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 aor- tic 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 pa- tients 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 (REPRINTED) ARCH DERMATOL/ VOL 147 (NO. 2), FEB 2011 WWW.ARCHDERMATOL.COM 223 ©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 re- paired surgically. Numerous other tortuous cervicocra- nial vessels had been identified radiographically. He had also undergone surgical correction of the talipes equino- varus 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 syn- drome. 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 at- rophoderma vermiculatum (Figure 4). Other facial fea- tures 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. (REPRINTED) ARCH DERMATOL/ VOL 147 (NO. 2), FEB 2011 WWW.ARCHDERMATOL.COM 224 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 CASE 3 CASE 4 A 36-year-old woman with LDS presented with numer- A 37-year-old woman with LDS presented with numer- ous facial milia. She reported that the milia had been pres- ous facial milia. She reported that the milia had been pres- ent 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 diag- nosed 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 aneu- rysm syndromes, including Marfan syndrome, vascular Ehlers-Danlos syndrome, and Shprintzen-Goldberg