristic including rarer disease manifestations, would likely enhance the
marbled cutaneous appearance. identification and diagnosis of this disorder. Additionally,
a complete appreciation of these rarer findings may prevent
secondary sequalae related to these pathologies.
Table 1. Kienast & Hoeger’s proposed diagnostic algorithm for CMTC.
Major criteria Minor criteria
Ocular anomalies in CMTC
at least 2 required for CMTC
all required for CMTC diagnosis diagnosis We reviewed all published reports and, after excluding cases
(I) Congenital reticular erythema, unresponsive (1) Fading of erythema that likely represented distinct disorders mimicking CMTC,
to local warming within 2 years
(2) Port wine stain outside
identified 33 CMTC patients who displayed ocular abnorm-
(II) Absence of venectasia within the lesions of lesions alities. We list these cases in chronological order of publica-
(3) Atrophy within lesion tion date, and detail the age of the patient at the time of
(4) Telangiectasia
(5) Ulceration
discovery of the ocular finding, their sex, the ocular findings
associated with their disease, and the medical or surgical
intervention (Table 3). In addition to these reports we have
observed a CMTC patient with similar posterior segment
several major and minor clinical features (Table 1). findings (Figure 2).
Interestingly, their assessment also noted several systemic
features associated with CMTC including body asymmetry,
additional vascular abnormalities, neurologic symptoms, syn- Major insights into CMTC’s ocular manifestations
dactyly, and ocular abnormalities, although the latter was Prevalence and types of ocular findings
noted to be observed infrequently (4). Since many of Table 3 provides a comprehensive dataset regarding specific ocu-
CMTC’s clinical features overlap with other disorders it is lar findings and their frequency in CMTC. Glaucoma, regarded as

Table 2. Conditions that mimic the clinical features of CMTC.

Condition
Adams-Oliver syndrome
Bockenheimer’s syndrome
(genuine diffuse phlebectasia)
Klippel-Trenaunay syndrome
Megalencephaly – capillary
malformations
Neonatal lupus erythematous
Phacomatosis
pigmentovascularis type V
Physiologic cutis marmorata
Sturge-Weber syndrome
*Italicized clinical findings indicate overlap with CMTC’s hallmark features (as indicated in Table 1).
Definitive or potential causes Characteristic clinical findings
ARHGAP31, RBPJ, EOGT, Major: Terminal transverse limb defects, aplasia cutis congenita, family history
NOTCH1, DLL4, & DOCK6 (10) Minor: CMTC, cardiac defects, vascular anomalies
Other: Neurological anomalies, intellectual disability, developmental delay, seizures, ocular
findings (11)
Unknown Progressive, painful venectasias that typically occur in a single limb (4)
Mosaic PIK3CA mutations (12) Port wine stain, varicose veins or venous malformations, & hypertrophy of bone and/or soft
tissues (13)
Mosaic PIK3CA mutations (14) Major: Macrocephaly, CMTC, & port wine stain
Minor: Asymmetry or overgrowth, developmental delay, intellectual disability,
hydrocephalus, frontal bossing, midline facial capillary malformations, syn- or polydactyl,
joint hypermobility, hyperelastic skin, & neonatal hypotonia (15–17)
Transplacental, maternal Self-limited, annular erythematous or polycystic plaques, periorbital erythema, cutis
autoantibodies (18) marmorata, cardiac anomalies, hepatic dysregulation, hematologic abnormalities,
neurological findings, & splenic symptoms (18)
Unknown Epidermal nevi, dermal melanocytosis, CMTC, & mongolian spots (19)
Unknown Congenital reticular erythema, unresponsive to local warming (4)
Activating mosaic mutations in Port-wine stain, leptomeningeal angioma, ocular vascular abnormalities, glaucoma, seizures,
GNAQ (20) stroke, & intellectual disability (20)
 OPHTHALMIC GENETICS 3

Table 3. Thirty-three reported CMTC cases with ocular findings.

Age Sex Ocular finding(s) Intervention Reference
3 months F Congenital glaucoma (bilateral, onset at 14 weeks); Goniotomy- goniopuncture → repeat procedure for one Petrozzi et al. (10)
corneal edema; corneal opacity eye for glaucoma
2.5 years F Right eye: Glaucoma (unilateral, detected at 2.5 years old, Trabeculectomy for glaucoma Sato et al. (11)
measured with a Perkins tonometer); buphthalmos
3 days F Right eye: Congenital glaucoma (unilateral, measured Trabeculectomy → repeat procedure for glaucoma Sato et al. (11)
with a Perkins and Schiotz tonometer); buphthalmos;
epithelial & stromal corneal edema; corneal opacity
At birth M Congenital glaucoma (unilateral) Goniotomy for glaucoma Vazquez et al. (12)
1 month M Congenital glaucoma (bilateral) NR Picascia & Esterly (13)
NR NR Glaucoma (onset and distribution NR); abnormal filtration NR Lynch (14)
angle
NR NR Glaucoma (onset and distribution NR); abnormal filtration NR Lynch (14)
angle
2 months M Congenital glaucoma (unilateral, measured with a Schiotz Trabeculectomy for glaucoma Miranda et al. (15)
tonometer); corneal edema
At birth F Right eye: Neovascular, congenital glaucoma (by Schiotz Right eye: Lensectomy and vitrectomy to prevent or treat Shields et al. (16)
tonometry); congenital retinaldetachment; leukocoria; a retinal detachment → enucleation due to hyphema after
surgery
iris neovascularization; persistent pupillary membrane; Left eye: Atropine & corticosteroids for hyphema
iridolenticular adhesions Left eye: Corneal opacity;
leukocoria; iris neovascularization with secondary
hyphema; ectropion iridis
At birth M Congenital glaucoma (unilateral); corneal edema; Trabeculectomy → filtering operation for glaucoma (note: Kremer et al. (17)
buphthalmos nonexplosive suprachoroidal hemorrhage after surgery)
At birth F Congenital glaucoma (unilateral); corneal opacity; Pilocarpine and trabeculectomy → repeat trabeculectomy Mayatepek et al. (18)
heterochromia iridum secondary to anterior layer dysplasia for glaucoma
of the iris
7–12 years* M Glaucoma (onset and distribution NR) NR Pehr & Moroz (19)
3 weeks M Congenital glaucoma (bilateral, measured by goniometry) Trabeculectomy → repeat trabeculectomy and implant Weilepp & Eichenfield
placement for glaucoma (20)
At birth M Congenital glaucoma (distribution NR) None (infant expired) Mu et al. (21)
Left eye: Retinal detachment
Right eye: Telangiectasia
3 years F Right eye: Retinal detachment; peripheral retinal Laser ablation of extraretinal vasculature; vitrectomy (with Pendergast et al. (22)
avascularity and nonperfusion with fibrovascular plasmin adjunct) and
proliferation; subretinal
exudates; dragging of retinal vessels; alterations of membrane peeling to reattach retina Post-trauma event:
macular retinal pigment epithelium Lensectomy, vitrectomy, and membrane peeling for
Left eye: Peripheral retinal avascularity; retinal folds; vitreous hemorrhage, retinal folds, and adherent blood to
dragging of retinal vessels across optic disc; fibrovascular posterior lens capsule
proliferation; subretinal fluid; macular pigmentary
abnormalities
NR F Granular pigmentary abnormalities in retina NR Devillers et al. (23)
NR M Small optic discs NR Devillers et al. (23)
NR M Persistent hyaloid artery NR Devillers et al. (23)
NR NR Congenital glaucoma (unilateral) Trabeculectomy & filtering operation for glaucoma Amitai et al. (1)
9 years M Glaucoma (bilateral, onset at 9 years old, measured by Topical anti- hypertensive therapy→ drainage surgery with Murphy et al. (24)
Tono-pen); optic disc cupping; dilated scleral vessels; double plate Molteno implants with once daily timolol
pigmented and amorphous trabecular meshwork 0.5% for glaucoma
4 months F Congenital glaucoma (bilateral, measured with a Schiotz Trabeculectomy → twice daily timolol 0.5% → 3x Spitzer et al. (25)
tonometer); enlarged corneal diameter; persistent uveal cyclocryocoagulation→ 2x cyclodestructive interventions &
tissue; corneal clouding 2x repeat trabeculectomy with mitomycin C (left eye) for
glaucoma
11 months F Retinal Microaneurysms; telangiectatic vessels; Laser photocoagulation for areas of nonperfusion Soohoo et al. (26)
vessel branching abnormalities; peripheral nonperfusion
5 days F Congenital glaucoma (unilateral) Trabeculectomy for glaucoma De Maio et al (3)
16 years F Peripheral retinal nonperfusion with neovascularization; Laser photocoagulation for areas of neovascularization Sassalos et al. (27)
peripheral lattice degeneration; lacy pattern of episcleral & and nonperfusion
endoscleral pigmentation
41 years F Optic disc drusen; peripheral retinal nonperfusion with Laser photocoagulation for areas of nonperfusion and Taleb et al. (28)
neovascularization; cataract neovascularization & cataract surgery
2 weeks F Both eyes (at 2 weeks): Retinal avascularity with lacy Both eyes: Laser photocoagulation for areas of Dedania et al.(29)
pattern of capillary dropout; peripheral nonperfusion; nonperfusion, followed by repeat procedure
retinal venous dilation; retinal venous loops; terminal buds
with retinal hemorrhages; foveal hypoplasia; granular
appearance of macula; high iris insertion; immature angle
Both eyes (at 3 years): Horizontal gaze nystagmus
(nonsustained); exudative vitreoretinopathy
1 month F Congenital glaucoma (bilateral) Both eyes: Trabeculectomy for glaucoma Dedania et al. (29)
Both eyes: Choroidal
hemangioma; retinal venous tortuosity;
granular appearance of macula; corneal opacity
3 weeks F Granular appearance of macula; retinal vascular None Dedania et al. (29)
abnormalities (straightening of nasal retinal vessels)
(Continued )
4 M. S. ELITT ET AL.

Table 3. (Continued).
Age Sex Ocular finding(s) Intervention Reference
11 months F Both eyes: Retinal avascularity & nonperfusion with Left eye: Vitrectomy & scleral buckle for detached retina Dedania et al. (29)
neovascularization (progressing to rhegmatogenous & Both eyes: Laser photocoagulation for avascular retina
tractional retinal detachment in left eye); optic nerve
atrophy
3.5 months M Both eyes: Retinal avascularity with capillary dropout None Dedania et al. (29)
4 years F Congenital glaucoma (distribution NR) Right eye: Laser photocoagulation for retinal avascularity Dedania et al. (29)
Left eye: Cataract; phthisis bulbi with calcifications;
posterior synechiae
Right eye: Retinal avascularity, peripheral nonperfusion,
and fibrovascular proliferation; macular pigmentary
abnormalities
2 years M Both eyes: Retinal avascularity with fibrovascular Right eye: Vitrectomy for detached retina Dedania et al. (29)
proliferation; retinal detachment (macula)
2 months F Both eyes: Granular appearance of macula; retinal None Dedania et al. (29)
avascularity with lacy pattern of capillary dropout;
increased foveal
avascular zone; terminal bulbs; retinal venous dilation;
immature angle
Left eye: Retinal venous loops
*Exact age not provided, NR (none reported)

the archetypal ocular pathology in CMTC, was identified in 67%
(22/33) of these reports. Of these cases 77% (17/22) presented with
congenital glaucoma, 9% (2/22) displayed childhood-onset glau-
coma at 2.5 and 9 years of age, respectively, and 14% (3/22) did
not report an age of onset. Interestingly, while glaucoma was the
predominant finding in earlier CMTC literature, within the last
decade it was only reported in 20% (2/10) of reported cases. In
contrast, posterior segment anomalies, including retinal perfusion
defects and vascular abnormalities, while rarely mentioned in
these earlier publications, were present in 100% (10/10) of these
cases. We believe this shift in prevalence is likely artifactual in
nature, possibly due to underreporting or incomplete investiga-
tion. Further investigations will be necessary to clarify the true
percentages of these distinct pathologies.
Age of onset of ocular anomalies
Another key insight from Table 3 is the age of initial pre-
sentation of the patients’ ocular findings. In the majority of

Figure 2. Right eye fundus photographs of a CMTC patient showing mild retinal vessel tortuosity and a prominent choroidal pattern in the area around the optic
nerve that could be described as “marbleized.” The optic nerve and fovea are normal.

cases ocular pathologies were discovered prior to the patients’
first birthday, with only 8 patients presenting with ocular
anomalies at later ages. Unfortunately, these 24% (8/33) case
reports make no mention of examinations prior to the identi-
fication of the patients’ ocular findings so it is unknown if
anomalies existed at earlier ages. Future investigations con-
sisting of concomitant ophthalmologic evaluation with CMTC
diagnosis, as well as throughout life, would provide insights
into the natural history of these ocular pathologies.
Treatment approach of ocular pathologies
As displayed in Table 3, standard treatment approaches including
anti-hypertensive medications, trabeculectomy, laser photocoagu-
lation, and vitrectomy have been successfully employed in the
treatment of CMTC patients. Additionally, no atypical complica-
tions have manifested with any medical or surgical intervention.
Presently the data does not support the need for unusual con-
siderations in the ophthalmic management of CMTC patients.
Are ocular findings in CMTC rare?
Ocular abnormalities are considered rare manifestations in
CMTC patients. In fact, Kienast and Hoeger indicated in their
2009 report that only 3.7% of reported CMTC cases possessed
these clinical findings (4). However, as noted above, ocular pathol-
ogies have now been described in 33 CMTC patients (out of ~300
total reports), potentially indicating a higher rate. Importantly,
underreporting from incomplete or absent ophthalmologic exam-
inations (30) may also be complicating the accurate measure of
these findings in CMTC. To this latter point, many of the initial
reports in Table 3 only commented on intraocular pressure test-
ing, which may account for the absence of posterior segment
anomalies seen in more recent case reports. Further studies
using comprehensive pediatric ophthalmic examinations in
unbiased CMTC patient samples will be needed to elucidate the
true frequency of ocular findings in this disorder.
Recommendations for the ophthalmic approach to CMTC
Based on the frequency of congenital glaucoma and retinal
pathology in CMTC, we recommend that patients be screened
with a comprehensive eye exam, including intraocular pressure
measurement and dilated fundus examination, at the time of
initial diagnosis. When particular pathologies are detected (i.e.
glaucoma) standard medical or surgical interventions should be
promptly initiated to prevent secondary sequalae. Additionally,
we recommend that all CMTC patients (even patients with
a normal baseline exam) be followed by an ophthalmologist,
given the unknown natural history of these ocular anomalies.
Potential etiologies for CMTC
CMTC has several peculiar features that collectively may
provide insight into the cause of this disorder. In particular
most cases are sporadic, with only rare reports of heritability
(31). Additionally patients always harbor normal tissue out-
side of the regions of disease (4). Several etiologies have been
suggested to explain these findings, including environmental
factors, single gene mutations, and somatic mosaicism, with
OPHTHALMIC GENETICS 5
the latter representing the leading candidate. We will review
evidence for these proposed mechanisms below and detail
current research efforts in establishing a cause for CMTC.
Environmental factors
Four reports have described the development of CMTC fea-
tures in the context of possible in utero teratogens. In 1979
Schultz and Kocoshis reported fetal ascites, in utero alpha-1
antitrypsin level elevation, and transient hepatosplenomegaly
in a patient born with CMTC. While the authors speculated
that these findings could merely represent associated symp-
toms of CMTC, they also suggested the possibility of a viral
exposure leading to the overall clinical presentation (32).
Bhargava and colleagues also considered a causal link to an
in utero viral infection for a patient exhibiting several features
of CMTC. Importantly, the patient also demonstrated intel-
lectual disability, hypertrichosis of the eyelashes, splenome-
galy, laryngomalacia, and bilateral retinoblastomas (33),
which are not typical signs of CMTC and likely indicative of
a distinct disease process. Separately, Chen and colleagues
noted transient fetal ascites along with an elevated beta
human chorionic gonadotropin level in a patient with possible
CMTC, although the authors noted that the patient’s presen-
tation was suspicious for Adams-Oliver syndrome (34). While
fetal ascites and possible viral infections were common man-
ifestations across these reports, the uncertainly in the diagno-
sis of CMTC makes the significance of these findings unclear.
The best evidence for an environmental etiology came from
Rogers and Poyzer (35). These authors noted a particularly high
incidence of CMTC coupled with a striking temporal and geogra-
phical relationship, suggestive of a possible common causal envir-
onmental exposure. Specifically, four cases of CMTC were noted
in a 19.2 kilometer radius within Sydney, Australia from
April 1978 and September 1979, an extraordinary discovery for
such a rare disorder. Importantly, the authors stated that they were
unable to identify a shared environmental factor that may have
been responsible for the development of CMTC in these patients
(35). Collectively, while an environmental factor mechanism may
fit the primarily sporadic and non-heritable profile of CMTC, the
evidence for this etiology is currently limited. A large-scale inves-
tigation of CMTC patients with well documented gestational
histories and exposures may be required to further explore this
causation.
Single gene mutations
There has been a sole report of a single gene mutation as
potential causative factor in CMTC. In 2015 Alkuraya and
colleagues used whole exome sequencing to identity a potential
homozygous recessive truncation of ARL6IP6 (OMIM # 616495)
in a patient with possible CMTC (36). Interestingly, mutations in
ARL6IP6 had previously been associated with early-onset
ischemic stroke (37), another vascular-based condition, which
provided mechanistic validity to this finding. Unfortunately
a publication by the same author later reclassified this mutation
as “likely benign,” casting doubt on the original report (38).
Nevertheless we include this information here for clarity to the
medical, scientific, and patient communities.
6 M. S. ELITT ET AL.
Somatic mosaicism
In 1986 Rudolf Happle postulated the complex mechanism of
mosaicism with embryonically lethal genetic mutations, providing
an explanation for the unusual cutaneous disease patterns and
non-mendelian inheritance seen in several disorders, including
CMTC (39). In this concept, an embryonically lethal dominant
or recessive mutation would emerge in a cell at the post-zygotic
stage through a spontaneous mutation or semiconservative repli-
cation of a half-chromatid mutation, creating a mosaic embryo
containing both genetically normal and abnormal tissues.
Critically, Happle claimed that this unique developmental timeline
would protect the embryo from mutation-induced fetal demise
while also presenting a heritability block due to the embryonic
lethality when present at the zygotic stage. Collectively, this idea
could explain two prominent features of CMTC: (1) The presence
of normal tissue outside of the vascular lesions and (2) non-
mendelian inheritance patterns (5). However, rare reports of gen-
erational inheritance (40) and CMTC in sibling family members
(41) present problems for this etiologic explanation which is pre-
dicated on a lack of heritability. To address this apparent conflict,
Danarti, Konig, and Happle suggested a paradominant mode
inheritance for CMTC (31,42), representing a slight modification
to Happle’s original mosaicism model. In this idea mutations
would be embryonically lethal when homozygous but tolerated
when heterozygous, allowing for generational inheritance in car-
riers but precluding the emergence of non-mosaic, homozygous
individuals. Similar to Happle’s original proposal, if a loss of
heterozygosity occurred at a post-zygotic stage due to recombina-
tion, gene conversion, or a spontaneous mutation (43), and gen-
erated a mosaic embryo containing both genetically normal and
abnormal tissue, the mutant cells could be tolerated (31). As such
this could explain the potential for rare inheritance in CMTC
while still satisfying non-mendelian inheritance and cutaneous
lesion patterns seen in the disease.
Mosaic mutations have been established in several other
disorders including Sturge–Weber Syndrome (44), non-
syndromic port wine stains (44), McCune–Albright syndrome
(45), and Proteus syndrome (46) but genetic studies have yet to
confirm this mechanism for CMTC. Recently Sassalos and col-
leagues suggested the possibility of mosaic GNA11 mutation as
a potential cause for CMTC (27) but this finding has yet to be
replicated by other groups. Unfortunately, the rarity of the dis-
order creates substantial difficultly in recruiting the patient
numbers needed to confirm this mechanism for CMTC.
Nonetheless, we are aware of two ongoing CMTC genetic
research studies in the United States and Europe, directed by
Dr. Beth Drolet at University of Wisconsin and Dr. Miikka
Vikkula at the Université catholique de Louvain, respectively.
We hope that their mention here will accelerate enrollment in
these studies and hasten the etiological elucidation of CMTC.
Conclusions
Investigations of CMTC are complicated by the lack of an
established etiology, non-standardized diagnostic guidelines,
and rarity of the disorder. Examinations into CMTC’s ocular
manifestations – which seemingly occur in a fraction of
patients – represent an even greater challenge. In spite of
these difficulties our review illustrates several reproducible
patterns in the ocular findings of CMTC including glaucoma
and posterior segment pathologies, which typically occur con-
comitantly with the characteristic congenital cutaneous vas-
cular features that define the disorder. Based on our
confidence in this dataset we propose specific clinical guide-
lines for ophthalmic screening and treatment in CMTC
patients. We encourage additional reporting under this frame-
work, which we hope will continue to refine our understand-
ing of the ocular manifestations of CMTC, as well as CMTC
as a whole. Finally, we hope that further characterization of
these ocular findings will lead to improved disease classifica-
tion and aid in patient recruitment for ongoing genetic
research efforts for CMTC.
Acknowledgments
M.S.E. is supported by NIH T32GM007250.
Funding
This work was supported by the National Institutes of Health
[T32GM007250].
Declaration of interest
Case Western Reserve University holds equity in Convelo Therapeutics,
which has licensed patents from Case Western Reserve University inven-
tor M.S.E. The authors report no other conflicts of interest. The authors
alone are responsible for the content and writing of the paper.
ORCID
Matthew S. Elitt http://orcid.org/0000-0002-7296-164X
Elias Traboulsi http://orcid.org/0000-0001-8870-7673
References
1. Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M,
Metzker A. Cutis marmorata telangiectatica congenita: clinical
findings in 85 patients. Pediatr Dermatol. 2000;17(2):100–04.
doi:10.1046/j.1525-1470.2000.01723.x.
2. Van Lohuizen C. Über eine seltene angeborene Hautanomalie
(Cutis marmorata telangiectatica congenita). Acta Derm
Venereol. 1922;3:202–11.
3. De Maio C, Pomero G, Delogu A, Briatore E, Bertero M,
Gancia P. Cutis marmorata telangiectatica congenita in
a preterm female newborn: case report and review of the
literature. Pediatr Med Chir. 2014;36(4):90.
4. Kienast AK, Hoeger PH. Cutis marmorata telangiectatica conge-
nita: a prospective study of 27 cases and review of the literature
with proposal of diagnostic criteria. Clin Exp Dermatol. 2009;34
(3):319–23.doi:10.1111/ced.2009.34.issue-3.
5. Shareef S, Horowitz D. Cutis Marmorata Telangiectatica
Congenita. Treasure Island (FL): StatPearls; 2019.
6. Way BH, Herrmann J, Gilbert EF, Johnson SA, Opitz JM. Cutis
marmorata telangiectatica congenita. J Cutan Pathol. 1974;1
(1):10–25.doi:10.1111/cup.1974.1.issue-1.
7. Fujita M, Darmstadt GL, Dinulos JG. Cutis marmorata telangiecta-
tica congenita with hemangiomatous histopathologic features. J Am
Acad Dermatol. 2003;48(6):950–54.doi:10.1067/mjd.2003.301.
8. South DA, Jacobs AH. Cutis marmorata telangiectatica congenita
(congenital generalized phlebectasia). J Pediatr. 1978;93
(6):944–49.doi:10.1016/S0022-3476(78)81216-5.

9. Levy R, Lam JM. Cutis marmorata telangiectatica congenita:
a mimicker of a common disorder. CMAJ. 2011;183(4):E249–51.
doi:10.1503/cmaj.091749.
10. Petrozzi JW, Rahn EK, Mofenson H, Greensher J. Cutis marmor-
ata telangiectatica congenita. Arch Dermatol. 1970;101(1):74–77.
doi:10.1001/archderm.1970.04000010076013.
11. Sato SE, Herschler J, Lynch PJ, Hodes BL, Fryczkowski AW,
Schlosser HD. Congenital glaucoma associated with cutis mar-
morata telangiectatica congenita: two case reports. J Pediatr
Ophthalmol Strabismus. 1988;25(1):13–17.
12. Vazquez F, Lopez B, Requena L, Garcia-Perez A. Congenital glau-
coma and cutis marmorata telangiectatica: report of the second
case. Dermatologica. 1988;177(3):193–94.doi:10.1159/000248546.
13. Picascia DD, Esterly NB. Cutis marmorata telangiectatica conge-
nita: report of 22 cases. J Am Acad Dermatol. 1989;20
(6):1098–104.doi:10.1016/S0190-9622(89)70140-7.
14. Lynch PJ. Cutis marmorata telangiectatica congenita associated
with congenital glaucoma. J Am Acad Dermatol. 1990;22(5 Pt
1):857.doi:10.1016/S0190-9622(08)81187-5.
15. Miranda I, Alonso MJ, Jimenez M, Tomas-Barberan S, Ferro M, Ruiz R.
Cutis marmorata telangiectatica congenita and glaucoma. Ophthalmic
Paediatr Genet. 1990;11(2):129–32.doi:10.3109/13816819009012958.
16. Shields JA, Shields CL, Koller HP, Federman JL, Koblenzer P,
Barbera LS. Cutis marmorata telangiectatica congenita associated
with bilateral congenital retinal detachment. Retina. 1990;10
(2):135–39.doi:10.1097/00006982-199004000-00009.
17. Kremer I, Metzker A, Yassur Y. Intraoperative suprachoroidal
hemorrhage in congenital glaucoma associated with cutis mar-
morata telangiectatica congenita. Arch Ophthalmol. 1991;109
(9):1199–200.doi:10.1001/archopht.1991.01080090023013.
18. Mayatepek E, Krastel H, Volcker HE, Pfau B, Almasan K. Congenital
glaucoma in cutis marmorata teleangiectatica congenita.
Ophthalmologica. 1991;202(4):191–93.doi:10.1159/000310195.
19. Pehr K, Moroz B. Cutis marmorata telangiectatica congenita:
long-term follow-up, review of the literature, and report of a case
in conjunction with congenital hypothyroidism. Pediatr Dermatol.
1993;10(1):6–11.doi:10.1111/j.1525-1470.1993.tb00002.x.
20. Weilepp AE, Eichenfield LF. Association of glaucoma with cutis
marmorata telangiectatica congenita: a localized anatomic
malformation. J Am Acad Dermatol. 1996;35(2 Pt 1):276–78.
doi:10.1016/S0190-9622(96)90354-0.
21. Mu SC, Hung HY, Chiu NC, Chen HH, Chen LJ. Cutis marmor-
ata telangiectatica congenita with cerebral and ophthalmic
anomalies: report of one case. Zhonghua Min Guo Xiao Er Ke
Yi Xue Hui Za Zhi. 1997;38(1):65–68.
22. Pendergast SD, Trese MT, Shastry BS. Ocular findings in cutis mar-
morata telangiectatica congenita. Bilateral exudative vitreoretinopathy.
Retina. 1997;17(4):306–09.doi:10.1097/00006982-199717040-00005.
23. Devillers AC, de Waard-van der Spek FB, Oranje AP. Cutis mar-
morata telangiectatica congenita: clinical features in 35 cases. Arch
Dermatol. 1999;135(1):34–38.doi:10.1001/archderm.135.1.34.
24. Murphy CC, Khong CH, Ward WJ, Morgan WH. Late-onset
pediatric glaucoma associated with cutis marmorata telangiecta-
tica congenita managed with Molteno implant surgery: case report
and review of the literature. J Aapos. 2007;11(5):519–21.
doi:10.1016/j.jaapos.2007.03.015.
25. Spitzer MS, Szurman P, Rohrbach JM, Aisenbrey S. Bilateral
congenital glaucoma in a child with cutis marmorata telangiecta-
tica congenita: a case report. Klin Monbl Augenheilkd. 2007;224
(1):66–69.doi:10.1055/s-2006-927216.
26. Soohoo JR, McCourt EA, Lenahan DS, Oliver SC. Fluorescein
angiogram findings in a case of cutis marmorata telangiectatica
congenita. Ophthalmic Surg Lasers Imaging Retina. 2013;44
(4):398–400.doi:10.3928/23258160-20130604-01.
27. Sassalos TM, Fields TS, Levine R, Gao H. Retinal neovascularization
from a patient with cutis marmorata telangiectatica congenita. Retin
Cases Brief Rep. 2018. doi:10.1097/ICB.0000000000000736.
28. Taleb EA, Nagpal MP, Mehrotra NS, Bhatt K. Retinal findings in a case
of presumed cutis marmorata telangiectatica congenita. Retin Cases
Brief Rep. 2018;12(4):322–25.doi:10.1097/ICB.0000000000000492.
OPHTHALMIC GENETICS 7
29. Dedania VS, Moinuddin O, Lagrou LM, Sathrasala S, Cord
Medina FM, Del Monte MA, Chang, E.Y., Bohnsack, B.L., Besirli, C.
G. Ocular manifestations of cutis marmorata telangiectatica congenita.
Ophthalmol Retina. 2019;3(9):791–801.doi:10.1016/j.oret.2019.03.025.
30. Ilhan O, Ozer EA, Ozdemir SA, Akbay S, Memur S, Kanar B,
Akar M, Sutcuoglu S, Tatli MM. Congenital cutis marmorata telan-
giectatica and syndactyly in a preterm: case report. Arch Argent
Pediatr. 2016;114(2):e111–3.doi:10.5546/aap.2016.eng.e111.
31. Danarti R, Happle R, Konig A. Paradominant inheritance may explain
familial occurrence of Cutis marmorata telangiectatica congenita.
Dermatology. 2001;203(3):208–11.doi:10.1159/000051750.
32. Schultz RB, Kocoshis S. Cutis marmorata telangiectatica congenita
and neonatal ascites. J Pediatr. 1979;95(1):157.doi:10.1016/S0022-
3476(79)80117-1.
33. Bhargava P, Kuldeep CM, Mathur NK. Cutis marmorata telan-
giectatica congenita with multiple congenital anomalies.
Further clues for a teratogenic cause. Dermatology. 1998;196
(3):368–70.
34. Chen CP, Chen HC, Liu FF, Jan SW, Chern SR, Wang TY, H-
Y Hung. Cutis marmorata telangiectatica congenita associated
with an elevated maternal serum human chorionic gonadotrophin
level and transitory isolated fetal ascites. Br J Dermatol. 1997;136
(2):267–71.doi:10.1111/j.1365-2133.1997.tb14912.x.
35. Rogers M, Poyzer KG. Cutis marmorata telangiectatica congenita.
Arch Dermatol. 1982;118(11):895–99.doi:10.1001/archderm.1982.
01650230023020.
36. Abumansour IS, Hijazi H, Alazmi A, Alzahrani F, Bashiri FA,
Hassan H, Alhaddab M, Alkuraya FS. ARL6IP6, a susceptibility
locus for ischemic stroke, is mutated in a patient with syndromic
cutis marmorata telangiectatica congenita. Hum Genet. 2015;134
(8):815–22.doi:10.1007/s00439-015-1561-6.
37. Cheng YC, O’Connell JR, Cole JW, Stine OC, Dueker N, McArdle PF,
Sparks MJ, Shen J, Laurie CC, Nelson S, et al. Genome-wide associa-
tion analysis of ischemic stroke in young adults. G3 (Bethesda). 2011;1
(6):505–14.doi:10.1534/g3.111.001164.
38. Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R,
Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S,
et al. Lessons learned from large-scale, first-tier clinical exome
sequencing in a highly consanguineous population. Am J Hum
Genet. 2019;104(6):1182–201.doi:10.1016/j.ajhg.2019.04.011.
39. Happle R. Lethal genes surviving by mosaicism: a possible explanation
for sporadic birth defects involving the skin. J Am Acad Dermatol.
1987;16(4):899–906.doi:10.1016/S0190-9622(87)80249-9.
40. Kurczynski TW. Hereditary cutis marmorata telangiectatica
congenita. Pediatrics. 1982;70(1):52–53.
41. Andreev VC, Pramatarov K. Cutis mamorata telangiectatica con-
genita in two sisters. Br J Dermatol. 1979;101(3):345–50.
doi:10.1111/j.1365-2133.1979.tb05630.x.
42. Happle R. Mosaicism in human skin. Understanding the patterns
and mechanisms. Arch Dermatol. 1993;129(11):1460–70.
doi:10.1001/archderm.1993.01680320094012.
43. Steijlen PM, van Steensel MA. Paradominant inheritance,
a hypothesis explaining occasional familial occurrence of
sporadic syndromes. Am J Med Genet. 1999;85(4):359–60.
doi:10.1002/(SICI)1096-8628(19990806)85:4<359::AID-AJMG
10>3.0.CO;2-V.
44. Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP,
Cohen B, North PE, Marchuk DA, Comi AM, Pevsner J, et al.
Sturge-Weber syndrome and port-wine stains caused by somatic
mutation in GNAQ. N Engl J Med. 2013;368(21):1971–79.
doi:10.1056/NEJMoa1213507.
45. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E,
Spiegel AM. Activating mutations of the stimulatory G protein in
the McCune-Albright syndrome. N Engl J Med. 1991;325
(24):1688–95.doi:10.1056/NEJM199112123252403.
46. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K,
Turner J, Cannons JL, Bick D, Blakemore L, et al. A mosaic
activating mutation in AKT1 associated with the Proteus
syndrome. N Engl J Med. 2011;365(7):611–19.doi:10.1056/
NEJMoa1104017.