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Ocular Manifestations of Cutis Marmorata Telangiectatica Congenita
Ocular Manifestations of Cutis Marmorata Telangiectatica Congenita Vaidehi S. Dedania, MD,1 Omar Moinuddin, MD,2 Lisa M. Lagrou, MD,3 Sanjana Sathrasala,2 Flavio Mac Cord Medina, MD,4,5 Monte A. Del Monte, MD,2 Emmanuel Y. Chang, MD, PhD,6,7,8 Brenda L. Bohnsack, MD, PhD,2 Cagri G. Besirli, MD, PhD2 Purpose: To describe the range of ocular manifestations in cutis marmorata telangectatica congenita (CMTC). Design: Multicenter, retrospective, nonconsecutive case series. Participants: Patients with a diagnosis of CMTC referred for ophthalmologic evaluation between January 1, 2015, and December 31, 2018. Methods: Evaluation of ocular findings at presentation, systemic manifestations suggestive of a diagnosis of CMTC, genetic testing, and visual outcomes after treatment. Main Outcome Measures: Visual acuity, findings on ophthalmoscopy, and results of fluorescein angiography. Results: Nine patients with CMTC diagnosed clinically based on stereotypical cutaneous vascular malformations were included. The median age at presentation was 8 weeks (range, 2 weekse4 years). Six patients were female and 3 were male. Avascular retina was identified on dilated fundus examination, fluorescein angiography, or both in 11 eyes of 6 patients. Retinal neovascularization was present bilaterally in 2 patients at presentation. One patient demonstrated retinal venous tortuosity, and another patient showed mild straightening of nasal retinal vessels in both eyes. Two patients (2 eyes) demonstrated retinal detachment (RD). Both were managed surgically. One infant demonstrated RD, whereas the other child showed extensive neovascularization and later progressed to combined tractional-rhegmatogenous detachment. A unique constellation of lacy peripheral capillary anomalies with prominent terminal vascular bulbs was noted in 3 patients. Granular pigment abnormalities were noted in the macula in 5 patients. Two patients demonstrated glaucoma, 1 requiring surgical intervention. Two patients demonstrated features of Adams-Oliver syndrome, with genetic testing identifying a Notch1 mutation in 1 patient. Conclusions: Retinal vascular abnormalities in CMTC may occur more frequently than recognized previously. Given the variability of ocular involvement and the potential for rapidly progressive retinal vascular abnormalities and development of RD, complete ophthalmologic evaluation including measurement of intraocular pressure, gonioscopy, dilated fundus examination, and fluorescein angiography is recommended in infants with suspected CMTC shortly after birth. The distinct pattern of lacy capillary anomalies with prominent terminal bulbs seen in CMTC has not been described in other syndromes of vascular dysgenesis. Therefore, ophthalmic examination may be a valuable method to distinguish CMTC from other disorders demonstrating similar dermatologic and systemic manifestations. Ophthalmology Retina 2019;3:791-801 ª 2019 by the American Academy of Ophthalmology
Cutis marmorata telangiectatica congenita (CMTC) was reported first in 1922 by van Lohuizen.1 Cutis marmorata telangiectatica congenita is a rare, spontaneous, cutaneous vascular anomaly characterized by persistent pink-blue mottled appearance (cutis marmorata) unrelated to external temperature and venous lakes (phlebectasias) in the absence of varicose veins (venectasisas).2 Cutis marmorata telangiectatica congenita may be associated with telangiectasias and ulceration of the skin overlying the vascular malformations (Fig 1A), which can cause atrophy and precipitate superimposed infections that may be life threatening in infants.2 Additionally, patients can show a facial port wine stain (nevus flammeus).3 In most cases, 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
vascular skin lesions (Fig 1B) typically fade within 3 Dermatopathologic analysis years after birth.3 demonstrates nonspecific findings, including swollen endothelial cells, dilated capillaries and veins, and venous lakes found within the dermis layer of the skin.4,5 Systemic anomalies such as limb asymmetry, renal hypoplasia, and syndactyly have been reported in up to 61% of cases of CMTC.3 Ocular abnormalities in CMTC include glaucoma,6 peripheral retinal vasculopathy and nonperfusion,7 exudative vitreoretinopathy,8 and congenital RD.9 To date, the most commonly reported ocular finding in CMTC is glaucoma.3,6,8 The pathophysiologic features of these https://doi.org/10.1016/j.oret.2019.03.025 ISSN 2468-6530/19
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Figure 1. External photographs demonstrating cutaneous manifestations in a patient with cutis marmorata telangiectatica congenita (CMTC). A, Localized venous malformation on the scalp with overlying ulceration. B, Reticular vascular malformations with a venous malformation of the abdominal midline, typical for CMTC.
ocular manifestations are not well understood, although widespread primary dysfunction of veins, venules, capillaries, and possibly arterioles likely is a major disease component.4,5 The incidence of ocular findings in CMTC remains unknown and difficult to approximate, likely because of the rarity of this condition and its nonspecific presentation. Herein, we report a series of 9 patients with CMTC demonstrating various ocular manifestations including retinal vasculopathy and infantile-onset glaucoma. To the best of our knowledge, this report represents the largest case series of ocular manifestations in CMTC. Moreover, we present a comprehensive characterization of these ocular manifestations through the use of multimodal retinal imaging along with a relevant review of the literature on the subject.
Methods Research conducted was in compliance with the Health Insurance Portability and Accountability Act and the tenets of the Declaration of Helsinki, while abiding all regional, national, and international laws of the institutions involved in this study. Every effort was made by the investigators to protect the rights of patients during this study. This study is in concordance with the tenets of the ethics committee of each contributing center and was approved by the institutional review boards at each of these respective institutions. Patients with a diagnosis of CMTC referred for ophthalmologic evaluation and found to have ocular pathologic features not attributed to any other cause between January 1, 2015, and December 31, 2018, were included in this study. Collected data included findings from complete ophthalmologic examination and imaging throughout the course of follow-up, details of treatment (where applicable), results of neurologic imaging to assess for intracranial vascular lesions, and other systemic manifestations or complications of CMTC. Informed parental consent was obtained to allow the release of patient photographs for the purpose of research.
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Results A total of 9 patients (6 females, 3 males) were included in this study. The median age at presentation was 8 weeks, with a range of 2 weeks to 4 years. All children were born full term with an unremarkable birth history, with the exception of 1 infant born at 35 5/7 weeks’ gestational age whose neonatal course was complicated by severe pulmonary hypertension. A positive or suspected family history of CMTC in previous generations was not reported in any of the patients. However, 2 of the patients included in this series are siblings and are the offspring of nonconsanguineous parents. Two unrelated patients demonstrated clinical features of Adams-Oliver syndrome, of which 1 child was found to have a congenital heart defect (patent foramen ovale) common to this disorder. All patients in this study underwent genetic testing to identify genetic mutations commonly associated with other systemic conditions with similar presentations as CMTC. A genetic mutation (Notch1) was identified only in 1 of the children diagnosed with Adams-Oliver syndrome. All 9 patients in this series demonstrated 1 or more dermatologic manifestations commonly reported in CMTC including hypervascularity, mottling of the skin, telangiectasis, and ulceration. Additionally, 2 patients showed a unilateral port wine stain. Of the 9 patients in this series, 2 children experienced serious complications secondary to intracranial vascular anomalies. One of these patients experienced a hemorrhagic stroke at 11 months of age, despite normal brain magnetic resonance imaging and angiography results obtained at 3 months of age. Extensive ischemic encephalopathy in watershed distribution was observed in another patient, with a history of pulmonary vein stenosis requiring stenting shortly after birth possibly contributing to vascular insult. Other serious organ involvement, including a history of patent foramen ovale, developmental delay, epilepsy, and distal leg atrophy, were present in 4 of the 9 patients. All patients included in this study received thorough retinal evaluation by 1 year of age. With regard to the ocular manifestations of CMTC (Table 1), retinal abnormalities were observed
Table 1. Patients with Ocular Manifestations of Cutis Marmorata Telangiectatica Congenita Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 1
2 wks
F
Full Term Y
Visual Acuity Aversive to light both eyes
Anterior Segment High iris insertion with scalloped iris at insertion and immature angle structures
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Treatment
Periphery Avascular retina both eyes Mild venous dilation both eyes Venous loops both eyes Terminal buds with retinal hemorrhages both eyes
N
Laser photocoagulation to avascular retina both eyes (at 2 wks and 3 mos of age)
Y
Patent foramen ovale Subarachnoid hemorrhage Epilepsy
3 yrs of age Exudative vitreoretinopathy both eyes 2.4 cy/cm right eye 3.2 cy/cm left eye Intermittent esotropia both eyes Intermittent horizontal gaze evoked nonsustained nystagmus both eyes
Y
Ab externo trabeculotomy both eyes
Y
Nevus flammeus Developmental delay (mild)
18 yrs of age 20/20 right eye 20/25 left eye
Macula Granular appearance both eyes No foveal depression both eyes
1 mo
F
Y
BTL both eyes Corneal clouding Periphery Enlarged corneal Diffuse choroidal diameter hemangioma both eyes Venous tortuosity both eyes Macula Granular appearance both eyes
(Continued)
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FA Patchy choroidal filling both eyes Lack of FAZ both eyes Peripheral nonperfusion with dilated vascular terminals both eyes Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Late leakage both eyes 2
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Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 3
3 wks
F
Full Term Y
Visual Acuity Aversive to light both eyes
Anterior Segment Scalloped iris at insertion and immature angle structures
Treatment
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Periphery Mild straightening of the nasal retinal vessels both eyes
N
None
Y
None
2 yrs of age 20/25 right eye 20/20 left eye
N
Laser photocoagulation to avascular retina both eyes Surgical intervention for retinal detachment left eye Vitrectomy and scleral buckle
Y
None
2.25 yrs of age Fix and follow both eyes
N
None
Y
None
7 mos of age Fix and follow both eyes
Macula Granular appearance both eyes No foveal depression both eyes FA Normal both eyes 4*
11 mos
F
Y
Fix and follow None both eyes
Periphery Avascular retina both eyes Peripheral neovascularization: mild right eye, severe left eye Progression to combined rhegmatogenous and tractional retinal detachment left eye Optic nerve Atrophy both eyes FA Peripheral nonperfusion and leakage both eyes
5*
3.5 mos
M
Y
CSM both eyes
None
Periphery Avascular retina both eyes FA Capillary dropout both eyes No peripheral leakage or terminal bulbs both eyes
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Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 6
4 yrs
F
Full Term Y
Visual Acuity
Anterior Segment
Posterior Segment
20/60 right eye Cataract left eye Periphery NLP left eye Posterior synechiae Avascular retina left eye right eye Extensive fibrovascular proliferation right eye No view left eye
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Treatment
Y
Laser photocoagulation to avascular retina right eye2
Y
Seizures
8 yrs of age 20/70 right eye NLP left eye
Surgical intervention for recurrent retinal detachment right eye Vitrectomy
Y
Distal leg atrophy (unilateral)
4 yrs of age NLP both eyes
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Macula Pigmentary abnormalities right eye FA Peripheral nonperfusion right eye Leakage right eye
2 yrs
M
Y
LP both eyes
None
Periphery Avascular retina both eyes Extensive fibrovascular proliferation both eyes Macula Detached both eyes
d
(Continued)
Ocular Manifestations in CMTC
7
B-scan ultrasound Diffuse calcifications left eye Phthisis bulbi left eye
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Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 8
5 wks
M
Full Term
Visual Acuity
N (induced CSM both at 35 5/7 eyes wks for pre-eclampsia)
Anterior Segment None
Glaucoma
Treatment
Periphery Avascular retina (zone II) with neovascularization (stage 3) both eyes Mild venous dilation both eyes Terminal buds both eyes Vitreous hemorrhage left eye Progression of retinal vasculopathy after treatment both eyes
N
Intravitreal Avastin 0.25 mg/ 0.1 mL (43.5 wks’ PMA) Laser photocoagulation to avascular retina both eyes (55 wks’ PMA and 2 yrs of age)
N
None
Major Systemic Findings or Disorders
Y
Birth weight 2750 g Adams-Oliver syndrome Severe pulmonary hypertension with stenosis of 4 veins
Most Recent Follow-up d
FA Peripheral nonperfusion with dilated vascular terminals both eyes Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Late leakage both eyes 9
2 mos
F
Y
BTL both eyes Immature angles
Periphery Mild venous dilation both eyes Venous loop left eye
d
3 mos of age Fix and follow both eyes
Macula Granular appearance both eyes FA Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Increased FAZ both eyes
BTL ¼ blinks to light; CSM ¼ central-steady-maintained; F ¼ female; FA ¼ fluorescein angiography; FAZ ¼ foveal avascular zone; LP ¼ light perception; M ¼ male; N ¼ no; NLP ¼ no light perception; PMA ¼ postmenstrual age; Y ¼ yes; d ¼ not assessed/not available. *Siblings.
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Figure 2. Fundus photographs and fluorescein angiography images from patient 1. Fundus photograph of the right eye (A) at presentation, (B) at follow-up 3 months later, and (C) at follow-up 6 months after presentation demonstrating an abrupt termination of vessels with terminal bulbs and progression of vascular tortuosity and dilation despite adequate treatment with laser photocoagulation to areas of nonperfusion. Similar progression of left eye vascular abnormalities after laser photocoagulation to areas of (E) nonperfusion and (F) magnified area of vascular abnormalities and terminal bulbs with (G) corresponding fundus photograph.
within the first year of life in all patients and within 1 month of age in 3 patients. Peripheral retinal avascularity (Fig 2) was noted in 6 patients (11 eyes), of whom 2 patients (4 eyes) demonstrated significant retinal neovascularization at presentation. Four of these patients were treated with laser photocoagulation to the avascular retina. One patient demonstrated extensive neovascularization in the periphery (Fig 3) and progressed to a combined tractional-rhegmatogenous RD that later required surgical intervention with pars plana vitrectomy. Retinal detachment was observed in 1 eye of 2 patients, with 1 patient diagnosed at presentation. Both eyes with RD were treated surgically without complication. One child was treated with pars plana vitrectomy, whereas the other was treated with pars plana vitrectomy and scleral buckling. One patient showed a diffuse choroidal hemangioma in the right eye, and another patient demonstrated a patchy pattern of choroidal filling on fluorescein angiography (FA) in both eyes. Granular pigmentary abnormalities (Fig 4) in the macula were noted in 5 of the 9 patients. Additionally, 3 patients in this case series demonstrated retinal vascular findings not previously reported in CMTC. Capillary dropout with prominent terminal bulbs in the peripheral vessels was observed (Figs 2EeG and 5). Interestingly, dilated fundoscopic examination in the first week of life revealed only avascular peripheral retina in 1 of these patients. However, 2 of these 3 infants later demonstrated retinal or vitreous hemorrhage
by 2 weeks of age, indicating these vascular anomalies are rapidly progressive. In 1 of these 3 patients, a blunted foveal reflex was noted that corresponded to the absence of a foveal avascular zone noted on FA.
Discussion Cutis marmorata telangiectatica congenita is a rare disorder associated with multiple ocular findings, including glaucoma and retinal vascular abnormalities.6e9 Glaucoma is the most commonly reported eye finding in CMTC and previously was reported in 16 patients.3,6,9e16 Although most cases of glaucoma in patients with CMTC are of infantile onset, 2 cases have been reported to develop at 9 and 15 years of age.10,14 Several other ophthalmic anomalies have been reported in patients with CMTC, including congenital cataract,17 retinoblastoma,18 optic disc drusen,19 persistence of hyaloid artery,20 and small optical discs associated with cerebral atrophy.20 The pathophysiologic features of glaucoma in CMTC are hypothesized to be similar to those of glaucoma observed secondary to Sturge-Weber syndrome, which is attributable to angle dysgenesis in infants and increased episcleral venous pressure in older children.15,21 Nevus flammeus
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Figure 3. Fundus photographs and fluorescein angiography images from patient 4. Fundus photographs of the left eye demonstrating (A, B) avascular retina and severe peripheral neovascularization with retinal detachment at presentation, which (C, D) resolved after vitrectomy, scleral buckle, and laser photocoagulation.
often is associated with glaucoma in CMTC, especially in unilateral cases.10 The management of glaucoma in CMTC includes angle surgery, trabeculectomy, and glaucoma drainage device implantation, with trabeculotomy as the most commonly reported initial intervention. Because of the rarity of this condition, evidence-based data on the management of CMTC is limited. Six cases of infantileonset glaucoma initially were managed with trabeculotomy,
of which 1 case was complicated by suprachoroidal hemorrhage; 2 other children later required repeat trabeculotomy.3,6,12,15 In addition, there is 1 report of intraocular pressure control with a Molteno implant in an older child with CMTC.10 The collective experience of previous case reports, in combination with our management experience as presented in this series, suggests that the surgical management of glaucoma associated with CMTC is
Figure 4. Fundus photograph and fluorescein angiogram of the right eye of patient 3: (A) fundus photograph and (B) fluorescein angiogram demonstrating straightening of retinal vessels nasally and granular appearance of the macula with lack of foveal avascular zone.
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Figure 5. Fluorescein angiograms from patient 8 after treatment with laser photocoagulation: (A) right eye and (B) left eye showing laser application to areas of peripheral nonperfusion with dilated vascular terminals, lacy pattern of capillary dropout, and terminal bulbs.
similar to that of Sturge-Weber syndrome.21e23 Further studies are needed to assess the prognosis of patients with infantile glaucoma associated with CMTC. This case series demonstrated that CMTC is associated commonly with retinal pathologic features ranging from very mild findings, such as straightening of retinal vessels, to more severe findings of peripheral nonperfusion, exudative vitreoretinopathy, and RD. We concur that the onset of retinal abnormalities in CMTC demonstrates a progressive and variable time course spanning from within the first week of life to 2 years of age, and possibly beyond, as reported previously.6e9 SooHoo et al7 originally reported peripheral retinal avascularity in a patient with CMTC. We also report incomplete peripheral retinal perfusion or secondary retinal nonperfusion in 6 of our patients and find that peripheral avascularity is the most commonly observed retinal abnormality. Four of these 6 patients remained stable after treatment with laser photocoagulation to the avascular retina. Only 1 eye, which was complicated by severe neovascularization and previously failed treatment with an injection of intravitreal bevacizumab (0.25 mg/0.1 mL), required surgical intervention at a later time for a combined tractional-rhegmatogenous RD. Previous reports of RD observed in patients with CMTC describe bilateral congenital RD in an infant with neovascular glaucoma9 and tractional RD in both eyes of an infant with exudative vitreoretinopathy.8 We also describe a lace-like pattern of capillary dropout with prominent terminal bulbs noted in the retinal periphery on FA in 3 biologically unrelated patients with CMTC. This novel finding may represent one of the first manifestations of CMTC and a potential ocular signature that may aid in the early diagnosis of this rare condition. Similar to other childhood diseases associated with retinal vasculopathies, such as familial exudative vitreoretinopathy and incontinentia pigmenti, a suspected diagnosis of CMTC warrants complete ophthalmologic examination and FA immediately after birth and regularly during the first few months of life.24,25 Because retinal disease in CMTC can progress rapidly, there is a risk for
significant visual morbidity. This in part may be secondary to the sequelae of nonperfusion. If left untreated, ischemia secondary to peripheral retinal avascularity promotes the production of vascular endothelial growth factor and other cytokines involved in regulating retinal angiogenesis.26,27 Upregulation of these factors can lead to pathologic retinal neovascularization with the vitreous serving as a scaffold where vitreoretinal adhesions form, and RD can develop as the vitreous continues to pull away from the retina.28,29 Therefore, timely intervention with laser photocoagulation to areas of peripheral retinal nonperfusion is advisable. Likewise, the possibility for choroidal involvement is an important consideration during management. Choroidal vascular anomalies may increase the risk of delayed or intraoperative suprachoroidal hemorrhage or of exudative RD similar to those observed in Sturge-Weber syndrome.23,30,31 Patients with CMTC not only have reported retinal and cutaneous vascular abnormalities, but also cerebral vascular anomalies. Kremer et al12 reported a patient with CMTC who showed hemorrhagic choroidal detachments during a filtering procedure. Neuroimaging later revealed a concurrent left hemispheric vascular abnormality. Similarly, one of the patients in this series experienced a hemorrhagic stroke at 11 months of age, although brain imaging did not reveal any lesions. Further research investigating vascular malformations in CMTC will advance our understanding of this rare disorder and may provide valuable insight into this possible association between the central nervous system and ocular pathologic features. Cutis marmorata telangiectatica congenita is associated with approximately 20% of reported cases of Adams-Oliver syndrome,32 a rare congenital disorder first described in 1945.33 Adams-Oliver syndrome is characterized by widespread pathologic features, including congenital scalp defects; limb size discrepancies most commonly involving the lower limbs; cleft lip or palate, or both; mottled skin; hypervascularity; failure to thrive; developmental delay; and
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Ophthalmology Retina Volume 3, Number 9, September 2019 complex cardiovascular and central nervous system malformations.32,34 Congenital heart defects, as reported in one patient in our series, are reported in 13.4% of patients with Adams-Oliver syndrome.35 The most frequent method of inheritance of Adams-Oliver syndrome is autosomal dominant transmission.36 Cutis marmorata telangiectatica congenita, in contrast, is hypothesized to be caused by a sporadic gene mutation because most patients with CMTC have no documented family history.3 Happle37 suggested that the lethal gene hypothesis may contribute to the sporadic nature of this disease. This also may explain in part the patchy distribution of organ involvement.32 To date, there exists only 1 report of presumed autosomal dominant inheritance of CMTC with hypothesized incomplete penetrance in 3 generations.38 Outside of this series, there exists only 1 other report of CMTC documented in biological siblings.39 A homozygous truncating mutation in the ARL1P6 gene was reported recently in a patient with CMTC who also showed developmental delay, dysmorphism, transient ischemic attacks, and cerebral vascular malformations.40 Some evidence may suggest that environmental factors or certain teratogens may be associated with this rare disorder, because 1 report documented 4 cases of CMTC from a single geographic area within an 18-month period.41 Although glaucoma previously was recognized as the most common ocular finding in patients with this condition, in our series, glaucoma was diagnosed in only 2 patients, whereas retinal vascular abnormalities were present in all 9 patients. Three patients showed mild retinal involvement, and the remaining 6 patients showed significant retinal pathologic features, including peripheral retinal nonperfusion, fibrovascular proliferation, and RD. Three patients demonstrated a lacy pattern of capillary dropout coupled with terminal bulbs in the retinal periphery. This unique retinal finding to date has been described only in CMTC. Despite the many findings presented in this case series, a major limitation of this research is the considerable degree of inherent selection bias. In addition to being a retrospective analysis, the inclusion of patients in this study was nonrandomized, nonconsecutive, and made up entirely of select patients seeking treatment from select ophthalmologists. Given that CTMC is an extremely rare disease, the selection bias inherent to this study cannot be minimized. Therefore, we cannot be sure that the entire spectrum of CMTC and its ocular manifestations are captured in this study. Nevertheless, early identification and intervention are critical to prevent damage to the retina at a developmentally critical age and to impede vision loss secondary to RD. In patients with dermatologic or other systemic manifestations suggestive of CMTC, we recommend complete ophthalmologic evaluation immediately after birth, including intraocular pressure measurement, gonioscopy, dilated fundoscopic examination, and FA. Timely diagnosis and treatment of glaucoma, retinal vasculopathy, and RD are critical for preventing permanent vision loss in children with CMTC and impeding the burden of disease posed by this rare illness.
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20. Devillers AC, de Waard-van der Spek FB, Oranje AP. Cutis marmorata telangiectatica congenita: clinical features in 35 cases. Arch Dermatol. 1999;135:34e38. 21. Mantelli F, Bruscolini A, La Cava M, et al. Ocular manifestations of Sturge-Weber syndrome: pathogenesis, diagnosis, and management. Clin Ophthalmol. 2016;10:871e878. 22. Van Emelen C, Goethals M, Dralands L, Casteels I. Treatment of glaucoma in children with Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus. 2000;37:29e34. 23. Iwach AG, Hoskins Jr HD, Hetherington Jr J, Shaffer RN. Analysis of surgical and medical management of glaucoma in Sturge-Weber syndrome. Ophthalmology. 1990;97:904e909. 24. Landy SJ, Donnai D. Incontinentia pigmenti (Bloch-Sulzberger syndrome). J Med Genet. 1993;30:53e59. 25. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68:578e594. 26. Pe’er J, Shweiki D, Itin A, et al. Hypoxia-induced expression of vascular endothelial growth factor by retinal cells is a common factor in neovascularizing ocular diseases. Lab Invest. 1995;72:638e645. 27. Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol. 1995;113:1538e1544. 28. Ghazi NG, Green WR. Pathology and pathogenesis of retinal detachment. Eye. 2002;16:411e421. 29. Green WR, Sebag J. Vitreous and vitreo-retinal interface. In: Ryan SJ, ed. Retina. Vol 3. St. Louis, MO: Mosby, Inc; 2001:1882e1960. 30. Cohen VM, Rundle PA, Rennie IG. Choroidal hemangiomas with exudative retinal detachments during pregnancy. Arch Ophthalmol. 2002;120:862e864.
31. Scott IU, Alexandrakis G, Cordahi GJ, Murray TG. Diffuse and circumscribed choroidal hemangiomas in a patient with Sturge-Weber syndrome. Arch Ophthalmol. 1999;117: 406e407. 32. Hassed S, Li S, Mulvihill J, et al. Adams-Oliver syndrome review of the literature: refining the diagnostic phenotype. Am J Med Genet A. 2017;173:790e800. 33. Adams FH, Oliver CP. Hereditary deformities in man: due to arrested development. J Hered. 1945;36:3e7. 34. Whitley CB, Gorlin RJ. Adams-Oliver syndrome revisited. Am J Med Genet. 1991;40:319e326. 35. Pierpont ME, Moller JH, Gorlin RJ, Edwards JE. Congenital cardiac, pulmonary, and vascular malformations in oculoauriculovertebral dysplasia. Pediatr Cardiol. 1982;2: 297e302. 36. Garzon MC, Schweiger E. Cutis marmorata telangiectatica congenita. Semin Cutan Med Surg. 2004;23:99e106. 37. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol. 1987;16:899e906. 38. Kurczynski TW. Hereditary cutis marmorata telangiectatica congenita. Pediatrics. 1982;70:52e53. 39. Andreev VC, Pramatarov K. Cutis marmorata telangiectatica congenita in two sisters. Br J Dermatol. 1979;101:345e350. 40. Abumansour IS, Hijazi H, Alazmi A, et al. ARL6IP6, a susceptibility locus for ischemic stroke, is mutated in a patient with syndromic cutis marmorata telangiectatica congenita. Hum Genet. 2015;134:815e822. 41. Rogers M, Poyzer KG. Cutis marmorata telangiectatica congenita. Arch Dermatol. 1982;118:895e899.
Footnotes and Financial Disclosures Originally received: December 18, 2018. Final revision: March 13, 2019. Accepted: March 26, 2019. Available online: May 1, 2019. Manuscript no. ORET_2019_77.
Study was performed as part of regular employment duties at University of Michigan. No additional funding was provided.
Department of Ophthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, Ann Arbor, Michigan.
HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the respective institutions approved the study. All research complied with the Health Insurance Portability and Accountability (HIPAA) Act of 1996 and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients’ parents to allow the release of patient photographs for the purpose of research.
3
Section of Ophthalmology, Department of Surgery, University of Calgary, Calgary, Canada.
No animal subjects were included in this study.
4
Universidade Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Conception and design: Dedania, Moinuddin, Besirli
5
Hospital Federal dos Servidores do Estado (HSE), Rio de Janeiro, Brazil.
Analysis and interpretation: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli
1
Department of Ophthalmology, New York University School of Medicine, New York, NewYork.
2
6
Retina and Vitreous of Texas, Houston, Texas. 7 Department of Ophthalmology, Houston Methodist Hospital, Houston, Texas. 8
Department of Ophthalmology, Baylor College of Medicine, Houston, Texas. Financial Disclosure(s): The author(s) have made the following disclosure(s): F.M.C.M.: Lecturer Novartis, Bayer E.Y.C.: Consultant Genentech/Allergan. B.L.B.: Financial support Alcon Research Institute, Eversight.
C.G.B.: Financial support Novartis, MeiraGtx, Spark Therapeutics. Supported by the Blind Children’s Center (B.L.B.).
Author Contributions:
Data collection: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli Obtained funding: N/A Overall responsibility: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli Abbreviations and Acronyms: CMTC ¼ cutis marmorata telangectatica congenita; FA ¼ fluorescein angiography. Correspondence: Cagri G. Besirli, MD, PhD, Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected] .edu.
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Cutis marmorata telangiectatica congenita (CMTC) was reported first in 1922 by van Lohuizen.1 Cutis marmorata telangiectatica congenita is a rare, spontaneous, cutaneous vascular anomaly characterized by persistent pink-blue mottled appearance (cutis marmorata) unrelated to external temperature and venous lakes (phlebectasias) in the absence of varicose veins (venectasisas).2 Cutis marmorata telangiectatica congenita may be associated with telangiectasias and ulceration of the skin overlying the vascular malformations (Fig 1A), which can cause atrophy and precipitate superimposed infections that may be life threatening in infants.2 Additionally, patients can show a facial port wine stain (nevus flammeus).3 In most cases, 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.
vascular skin lesions (Fig 1B) typically fade within 3 Dermatopathologic analysis years after birth.3 demonstrates nonspecific findings, including swollen endothelial cells, dilated capillaries and veins, and venous lakes found within the dermis layer of the skin.4,5 Systemic anomalies such as limb asymmetry, renal hypoplasia, and syndactyly have been reported in up to 61% of cases of CMTC.3 Ocular abnormalities in CMTC include glaucoma,6 peripheral retinal vasculopathy and nonperfusion,7 exudative vitreoretinopathy,8 and congenital RD.9 To date, the most commonly reported ocular finding in CMTC is glaucoma.3,6,8 The pathophysiologic features of these https://doi.org/10.1016/j.oret.2019.03.025 ISSN 2468-6530/19
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Figure 1. External photographs demonstrating cutaneous manifestations in a patient with cutis marmorata telangiectatica congenita (CMTC). A, Localized venous malformation on the scalp with overlying ulceration. B, Reticular vascular malformations with a venous malformation of the abdominal midline, typical for CMTC.
ocular manifestations are not well understood, although widespread primary dysfunction of veins, venules, capillaries, and possibly arterioles likely is a major disease component.4,5 The incidence of ocular findings in CMTC remains unknown and difficult to approximate, likely because of the rarity of this condition and its nonspecific presentation. Herein, we report a series of 9 patients with CMTC demonstrating various ocular manifestations including retinal vasculopathy and infantile-onset glaucoma. To the best of our knowledge, this report represents the largest case series of ocular manifestations in CMTC. Moreover, we present a comprehensive characterization of these ocular manifestations through the use of multimodal retinal imaging along with a relevant review of the literature on the subject.
Methods Research conducted was in compliance with the Health Insurance Portability and Accountability Act and the tenets of the Declaration of Helsinki, while abiding all regional, national, and international laws of the institutions involved in this study. Every effort was made by the investigators to protect the rights of patients during this study. This study is in concordance with the tenets of the ethics committee of each contributing center and was approved by the institutional review boards at each of these respective institutions. Patients with a diagnosis of CMTC referred for ophthalmologic evaluation and found to have ocular pathologic features not attributed to any other cause between January 1, 2015, and December 31, 2018, were included in this study. Collected data included findings from complete ophthalmologic examination and imaging throughout the course of follow-up, details of treatment (where applicable), results of neurologic imaging to assess for intracranial vascular lesions, and other systemic manifestations or complications of CMTC. Informed parental consent was obtained to allow the release of patient photographs for the purpose of research.
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Results A total of 9 patients (6 females, 3 males) were included in this study. The median age at presentation was 8 weeks, with a range of 2 weeks to 4 years. All children were born full term with an unremarkable birth history, with the exception of 1 infant born at 35 5/7 weeks’ gestational age whose neonatal course was complicated by severe pulmonary hypertension. A positive or suspected family history of CMTC in previous generations was not reported in any of the patients. However, 2 of the patients included in this series are siblings and are the offspring of nonconsanguineous parents. Two unrelated patients demonstrated clinical features of Adams-Oliver syndrome, of which 1 child was found to have a congenital heart defect (patent foramen ovale) common to this disorder. All patients in this study underwent genetic testing to identify genetic mutations commonly associated with other systemic conditions with similar presentations as CMTC. A genetic mutation (Notch1) was identified only in 1 of the children diagnosed with Adams-Oliver syndrome. All 9 patients in this series demonstrated 1 or more dermatologic manifestations commonly reported in CMTC including hypervascularity, mottling of the skin, telangiectasis, and ulceration. Additionally, 2 patients showed a unilateral port wine stain. Of the 9 patients in this series, 2 children experienced serious complications secondary to intracranial vascular anomalies. One of these patients experienced a hemorrhagic stroke at 11 months of age, despite normal brain magnetic resonance imaging and angiography results obtained at 3 months of age. Extensive ischemic encephalopathy in watershed distribution was observed in another patient, with a history of pulmonary vein stenosis requiring stenting shortly after birth possibly contributing to vascular insult. Other serious organ involvement, including a history of patent foramen ovale, developmental delay, epilepsy, and distal leg atrophy, were present in 4 of the 9 patients. All patients included in this study received thorough retinal evaluation by 1 year of age. With regard to the ocular manifestations of CMTC (Table 1), retinal abnormalities were observed
Table 1. Patients with Ocular Manifestations of Cutis Marmorata Telangiectatica Congenita Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 1
2 wks
F
Full Term Y
Visual Acuity Aversive to light both eyes
Anterior Segment High iris insertion with scalloped iris at insertion and immature angle structures
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Treatment
Periphery Avascular retina both eyes Mild venous dilation both eyes Venous loops both eyes Terminal buds with retinal hemorrhages both eyes
N
Laser photocoagulation to avascular retina both eyes (at 2 wks and 3 mos of age)
Y
Patent foramen ovale Subarachnoid hemorrhage Epilepsy
3 yrs of age Exudative vitreoretinopathy both eyes 2.4 cy/cm right eye 3.2 cy/cm left eye Intermittent esotropia both eyes Intermittent horizontal gaze evoked nonsustained nystagmus both eyes
Y
Ab externo trabeculotomy both eyes
Y
Nevus flammeus Developmental delay (mild)
18 yrs of age 20/20 right eye 20/25 left eye
Macula Granular appearance both eyes No foveal depression both eyes
1 mo
F
Y
BTL both eyes Corneal clouding Periphery Enlarged corneal Diffuse choroidal diameter hemangioma both eyes Venous tortuosity both eyes Macula Granular appearance both eyes
(Continued)
Ocular Manifestations in CMTC
FA Patchy choroidal filling both eyes Lack of FAZ both eyes Peripheral nonperfusion with dilated vascular terminals both eyes Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Late leakage both eyes 2
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Posterior Segment
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Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 3
3 wks
F
Full Term Y
Visual Acuity Aversive to light both eyes
Anterior Segment Scalloped iris at insertion and immature angle structures
Treatment
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Periphery Mild straightening of the nasal retinal vessels both eyes
N
None
Y
None
2 yrs of age 20/25 right eye 20/20 left eye
N
Laser photocoagulation to avascular retina both eyes Surgical intervention for retinal detachment left eye Vitrectomy and scleral buckle
Y
None
2.25 yrs of age Fix and follow both eyes
N
None
Y
None
7 mos of age Fix and follow both eyes
Macula Granular appearance both eyes No foveal depression both eyes FA Normal both eyes 4*
11 mos
F
Y
Fix and follow None both eyes
Periphery Avascular retina both eyes Peripheral neovascularization: mild right eye, severe left eye Progression to combined rhegmatogenous and tractional retinal detachment left eye Optic nerve Atrophy both eyes FA Peripheral nonperfusion and leakage both eyes
5*
3.5 mos
M
Y
CSM both eyes
None
Periphery Avascular retina both eyes FA Capillary dropout both eyes No peripheral leakage or terminal bulbs both eyes
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Posterior Segment
Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 6
4 yrs
F
Full Term Y
Visual Acuity
Anterior Segment
Posterior Segment
20/60 right eye Cataract left eye Periphery NLP left eye Posterior synechiae Avascular retina left eye right eye Extensive fibrovascular proliferation right eye No view left eye
Vascular Cutaneous Lesions
Major Systemic Findings or Disorders
Most Recent Follow-up
Glaucoma
Treatment
Y
Laser photocoagulation to avascular retina right eye2
Y
Seizures
8 yrs of age 20/70 right eye NLP left eye
Surgical intervention for recurrent retinal detachment right eye Vitrectomy
Y
Distal leg atrophy (unilateral)
4 yrs of age NLP both eyes
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Macula Pigmentary abnormalities right eye FA Peripheral nonperfusion right eye Leakage right eye
2 yrs
M
Y
LP both eyes
None
Periphery Avascular retina both eyes Extensive fibrovascular proliferation both eyes Macula Detached both eyes
d
(Continued)
Ocular Manifestations in CMTC
7
B-scan ultrasound Diffuse calcifications left eye Phthisis bulbi left eye
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Table 1. (Continued.) Ophthalmologic Examination Findings at Presentation Patient Age at No. Presentation Gender 8
5 wks
M
Full Term
Visual Acuity
N (induced CSM both at 35 5/7 eyes wks for pre-eclampsia)
Anterior Segment None
Glaucoma
Treatment
Periphery Avascular retina (zone II) with neovascularization (stage 3) both eyes Mild venous dilation both eyes Terminal buds both eyes Vitreous hemorrhage left eye Progression of retinal vasculopathy after treatment both eyes
N
Intravitreal Avastin 0.25 mg/ 0.1 mL (43.5 wks’ PMA) Laser photocoagulation to avascular retina both eyes (55 wks’ PMA and 2 yrs of age)
N
None
Major Systemic Findings or Disorders
Y
Birth weight 2750 g Adams-Oliver syndrome Severe pulmonary hypertension with stenosis of 4 veins
Most Recent Follow-up d
FA Peripheral nonperfusion with dilated vascular terminals both eyes Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Late leakage both eyes 9
2 mos
F
Y
BTL both eyes Immature angles
Periphery Mild venous dilation both eyes Venous loop left eye
d
3 mos of age Fix and follow both eyes
Macula Granular appearance both eyes FA Lacy pattern of capillary dropout both eyes Terminal bulbs both eyes Increased FAZ both eyes
BTL ¼ blinks to light; CSM ¼ central-steady-maintained; F ¼ female; FA ¼ fluorescein angiography; FAZ ¼ foveal avascular zone; LP ¼ light perception; M ¼ male; N ¼ no; NLP ¼ no light perception; PMA ¼ postmenstrual age; Y ¼ yes; d ¼ not assessed/not available. *Siblings.
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Posterior Segment
Vascular Cutaneous Lesions
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Ocular Manifestations in CMTC
Figure 2. Fundus photographs and fluorescein angiography images from patient 1. Fundus photograph of the right eye (A) at presentation, (B) at follow-up 3 months later, and (C) at follow-up 6 months after presentation demonstrating an abrupt termination of vessels with terminal bulbs and progression of vascular tortuosity and dilation despite adequate treatment with laser photocoagulation to areas of nonperfusion. Similar progression of left eye vascular abnormalities after laser photocoagulation to areas of (E) nonperfusion and (F) magnified area of vascular abnormalities and terminal bulbs with (G) corresponding fundus photograph.
within the first year of life in all patients and within 1 month of age in 3 patients. Peripheral retinal avascularity (Fig 2) was noted in 6 patients (11 eyes), of whom 2 patients (4 eyes) demonstrated significant retinal neovascularization at presentation. Four of these patients were treated with laser photocoagulation to the avascular retina. One patient demonstrated extensive neovascularization in the periphery (Fig 3) and progressed to a combined tractional-rhegmatogenous RD that later required surgical intervention with pars plana vitrectomy. Retinal detachment was observed in 1 eye of 2 patients, with 1 patient diagnosed at presentation. Both eyes with RD were treated surgically without complication. One child was treated with pars plana vitrectomy, whereas the other was treated with pars plana vitrectomy and scleral buckling. One patient showed a diffuse choroidal hemangioma in the right eye, and another patient demonstrated a patchy pattern of choroidal filling on fluorescein angiography (FA) in both eyes. Granular pigmentary abnormalities (Fig 4) in the macula were noted in 5 of the 9 patients. Additionally, 3 patients in this case series demonstrated retinal vascular findings not previously reported in CMTC. Capillary dropout with prominent terminal bulbs in the peripheral vessels was observed (Figs 2EeG and 5). Interestingly, dilated fundoscopic examination in the first week of life revealed only avascular peripheral retina in 1 of these patients. However, 2 of these 3 infants later demonstrated retinal or vitreous hemorrhage
by 2 weeks of age, indicating these vascular anomalies are rapidly progressive. In 1 of these 3 patients, a blunted foveal reflex was noted that corresponded to the absence of a foveal avascular zone noted on FA.
Discussion Cutis marmorata telangiectatica congenita is a rare disorder associated with multiple ocular findings, including glaucoma and retinal vascular abnormalities.6e9 Glaucoma is the most commonly reported eye finding in CMTC and previously was reported in 16 patients.3,6,9e16 Although most cases of glaucoma in patients with CMTC are of infantile onset, 2 cases have been reported to develop at 9 and 15 years of age.10,14 Several other ophthalmic anomalies have been reported in patients with CMTC, including congenital cataract,17 retinoblastoma,18 optic disc drusen,19 persistence of hyaloid artery,20 and small optical discs associated with cerebral atrophy.20 The pathophysiologic features of glaucoma in CMTC are hypothesized to be similar to those of glaucoma observed secondary to Sturge-Weber syndrome, which is attributable to angle dysgenesis in infants and increased episcleral venous pressure in older children.15,21 Nevus flammeus
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Figure 3. Fundus photographs and fluorescein angiography images from patient 4. Fundus photographs of the left eye demonstrating (A, B) avascular retina and severe peripheral neovascularization with retinal detachment at presentation, which (C, D) resolved after vitrectomy, scleral buckle, and laser photocoagulation.
often is associated with glaucoma in CMTC, especially in unilateral cases.10 The management of glaucoma in CMTC includes angle surgery, trabeculectomy, and glaucoma drainage device implantation, with trabeculotomy as the most commonly reported initial intervention. Because of the rarity of this condition, evidence-based data on the management of CMTC is limited. Six cases of infantileonset glaucoma initially were managed with trabeculotomy,
of which 1 case was complicated by suprachoroidal hemorrhage; 2 other children later required repeat trabeculotomy.3,6,12,15 In addition, there is 1 report of intraocular pressure control with a Molteno implant in an older child with CMTC.10 The collective experience of previous case reports, in combination with our management experience as presented in this series, suggests that the surgical management of glaucoma associated with CMTC is
Figure 4. Fundus photograph and fluorescein angiogram of the right eye of patient 3: (A) fundus photograph and (B) fluorescein angiogram demonstrating straightening of retinal vessels nasally and granular appearance of the macula with lack of foveal avascular zone.
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Figure 5. Fluorescein angiograms from patient 8 after treatment with laser photocoagulation: (A) right eye and (B) left eye showing laser application to areas of peripheral nonperfusion with dilated vascular terminals, lacy pattern of capillary dropout, and terminal bulbs.
similar to that of Sturge-Weber syndrome.21e23 Further studies are needed to assess the prognosis of patients with infantile glaucoma associated with CMTC. This case series demonstrated that CMTC is associated commonly with retinal pathologic features ranging from very mild findings, such as straightening of retinal vessels, to more severe findings of peripheral nonperfusion, exudative vitreoretinopathy, and RD. We concur that the onset of retinal abnormalities in CMTC demonstrates a progressive and variable time course spanning from within the first week of life to 2 years of age, and possibly beyond, as reported previously.6e9 SooHoo et al7 originally reported peripheral retinal avascularity in a patient with CMTC. We also report incomplete peripheral retinal perfusion or secondary retinal nonperfusion in 6 of our patients and find that peripheral avascularity is the most commonly observed retinal abnormality. Four of these 6 patients remained stable after treatment with laser photocoagulation to the avascular retina. Only 1 eye, which was complicated by severe neovascularization and previously failed treatment with an injection of intravitreal bevacizumab (0.25 mg/0.1 mL), required surgical intervention at a later time for a combined tractional-rhegmatogenous RD. Previous reports of RD observed in patients with CMTC describe bilateral congenital RD in an infant with neovascular glaucoma9 and tractional RD in both eyes of an infant with exudative vitreoretinopathy.8 We also describe a lace-like pattern of capillary dropout with prominent terminal bulbs noted in the retinal periphery on FA in 3 biologically unrelated patients with CMTC. This novel finding may represent one of the first manifestations of CMTC and a potential ocular signature that may aid in the early diagnosis of this rare condition. Similar to other childhood diseases associated with retinal vasculopathies, such as familial exudative vitreoretinopathy and incontinentia pigmenti, a suspected diagnosis of CMTC warrants complete ophthalmologic examination and FA immediately after birth and regularly during the first few months of life.24,25 Because retinal disease in CMTC can progress rapidly, there is a risk for
significant visual morbidity. This in part may be secondary to the sequelae of nonperfusion. If left untreated, ischemia secondary to peripheral retinal avascularity promotes the production of vascular endothelial growth factor and other cytokines involved in regulating retinal angiogenesis.26,27 Upregulation of these factors can lead to pathologic retinal neovascularization with the vitreous serving as a scaffold where vitreoretinal adhesions form, and RD can develop as the vitreous continues to pull away from the retina.28,29 Therefore, timely intervention with laser photocoagulation to areas of peripheral retinal nonperfusion is advisable. Likewise, the possibility for choroidal involvement is an important consideration during management. Choroidal vascular anomalies may increase the risk of delayed or intraoperative suprachoroidal hemorrhage or of exudative RD similar to those observed in Sturge-Weber syndrome.23,30,31 Patients with CMTC not only have reported retinal and cutaneous vascular abnormalities, but also cerebral vascular anomalies. Kremer et al12 reported a patient with CMTC who showed hemorrhagic choroidal detachments during a filtering procedure. Neuroimaging later revealed a concurrent left hemispheric vascular abnormality. Similarly, one of the patients in this series experienced a hemorrhagic stroke at 11 months of age, although brain imaging did not reveal any lesions. Further research investigating vascular malformations in CMTC will advance our understanding of this rare disorder and may provide valuable insight into this possible association between the central nervous system and ocular pathologic features. Cutis marmorata telangiectatica congenita is associated with approximately 20% of reported cases of Adams-Oliver syndrome,32 a rare congenital disorder first described in 1945.33 Adams-Oliver syndrome is characterized by widespread pathologic features, including congenital scalp defects; limb size discrepancies most commonly involving the lower limbs; cleft lip or palate, or both; mottled skin; hypervascularity; failure to thrive; developmental delay; and
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Ophthalmology Retina Volume 3, Number 9, September 2019 complex cardiovascular and central nervous system malformations.32,34 Congenital heart defects, as reported in one patient in our series, are reported in 13.4% of patients with Adams-Oliver syndrome.35 The most frequent method of inheritance of Adams-Oliver syndrome is autosomal dominant transmission.36 Cutis marmorata telangiectatica congenita, in contrast, is hypothesized to be caused by a sporadic gene mutation because most patients with CMTC have no documented family history.3 Happle37 suggested that the lethal gene hypothesis may contribute to the sporadic nature of this disease. This also may explain in part the patchy distribution of organ involvement.32 To date, there exists only 1 report of presumed autosomal dominant inheritance of CMTC with hypothesized incomplete penetrance in 3 generations.38 Outside of this series, there exists only 1 other report of CMTC documented in biological siblings.39 A homozygous truncating mutation in the ARL1P6 gene was reported recently in a patient with CMTC who also showed developmental delay, dysmorphism, transient ischemic attacks, and cerebral vascular malformations.40 Some evidence may suggest that environmental factors or certain teratogens may be associated with this rare disorder, because 1 report documented 4 cases of CMTC from a single geographic area within an 18-month period.41 Although glaucoma previously was recognized as the most common ocular finding in patients with this condition, in our series, glaucoma was diagnosed in only 2 patients, whereas retinal vascular abnormalities were present in all 9 patients. Three patients showed mild retinal involvement, and the remaining 6 patients showed significant retinal pathologic features, including peripheral retinal nonperfusion, fibrovascular proliferation, and RD. Three patients demonstrated a lacy pattern of capillary dropout coupled with terminal bulbs in the retinal periphery. This unique retinal finding to date has been described only in CMTC. Despite the many findings presented in this case series, a major limitation of this research is the considerable degree of inherent selection bias. In addition to being a retrospective analysis, the inclusion of patients in this study was nonrandomized, nonconsecutive, and made up entirely of select patients seeking treatment from select ophthalmologists. Given that CTMC is an extremely rare disease, the selection bias inherent to this study cannot be minimized. Therefore, we cannot be sure that the entire spectrum of CMTC and its ocular manifestations are captured in this study. Nevertheless, early identification and intervention are critical to prevent damage to the retina at a developmentally critical age and to impede vision loss secondary to RD. In patients with dermatologic or other systemic manifestations suggestive of CMTC, we recommend complete ophthalmologic evaluation immediately after birth, including intraocular pressure measurement, gonioscopy, dilated fundoscopic examination, and FA. Timely diagnosis and treatment of glaucoma, retinal vasculopathy, and RD are critical for preventing permanent vision loss in children with CMTC and impeding the burden of disease posed by this rare illness.
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Footnotes and Financial Disclosures Originally received: December 18, 2018. Final revision: March 13, 2019. Accepted: March 26, 2019. Available online: May 1, 2019. Manuscript no. ORET_2019_77.
Study was performed as part of regular employment duties at University of Michigan. No additional funding was provided.
Department of Ophthalmology and Visual Sciences, University of Michigan, W. K. Kellogg Eye Center, Ann Arbor, Michigan.
HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the respective institutions approved the study. All research complied with the Health Insurance Portability and Accountability (HIPAA) Act of 1996 and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients’ parents to allow the release of patient photographs for the purpose of research.
3
Section of Ophthalmology, Department of Surgery, University of Calgary, Calgary, Canada.
No animal subjects were included in this study.
4
Universidade Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Conception and design: Dedania, Moinuddin, Besirli
5
Hospital Federal dos Servidores do Estado (HSE), Rio de Janeiro, Brazil.
Analysis and interpretation: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli
1
Department of Ophthalmology, New York University School of Medicine, New York, NewYork.
2
6
Retina and Vitreous of Texas, Houston, Texas. 7 Department of Ophthalmology, Houston Methodist Hospital, Houston, Texas. 8
Department of Ophthalmology, Baylor College of Medicine, Houston, Texas. Financial Disclosure(s): The author(s) have made the following disclosure(s): F.M.C.M.: Lecturer Novartis, Bayer E.Y.C.: Consultant Genentech/Allergan. B.L.B.: Financial support Alcon Research Institute, Eversight.
C.G.B.: Financial support Novartis, MeiraGtx, Spark Therapeutics. Supported by the Blind Children’s Center (B.L.B.).
Author Contributions:
Data collection: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli Obtained funding: N/A Overall responsibility: Dedania, Moinuddin, Lagrou, Sathrasala, Medina, Del Monte, Chang, Bohnsack, Besirli Abbreviations and Acronyms: CMTC ¼ cutis marmorata telangectatica congenita; FA ¼ fluorescein angiography. Correspondence: Cagri G. Besirli, MD, PhD, Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected] .edu.
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