Multiple Facial Milia in Patients with Loeys-Dietz Syndrome

OBSERVATION

ONLINE FIRST Multiple Facial Milia in Patients With Loeys-Dietz Syndrome

Brendan M. Lloyd, MD; Alan C. Braverman, MD; Milan J. Anadkat, MD

Background: Loeys-Dietz syndrome (LDS) results from cases, affected relatives were reported to have similar mutations in the TGFBR1 or TGFBR2 genes and is known findings. to cause aggressive cardiovascular disease, including aortic aneurysms and dissections at an early age. Cur- Conclusions: To our knowledge, the association of LDS rently, craniofacial, skeletal, and cardiovascular find- and facial milia has not been previously reported. Recogni- ings play an important role in early recognition of the tion of LDS is important because the aggressive aortic and disease. While many patients do have recognizable cu- arterial disease warrants early surgical therapy. Facial milia taneous features of LDS, little information about associ- and other cutaneous findings may possibly differentiate LDS ated skin findings has been reported. from Marfan syndrome and other related disorders, thereby facilitating early diagnosis. Interestingly, each of the 4 patients with LDS and facial milia had a mutation in TGFBR2 Observations: Four unrelated patients with LDS due despite widespread variability in other features of the disease. to a mutation in the TGFBR2 gene were observed to have numerous facial milia. All 4 patients reported Arch Dermatol. 2011;147(2):223-226. that the milia had been present since early childhood Published online October 18, 2010. and had increased in number with time. In some doi:10.1001/archdermatol.2010.284

OEYS-DIETZ SYNDROME (LDS) Numerous cardiovascular and skeletal (OMIM #609192) is a re- manifestations of LDS have been described cently described autosomal in several case series. The only reported cu- dominant disorder that is taneous findings to date include velvety and caused by mutations in translucent skin, easy bruising, varicose TGFBR1 or TGFBR2 (transforming growth veins, and atrophic scars.1,2,6 The facies of L 1,2 factor ␤[TGF-␤]-receptor) genes. Patients LDS are characterized by malar hypopla- with LDS have widespread manifestions sia, retrognathia, deformities and asymme- that may include arterial tortuosity, aortic try resulting from craniosynostosis, bluish aneurysms and dissections, craniosynosto- sclera, and hypertelorism. Other common sis, hypertelorism, cleft lip, cleft palate, skeletal abnormalities include arachnodac- bifid uvula, bluish sclera, arachnodactyly, tyly, pectus deformity, scoliosis, cervical pectus deformities, and velvety and trans- spine abnormalities, talipes equinovarus, lucent skin. Some authors have further clas- camptodactyly, and joint laxity. sified patients with LDS into type I (those To date, our institution follows up 25 in- with more severe craniofacial abnormalities) dividuals with LDS, each with a mutation in and type II (those with velvety and translu- TGFBR1 or TGFBR2. We describe 4 patients cent skin, resulting in easily visible veins), from this population with LDS who have nu- but there is considerable overlap.2 merous facial milia that have been present Abnormalities in TGF-␤ signaling are sinceearlychildhood.Toourknowledge,this known to be associated with Marfan syn- finding has not previously been reported in drome and other aneurysm syndromes.3,4 patientswith TGFBR1orTGFBR2mutations outside of a brief oral communication, which Marfan syndrome is characterized by mu- 7 tations in the fibrillin-1 gene (FBN1), included 1 of our 4 patients. We also report which produces structural defects in the otherpotentiallyrelevantcutaneousfindings extracellular matrix as well as increased in these patients in an attempt to summarize known skin manifestations of LDS. TGF-␤ signaling.5 Both structural and Author Affiliations: Division of regulatory abnormalities are thought to Dermatology (Drs Lloyd and REPORT OF CASES Anadkat) and Cardiovascular contribute to the pathogenesis. In LDS, the mutation occurs in TGFBR1 or TGFBR2, Division (Dr Braverman), CASE 1 Washington University School producing a different phenotype with some of Medicine, St. Louis, overlapping features but with much more An 18-year-old man with LDS presented Missouri. aggressive cardiovascular disease.2 with numerous facial milia, most notably

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 1. An 18-year-old man with Loeys-Dietz syndrome and numerous Figure 3. A 24-year-old woman with Loeys-Dietz syndrome and more than periocular milia (patient 1). 25 milia in and around the left orbit (patient 2). An atrophic scar is also visible.

and inspection of his oral cavity showed a high-arched palate and bifid uvula. His cardiovascular findings included aneurysms of his aortic root and left subclavian artery, which had been repaired surgically. Numerous other tortuous cervicocra- nial vessels had been identified radiographically. He had also undergone surgical correction of the talipes equinovarus and pectus excavatum. Other significant skeletal abnormalities included kyphoscoliosis, arachnodactyly, camptodactyly, and joint laxity. Before LDS was described in 2005, this patient had been incorrectly diagnosed as having Shprintzen-Goldberg syndrome. The correct diagnosis of LDS was confirmed in 2005 by the identification of a TGFBR2 mutation (p.Arg537Gly). His father, who had a surgically repaired aortic aneurysm, was also diagnosed as having LDS at that time. The father was not known to have facial milia.

CASE 2

A 24-year-old woman with LDS due to a mutation in TGFBR2 (p.Arg528His) presented with numerous facial milia in the orbital area, including the eyelids (Figure 3). Milia had also developed at sites of scarring, including within and around her wide atrophic sternotomy scar. She reported that the facial milia had been present since early childhood. Physical examination revealed prominent malar atrophoderma vermiculatum (Figure 4). Other facial features included hypertelorism and retrognathia. The oral cavity was notable for a high-arched palate and a broad Figure 2. The face of patient 1 is notable for hypertelorism, malar hyoplasia, and retrognathia. The sequelae of craniosynostosis after multiple repairs are uvula. The patient had undergone surgical resection also evident. Numerous milia are visible infraorbitally. of an ascending aortic aneurysm as well as replacement of both the aortic and the mitral valves. She had enlarge- ment of the pulmonary artery and marked tortuosity of in a periocular distribution (Figure 1). Detailed his- the carotid and vertebral arteries as well. Other skeletal tory from his mother indicated that his facial milia had findings included scoliosis, arachnodactyly, camptodac- been present since early childhood and had increased in tyly, and joint laxity (Figure 5). She also had under- number. The lesions had been “scraped off” numerous gone multiple operations to repair skeletal defects, in- times in childhood, only to recur within a short time. Ex- cluding a cleft palate, pectus excavatum, and talipes amination of his head and face revealed an abnormal cra- equinovarus, and had suffered a spontaneous uterine rup- nial structure consistent with craniosynostosis, hyper- ture that was not related to pregnancy and required an telorism, malar hypoplasia, and retrognathia (Figure 2), emergency hysterectomy.

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A 36-year-old woman with LDS presented with numer- A 37-year-old woman with LDS presented with numerous facial milia. She reported that the milia had been pres- ous facial milia. She reported that the milia had been present since early childhood. She also reported that her fa- ent since early childhood. Inspection of her skin re- ther, who had suffered a fatal aortic rupture, had similar vealed numerous striae. Examination of her oral cavity facial lesions. She has 2 children with LDS, one of whom revealed a high-arched palate and a bifid uvula. Her car- has facial lesions consistent with milia. diovascular surgical history consisted of an aortic root Examination of her oral cavity was notable for a replacement. She also had mitral valve prolapse and mild high-arched palate. She did not have a noticeably tortuosity of her cervical vessels. broad or bifid uvula. Skeletal abnormalities included Her skeletal abnormalities included pectus excava- mild arachnodactyly and joint laxity. She had velvety tum, scoliosis, and hyperflexibility. She had experi- skin and easily visible veins. She also had suffered a enced numerous joint dislocations. She also had been type A aortic dissection and had undergone surgical diagnosed as having Marfan syndrome until evaluation repair of an aortic root aneurysm and replacement of in our institution identified a TGFBR2 mutation her aortic valve. She subsequently required resection (p.Arg537Cys). of a descending aortic aneurysm. She had been diagnosed as having Marfan syndrome until analysis in our institution revealed a mutation in exon 5 of TGFBR2 COMMENT (p.Phe442Leu). It is imperative to diagnose LDS correctly because it is associated with very aggressive vascular disease.8 Also, because LDS may be confused with other familial aneurysm syndromes, including Marfan syndrome, vascular Ehlers-Danlos syndrome, and Shprintzen-Goldberg syndrome, it is important to identify the features that differentiate these conditions. Besides craniofacial defects such as hypertelorism, bifid uvula, and cleft palate, cer- tain cutaneous features may be very helpful in suggest- ing and confirming the diagnosis of LDS. Facial milia, which have not been specifically reported in other familial aneurysm syndromes, may be specific to LDS. More research is needed to verify this point, but facial milia may contribute to the proper recognition of LDS. Because we believe that facial milia may represent a phenotypic manifestation of LDS, we herein report 4 cases of LDS with facial milia that were seen in our institution. We would add facial milia to velvety and Figure 4. Atrophoderma vermiculatum is prominent on the cheeks of patient 2. The significance of this finding, which is present in 1 of our 4 patients, is translucent skin, easy bruising, varicose veins, and atro- unknown. phic scars as recognizable cutaneous features of LDS.

Figure 5. The hands of patient 2 display arachnodactyly, camptodactyly, and joint laxity.

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©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Further studies, examining a larger population of in which delayed diagnosis places patients at consider- affected patients, may demonstrate that other skin find- able risk. ings, including atrophoderma vermiculatum and striae and milia formation at sites of trauma, are associated Accepted for Publication: August 23, 2010. with LDS. Published Online: October 18, 2010. doi:10.1001 In our population of patients with LDS, milia were pres- /archdermatol.2010.284 ent in 4 out of 25 patients. The genetic defect was iden- Correspondence: Milan J. Anadkat, MD, Division of Der- tified in all 25 patients, and each family studied had a matology, Washington University School of Medicine, unique mutation. In our population, the presence of milia 4921 Parkview Pl, Ste 5B, St Louis, MO 63110 did not correlate with a specific genetic defect or with ([email protected]). other clinical findings in LDS. Aprroximately two- Author Contributions: All authors had full access to all thirds of our patients with LDS had a mutation in the data in the study and take responsibility for the in- TGFBR2, and one-third had a mutation in TGFBR1.Itis tegrity of the data and the accuracy of the data analysis. interesting that all 4 of our patients with milia harbored Study concept and design: Lloyd, Braverman, and Anad- a TGFBR2 mutation, but the phenotypes observed in these kat. Acquisition of data: Lloyd, Braverman, and Anadkat. patients were otherwise quite variable. There is wide- Analysis and interpretation of data: Lloyd, Braverman, and spread phenotypic variability among all patients with LDS, Anadkat. Drafting of the manuscript: Lloyd. Critical revi- with both TGFBR1 and TGFBR2 mutations, and there is sion of the manuscript for important intellectual content: variability in the phenotype within family members af- Braverman and Anadkat. fected by the same mutation. Currently, it is unclear Financial Disclosure: Dr Anadkat receives honoraria as whether the presence of milia in LDS is unique to mu- a speaker for and/or consultant to ImClone, Bristol- tations in TGFBR2 or whether the findings to date are Myers Squibb, and Eisai. He has also served without com- attributable to chance. As our cohort of patients with LDS pensation as an investigator for Hana Biosciences. grows, milia may or may not be observed in patients with TGFBR1 mutations. Persistent milia have been reported as a feature of sev- REFERENCES eral genodermatoses, including Bazex-Dupre-Christol syndrome, Rombo syndrome, Rasmussen syndrome (a vari- 1. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, ant of Brooke-Spiegler syndrome), orofacial digital craniofacial, neurocognitive and skeletal development caused by mutations in syndrome type 1, and atrichia with papular lesions. Of TGFBR1 or TGFBR2. Nat Genet. 2005;37(3):275-281. 2. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations note, patients with Rombo syndrome also have atropho- in the TGF-beta receptor. N Engl J Med. 2006;355(8):788-798. 9 derma vermiculatum. A physiologic explanation for the 3. Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 muta- formation of milia has not been fully elucidated. There- tions in Marfan syndrome. Nat Genet. 2004;36(8):855-860. fore, the exact mechanism explaining milia develop- 4. Pannu H, Fadulu VT, Chang J, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. ment in LDS is also unclear. The formation of facial milia 2005;112(4):513-520. in patients with LDS could be a primary manifestation 5. Mizuguchi T, Matsumoto N. Recent progress in genetics of Marfan syndrome and of a TGFBR mutation. However, to date, no known as- Marfan-associated disorders. J Hum Genet. 2007;52(1):1-12. sociations between TGF-␤ signaling and milia forma- 6. Aalberts JJ, van den Berg MP, Bergman JE, et al. The many faces of aggressive tion have been reported. Alternatively, patients with LDS aortic pathology: Loeys-Dietz syndrome. Neth Heart J. 2008;16(9):299-304. 7. Berk DR, Bayliss SJ. Milia: a review and classification. J Am Acad Dermatol. 2008; may simply be prone to secondary milia formation as a 59(6):1050-1063. result of improper repair mechanisms after minor trauma. 8. Williams JA, Loeys BL, Nwakanma LU, et al. Early surgical experience with Loeys- We present these findings to further characterize the Dietz: a new syndrome of aggressive thoracic aortic aneurysm disease. 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