European Journal of Pediatrics

, Volume 173, Issue 3, pp 387–391

Loeys–Dietz syndrome in a Southeast Asian Hospital: a case series

  • Teck Wah Ting
  • Angeline Hwei Meeng Lai
  • Jonathan Tze Liang Choo
  • Teng Hong Tan
Original Article

DOI: 10.1007/s00431-013-2187-0

Cite this article as:
Ting, T.W., Lai, A.H.M., Choo, J.T.L. et al. Eur J Pediatr (2014) 173: 387. doi:10.1007/s00431-013-2187-0

Abstract

Loeys–Dietz syndrome (LDS) is a heritable connective tissue disease in which the activity of the transforming growth factor (TGF) beta signalling pathway is disrupted. The clinical features of LDS represent a clinical continuum that includes LDS type 1, with cutaneous, vascular, skeletal and craniofacial findings, and LDS type 2, with cutaneous, vascular and skeletal findings. We describe five Asian patients with genetically confirmed LDS with mutations in either the TGFBR1 or TGFBR2 gene. Their clinical features were similar to those reported in Caucasian patients. Two patients have novel mutations in TGFBR2. Transcatheter occlusion of patent ductus arteriosus (PDA) was safe and successful in three patients. Treatment with Losartan for aortic root dilatation was well tolerated in our patients, but the outcome is mixed. Among the three patients with follow-up data, aortic root dilatation has improved in two patients but continues to progress in the third patient despite treatment. Conclusion: We describe two novel mutations in TGFBR2 leading to LDS; PDA is common in our patients and can be safely occluded via transcatheter procedure.

Keywords

Loeys–Dietz syndrome Aortic root aneurysm Transforming growth factor beta Connective tissue disease 

Abbreviations

LDS

Loeys–Dietz syndrome

MFS

Marfan syndrome

PDA

Patent ductus arteriosus

TGF

Transforming growth factor

Introduction

Loeys–Dietz syndrome (LDS) is an autosomal dominant disorder that disrupts the activity of the transforming growth factor (TGF) beta signalling pathway. First described in 2005 [4], it is a heritable connective tissue disorder affecting the vascular system (aortic root aneurysm, aneurysms and tortuosity of other arteries), the craniofacial region (hypertelorism, cleft palate, bifid uvula, craniosynostosis), the skeletal system (pectus deformities, scoliosis, hypermobile joints, arachnodactyly and talipes equinovarus), and the skin (translucent skin, atrophic scars). LDS type 1 (OMIM #609192, 610168), involves the skin, the vascular system, the skeletal system and the craniofacial features, while LDS type 2 (OMIM #608967, 610380) involves the skin, the vascular system and the skeletal system but without the craniofacial features. It is now increasingly recognised that both types are in a continuum of a common clinical spectrum [1]. There are no established diagnostic criteria, and genetic testing is therefore important for diagnosis. The underlying mutation is found in TGFBR2 (~70 %), followed by TGFBR1 (~20 %), SMAD3 (~5 %) or TGFB2 (~1 %) [5]. LDS types 1 and 2 are attributed to mutation in either TGFBR1 or TGFBR2. Patients with mutation in SMAD3 are recently classified as LDS type 3 (OMIM #613795) and have joint abnormalities like osteoarthritis [9], while those with mutation in TGFB2 have been classified as LDS type 4 (OMIM #614816).

Most cases reported in the literature are from Western populations [6]. Recent publications compared the phenotype of Asian patients with LDS, with Western patients [2, 3, 8, 12]. We describe the clinical features and genotypes of five patients with LDS seen in a tertiary children's hospital in Singapore and convey our experience in managing their cardiovascular complications.

Methodology

Our study is a retrospective review of these patients and was approved by the institutional review board of our hospital. Since 2007, five patients with LDS have been diagnosed and managed in our hospital. Transthoracic echocardiograms were done for all patients at diagnosis and at regular intervals during follow-up. Measurements were taken at the aortic annulus, sinus, sinotubular junction and ascending aorta with the aortic valve fully open at systole. These measurements are compared to population norms based on body surface area.

All our patients had mutation analysis of TGFBR1 and TGFBR2 done in a commercial laboratory (Laboratory for Molecular Medicine, Center for Genetics and Genomics, Harvard Medical School - Partners Healthcare Centre) and were not tested for SMAD3 and TGFB2.

Results

The clinical features of our patients are summarised in Table 1. The patients range in age from 2 to 9 years, with four females and one male. Apart from one patient of Indian–Caucasian descent, the rest are ethnic Chinese. None has any significant family history of LDS. Features seen in all five patients include palate abnormalities (two have bifid uvula, and three have cleft palate), aortic root aneurysm, arterial tortuosity and patent ductus arteriosus (PDA). Three patients have blue sclerae. One patient (patient 1) has features typical of LDS type 2 (translucent skin, bifid uvula and absence of craniofacial dysmorphism). There were two patients with cervical spine instability. One of them presented with acute torticollis at 6 years of age and was found to have anterior subluxation of C1, C2 and occipital condyle; she was treated conservatively. The other patient had asymptomatic anterolisthesis of C2 over C3, detected through screening at 1 year old.
Table 1

Clinical characteristics of patients

Characteristics

Patients

1

2

3

4

5

Our series

Loeys et al. [6] study (%)

LDS type

LDS type 2

LDS type 1

LDS type 1

LDS type 1

LDS type 1

  

Genetic mutation

Heterozygous c.1460G > A (p.Arg487Gln), Exon 7, TGFBR1

Heterozygous c.859 T > C (p.Trp287Arg), Exon 4, TGFBR2*

Heterozygous c.1546_1557del (p.Thr516_Glu519del), Exon 7, TGFBR2*

Heterozygous c.1583G > A (p.Arg528His), Exon 7, TGFBR2

Heterozygous c.1583G > A (p.Arg528His), Exon 7, TGFBR2

  

Age (as of 2012)

9 years

7 years

2 years

8 years

5 years

  

Sex

F

M

F

F

F

  

Hypertelorism

+

+

+

+

3/5

90

Cleft palate (abnormal uvula)

+ (Bifid uvula)

+ (Bifid uvula)

+ (Cleft palate)

+ (Cleft palate)

+ (Cleft palate)

5/5

90

Aortic root dilatation

+

+

+

+

+

5/5

98

Aortic root Z score (at presentation)

+11.45

+3.4

+3.1

+6.6

+4.9

  

Aneurysm of other vessels

+

1/5

52

Arterial tortuosity

+

+

+

+

+

5/5

84

Patent ductus arteriosus

+

+

+

+

+

5/5

35

Atrial septal defect

+

1/5

22

Craniosynostosis

+

+

2/5

48

Malar hypoplasia

+

1/5

60

Retrognathia

+

1/5

50

Blue sclerae

+

+

+

3/5

40

Ectopia lentis

0

Dolichostenomelia

18

Arachnodactyly

+

+

+

+

4/5

70

Pectus deformity

+

+

+

3/5

68

Scoliosis

+

+

2/5

50

Talipes equines varus

+

1/5

45

Camptodactyly

+

+

+

3/5

38

Joint laxity

+

+

+

+

4/5

68

Cervical spine instability

+

+

2/5

18

Velvety skin

28

Translucent skin

+

+

2/5

32

Developmental delay

15

*Novel mutation

One patient (patient 1) underwent surgical repair of the aortic root at 7 years of age. She had been diagnosed with LDS a few months earlier and already had severe aortic root aneurysm at presentation (43.3 mm at the sinus of Valsalva, Z score +11.5). Patients 1 and 3 were managed in other hospitals after the establishment of the diagnosis. All patients were started on Losartan upon confirmation of diagnosis. Our starting dose of Losartan was 0.7 mg/kg/day. The dose was titrated upwards gradually against the progression of the aortic root dilatation. Patient 2 had an aortic root dilatation with a maximum Z score of +5 at 4 years old; the dilatation improved to a Z score of +2.2 at 7 years old with Losartan 1.3 mg/kg/day. Patient 5 had an initial aortic root dilatation at a Z score of +5 at 1 year old; her dilatation peaked was at Z score of +7.8 at 5 years old before improving slightly to a Z score of +7.2 at 5.5 years old with Losartan 1.5 mg/kg/day. Patient 4 has progression of aortic root dilatation from a Z score of +6.6 at 4 years old to a Z score of +8.5 at 8 years old despite taking Losartan 1.5 mg/kg/day; her dose was then increased to 2 mg/kg/day. None of our patients had side effects such as hypotension and giddiness.

Three patients (patients 2, 4 and 5) underwent successful transcatheter device closure of their PDA between 3 and 7 years of age. We used coils for patients 2 and 4 with small PDA (2.6 mm at 5 years old and 2.4 mm at 7.5 years old, respectively) and Amplatzer duct occluder for patient 5 with moderate PDA (4 mm at 3 years old). These procedures have not been previously reported in patients with LDS. There were no difficulties with catheter manipulation, device delivery or stability. All three patients have remained well on follow-up for the past 2 to 3 years after the procedure with no residual shunt across PDA.

Genetic analysis

Heterozygous mutations in TGFBR1 or TGFBR2 were detected in all patients (Fig. 1). Two mutations have previously been reported in the literature [4, 6, 7]. The c.1583G > A (p.Arg528His) mutation in exon 7 of TGFBR2 was found in patients 4 and 5, both with LDS type 1. The c.1460G > A (p.Arg487Gln) mutation in exon 9 of TGFBR1 was found in patient 1 with LDS type 2. This mutation has been reported in LDS patients as well as a patient with isolated thoracic aortic aneurysms and dissections (TAAD) [7].
Fig. 1

Mutations in TGFBR1 and TGFBR2 found in our patients with Loeys–Dietz syndrome. The exons are numbered. The legends show the functional domains of the receptors encoded. Asterisk indicates novel mutation + indicates 2 patients have this mutation

Two novel mutations in TGFBR2 were detected in patients 2 and 3, both with LDS type 1. The first mutation, c.859 T > C (p.Trp287Arg) in Exon 4 of TGFBR2, is a missense mutation. The second mutation, c.1546_1557del (p.Thr516_Glu519del) in exon 7 of TGFBR2, is an in-frame deletion in the last exon of TGFBR2, which removes four amino acids. In both patients, genetic testing of EDTA blood from the clinically unaffected parents showed that the mutations were de novo. Given the characteristic clinical features in the patients, we concluded that the mutations are pathogenic.

Discussion

Our patients have the typical clinical features described in Western populations. This is similar to the findings of Yang et al. [12], who reported that the frequencies of clinical features in Korean LDS patients were similar to those in the Western populations. Blue sclerae, which was reported in 40 % of the patients described by Loeys et al. [6], were not found in the Korean LDS patients but are present in two of four of our Asian patients. It is likely that the clinical features of LDS do not differ significantly between ethnic groups.

The genetic mutations in our patients, including two previously unreported mutations, are located in or flanking the intracellular serine–threonine kinase domains of both receptors. This is consistent with the nature and location of TGFBR1 and TGFBR2 mutations in LDS reported in the literature [4]. We chose to investigate first the genes (TGFBR1 and TGFBR2) in which disease-associated mutations are more commonly detected. In patients with clinical features of LDS in whom no mutations are detected in TGFBR1 or TGFBR2, testing for mutations in SMAD3 and TGFB2 genes would be indicated but there was no such case in our series reported here.

High clinical suspicion and early diagnosis of LDS is important. The main differential diagnosis when aortic root dilatation is detected is Marfan syndrome (MFS). Up to 97 % of patients with MFS have a mutation in the Fibrillin-1 (FBN1) gene. Certain features in the diagnostic criteria in MFS like ectopia lentis and dolichostenomelia have not been reported in LDS. LDS should be considered as a possible underlying diagnosis when diagnostic criteria for MFS are not fulfilled, FBN1 gene mutation is not detected or craniofacial features suggestive of LDS are prominent.

The aortic root dilatation in patients with LDS progresses rapidly, and aortic dissection occurs at smaller diameter compared to MFS. Surgical intervention is also required earlier [11]. Losartan, an angiotensin II type 1 receptor antagonist, has anti-TGF beta activity and has been shown to slow the progression of aortic root dilatation. This is because the dilatation is due to paradoxical enhancement of TGF beta signalling as shown in MFS mouse models [10]. All our patients were started on Losartan just after confirmation of the diagnosis. Of the three patients who remained in our care, the response to treatment is mixed.

Three patients required transcatheter device closure of PDA. Preparation for the procedure, the procedure and post-operative recovery were similar to patients without underlying LDS. Therefore, this procedure can be considered a safe and effective alternative to surgery for LDS patients with PDA requiring closure.

Our study sample size is small, which may have influenced our results. As LDS is not a common disorder, we hope with this report to add to the knowledge base of the condition and to increase clinical awareness. Given the aggressive nature of the aortopathy in LDS, a high index of suspicion and early diagnosis of LDS is important so that timely treatment can be offered.

Conflict of interest

The authors declare that they have no conflict of interest.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Teck Wah Ting
    • 1
  • Angeline Hwei Meeng Lai
    • 1
  • Jonathan Tze Liang Choo
    • 2
  • Teng Hong Tan
    • 2
  1. 1.Genetics Service, Department of Paediatric MedicineKK Women’s and Children’s HospitalSingaporeSingapore
  2. 2.Cardiology Service, Department of Paediatric SubspecialtiesKK Women’s and Children’s HospitalSingaporeSingapore

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