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June 2015

Atrophoderma Vermiculatum: A Cutaneous Feature of Loeys-Dietz Syndrome

Author Affiliations
  • 1Department of Clinical Genetics, VU Medical Center, Amsterdam, the Netherlands
  • 2Department of Clinical Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, England
  • 3Department of Pediatrics, Academic Medical Center (AMC) University Hospital, Amsterdam, the Netherlands
JAMA Dermatol. 2015;151(6):675-677. doi:10.1001/jamadermatol.2014.4900

Atrophoderma vermiculatum (AV) is a rare skin disorder, typically presenting in childhood with a reticular pattern of skin atrophy on the cheeks, preauricular area, and forehead that seems to result from inflammation around follicular plugs. The causative mechanism leading to AV is unclear. It can present as an isolated skin manifestation, or AV can be part of other conditions including genetic disorders.1 Herein we report the association of AV with TGFBR2-related Loeys-Dietz syndrome (LDS).

Report of Cases

Patient 1

A 12-year-old boy with cardiac (widened aortic root and pulmonary artery, patent ductus arteriosus) and skeletal abnormalities (sagittal craniosynostosis, thoracic scoliosis, lordosis, pectus excavatum, long extremities, vertical talus, varus deformity, hyperlaxity) was diagnosed with LDS. Furthermore, dysmorphic facial features, amelogenesis imperfecta, and a high arched palate with lobulated uvula were also noted. A de novo pathogenic mutation in TGFBR2 (c.1639G>C p.Asp547His) was identified. At age 4 years, the patient had developed atrophic skin lesions on both cheeks, which stabilized after a few months of progression. At age 10 years, both cheeks showed reticulate atrophic lesions with a few follicular papules, which was diagnosed as AV (Figure, A).

Figure.  Clinical Images of 2 Patients With Atrophoderma Vermiculatum (AV) and Loeys-Dietz Syndrome
Clinical Images of 2 Patients With Atrophoderma Vermiculatum (AV) and Loeys-Dietz Syndrome

A, Close-up of cheek of patient 1 shows AV on both cheeks; a few follicular plugs can be observed. B, Full facial image of patient 2, age 11 years, shows sparse hair, receding frontal hair line, and a thin nose with hypoplastic alae nasi.

Patient 2

A 12-year-old boy (Figure, B) had been born with a cleft palate, associated Pierre Robin sequence, and talipes equinovarus. At age 6 years, he was noted to have mild reticulate scarring fitting the diagnosis of AV on both cheeks as well as milia in the infra-orbital region and the auricles. He also had cardiac (enlarged aortic annulus and aortic sinuses, aortic root dilatation, and bilateral carotid artery tortuosity) and skeletal abnormalities (postural scoliosis, mild pectus excavatum, metatarsus varus, joint hypermobility, bilateral fifth finger clinodactyly, and clinodactyly of left proximal interphalangeal joints II and III) and was diagnosed with LDS. In addition, a left inguinal hernia and a bifid uvula were documented. A de novo heterozygous mutation in TGFBR2 (c.1546_1557del12bp; p.Val516_Asp519del) was identified.


Both of the described patients had AV and LDS due to heterozygous TGFBR2 mutations; LDS is characterized by aggressive arterial aneurysms and widespread systemic involvement. To our knowledge, only 2 patients with AV and an aortic aneurysm syndrome have been reported in the literature. The first, a 14-year-old boy, was evaluated for Marfan syndrome, but genetic analysis of the FBN1 gene was not completed at the time of publication.2 The second, 24-year-old patient, was included in a study of 25 patients with LDS.3 She had multiple facial milia around the eyes and malar AV. A mutation in TGFBR2 was identified. Of additional interest, 3 other patients in that same study also had facial milia and a TGFBR2 mutation.3 Therefore, milia may be a feature of TGFBR2-related LDS.

Both AV and LDS are quite rare, so the association of these 2 conditions in several cases does not seem simple coincidence. It is difficult to explain the occurrence of AV in patients with LDS. The pathogenesis of LDS is aberrant TGF-β signaling due to mutations in TGFBR1/2, but many questions still remain. Similarly, the pathogenesis of AV is largely unknown.

It has been hypothesized that the keratinocytes in patients with AV mediate release of inflammatory cytokines in response to the plug formation. This inflammation then leads to fibrosis and atrophy.4 It may be that TGF-β signaling may also be involved because it is known that TGF-β signaling plays an important role in wound healing and scar formation. In LDS, atrophic scars and delayed wound healing have been reported.5 Interestingly, TGFBR1 null mutations cause multiple self-healing squamous epithelioma (MSSE)6 with subsequent atrophic scarring, which is also typical for AV. However, patients with MSSE do not have features of LDS, which is usually caused by missense mutations in the TGFBR1- or TGFBR2-kinase domain.5 Further investigations are needed to clarify the relationship between AV and LDS.

In conclusion, it appears that AV should be added as a cutaneous feature of LDS, possibly more specifically TGFBR2-related LDS. In view of the crucial importance of early detection and management of aortopathy in LDS, we suggest a careful evaluation for clinical features of LDS, including cardiac ultrasonography and possibly TGFBR1/2 DNA analysis in every patient presenting with AV.

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Article Information

Corresponding Author: Jan M. Cobben, MD, PhD, Department of Pediatrics, AMC University Hospital, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (j.m.cobben@amc.uva.nl).

Published Online: January 7, 2015. doi:10.1001/jamadermatol.2014.4900.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the affected individuals and their families for their kind cooperation. Also, we thank our colleagues Alessandra Maugeri, PhD, Gerard Pals, PhD (Department of Clinical Genetics, VU Medical Center), Ad P. Backx, MD, PhD (Department of Pediatric Cardiology, AMC University Hospital), John M. Simpson MD, PhD (Department of Pediatric Cardiology, Guy’s and St Thomas’ NHS Foundation Trust), and Maritza A. Middelkamp-Hup, MD (Department of Dermatology, AMC University Hospital) for their help with interpretation of data.

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