Abstract
Haemifacial microsomia is an asymmetrical congenital tissue malformation developed from the first and second branchial arches with or without multi-system involvement. Alternatively recognised as Goldenhar syndrome or oculoauriculovertebral spectrum (OAVS), it is an aetiologically heterogeneous group of disorders showing dominant trends in inheritable form.
We present a case of a boy in early childhood with concomitant craniofacial features of craniofacial microsomia with Loeys-Dietz syndrome. He had a unilateral hypoplastic face, asymmetrical ear malformations and multiple preauricular tags with epibulbar dermoid (features suggestive of Goldenhar syndrome). On detailed clinical evaluation, he met Beighton’s criteria and was diagnosed with arterial tortuosity. Further molecular testing confirmed the diagnosis of Loeys-Dietz syndrome type II.
Loeys-Dietz syndrome is characterised by aortic root enlargement or type A dissection with or without other vascular malformations and facial midline defects. Molecular testing is required to establish the diagnosis because of overlapping features with other connective tissue disorders.
Keywords: Genetics, Paediatrics
Background
Goldenhar syndrome is part of a spectrum of various phenotypic syndromes resulting from in utero axial mesodermal dysplasia. Typically, it is characterised by facial asymmetry and a range of anomalies affecting the dysplastic derivatives of the axial mesoderm. In most cases, there is no identifiable genetic cause, and the condition is considered to have a multifactorial inheritance pattern.1 The treatment for patients is primarily focused on managing symptoms, with many individuals opting for surgical interventions to address cosmetic concerns.
On the other hand, Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder distinguished by features such as hypertelorism, a bifid or broad uvula, cleft palate, aortic aneurysms and arterial tortuosity.2 LDS is associated with pathogenic variants in genes related to the transforming growth factor β (TGF-β) signalling pathway, including TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3.3 Molecular testing is crucial in diagnosing LDS due to its clinical overlap with conditions like the oculoauriculovertebral spectrum (OAVS) and other connective tissue disorders, such as Marfan syndrome.4
Case presentation
A boy in his early childhood, a known case of Goldenhar syndrome, born out of a non-consanguineous marriage sought medical attention for complaints of on and off cough and cold for the last 1 year. There were no other significant associated complaints at the time of presentation. He was diagnosed with Goldenhar syndrome at 2 years of age with a history of surgical removal of epibulbar dermoid 2 years back. There is a family history of valvular heart disease in the paternal grandmother for which she underwent valve replacement at the age of 58 years and expired 4 months later.
On examination, he had an asymmetrical hypoplastic face (figure 1A), bilateral cloudy cornea, reversed bilateral epicanthal folds, wide philtrum, preauricular tags (figure 1B) and asymmetrical ears. Anthropometry was normal (weight and height for age between median to −1SD and head circumference between −1SD to −2 SD as per WHO charts). He had pectus carinatum. The hearing assessment revealed the bilateral mixed type of hearing loss. Examination of the musculoskeleton revealed significant joint laxity with the rest of the examination being normal. Joint laxity is not a characteristic feature of the Goldenhar syndrome spectrum, which leads to clinical suspicion of additional disease processes and further workup.
Figure 1.
Clinical photograph showing asymmetrical hypoplastic face and preauricular tags on the right side of the face.
Investigations
On syndromic evaluation, 2D echocardiography showed a 5 mm ostium secundum atrial septal defect with a left-to-right flow with normal aortic dimensions. Non-contrast CT of the head and face with 3D reconstruction showed right-sided mandibular hypoplasia, reduced volume of right-sided sphenoid and maxillary sinuses and axial CT images showed smooth irregular inner table outline for which he was advised further evaluation. His magnetic resonance angiography of the head and neck revealed tortuous and prominent bilateral internal carotid and vertebral arteries (figure 2A and B). Furthermore, whole exome sequencing (next-generation sequencing, NGS) revealed a heterozygous pathogenic variant in the TGFBR2(+) gene on intron 7, variant- c.1599+1G>T (5’ splice site) pathogenic according to the American College of Medical Genetics classification, and it was validated by Sanger sequencing, confirming the diagnosis of Loeys-Dietz syndrome type 2. Joint laxity in the father’s clinical exome sequencing revealed the same pathogenic variant.
Figure 2.
3D TOF MR images showing tortuosity of the neck and cerebral vessels.
Outcome and follow-up
The child is on regular 6 monthly follow-ups and is doing well.
Discussion
Goldenhar syndrome or OAVS, a disorder of embryogenesis has a multifactorial inheritance with the majority of cases being sporadic. The typical estimated prevalence of OAVS is approximately 1 in 5600 individuals.5 However, a more recent study based on registries, published in 2014, reported a lower prevalence of 1 case per 26 370 individuals.6 From a clinical perspective, this condition manifests a range of anomalies. These include ocular abnormalities like microphthalmia, anophthalmia, epibulbar dermoid and eyelid colobomas. Aural defects such as preauricular tags, anotia, microtia and hearing loss are also common. Additionally, vertebral anomalies like scoliosis, hemivertebrae and cervical fusion may be present. Mandibular hypoplasia is frequently observed, particularly unilateral mandibular hypoplasia, which contributes to the condition known as haemifacial microsomia in most cases.7
In 2005, Loeys and Dietz first described LDS in 10 cases exhibiting a clinical triad of hypertelorism, bifid uvula/cleft palate and aortic/arterial aneurysms and tortuosity.8 LDS is a multisystem disease involving the cardiovascular, craniofacial, cutaneous and skeletal systems with a high risk for aortic aneurysms and dissections.4 The prevalence of LDS is unknown.9 LDS is categorised into four types, that is, LDS 1, LDS 2, LDS 3 and LDS 4 with mutations in TGF-β signalling pathway-related genes: TGFBR1, TGFBR2, SMAD3 and TGFB2, respectively.3
Clinically, LDS overlaps with OAVS such as Goldenhar syndrome and connective tissue disorders like Marfans’ syndrome.
Diagnosis of LDS in a proband with characteristic clinical findings is based on the presence of a heterozygous pathogenic variant of the causative gene and either of the following:
Aortic root enlargement or type A dissection
Characteristic clinical findings mainly arterial tortuosity, prominently including the head and neck vessels.10
Our patient was diagnosed with Goldenhar syndrome based on clinical findings of asymmetrical hypoplastic face, epicanthal folds, preauricular tags and epibulbar dermoid. Significant joint laxity with a positive Beighton criteria with a score of six out of nine on clinical examination along with vascular anomalies prompted further evaluation in the present case with appropriate investigations on the line of LDS. Diagnosis of LDS 2 was confirmed by NGS and Sanger sequencing, showing a heterozygous pathogenic variant in the TGFBR2(+) gene on intron 7. TGFBR2 splicing variant appears to affect the non-canonical transcript ENST00000359013.4 but not the canonical transcript ENST00000295754.10.
It is crucial to establish the diagnosis because individuals with LDS need regular echocardiography at frequent intervals to monitor the condition of the ascending aorta, which is usually not required for patients with OAVS.9
Learning points.
Any case displaying characteristics indicative of Goldenhar syndrome or with birth defects should undergo a detailed clinical assessment especially joint laxity to rule out associated connective tissue disorders.
The presence of vascular anomalies within the Goldenhar syndrome phenotype may indicate the need to consider a diagnosis of Loeys-Dietz syndrome.
Genetic testing should be considered in rare cases with diagnostic dilemma for confirmation.
Footnotes
Contributors: The following authors were responsible for drafting the text, sourcing and editing clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: HV and NR. The following authors gave final approval of the manuscript: HV, NR, PKV and NKB.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Consent obtained from parent(s)/guardian(s).
References
- 1. Martelli H, Miranda R de, Fernandes CM, et al. Goldenhar syndrome: clinical features with orofacial emphasis. J Appl Oral Sci 2010;18:646–9. 10.1590/s1678-77572010000600019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788–98. 10.1056/NEJMoa055695 [DOI] [PubMed] [Google Scholar]
- 3. Schepers D, Tortora G, Morisaki H, et al. A Mutation update on the LDS-associated genes Tgfb2/3 and Smad2/3. Hum Mutat 2018;39:621–34. 10.1002/humu.23407 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Van Laer L, Proost D, Loeys BL. Educational paper: connective tissue disorders with vascular involvement: from gene to therapy. Eur J Pediatr 2013;172:997–1005. 10.1007/s00431-012-1773-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Grabb WC. The first and second brachial arch syndromes. Plast Reconstr Surg 1965;36:485–508. 10.1097/00006534-196511000-00001 [DOI] [PubMed] [Google Scholar]
- 6. Barisic I, Odak L, Loane M, et al. Prevalence, Prenatal diagnosis and clinical features of Oculo-Auriculo-vertebral spectrum: a Registry-based study in Europe. Eur J Hum Genet 2014;22:1026–33. 10.1038/ejhg.2013.287 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Hartsfield JK. Review of the etiologic heterogeneity of the Oculo-Auriculo-vertebral spectrum (Hemifacial Microsomia). Orthod Craniofac Res 2007;10:121–8. 10.1111/j.1601-6343.2007.00391.x [DOI] [PubMed] [Google Scholar]
- 8. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, Craniofacial, Neurocognitive and Skeletal development caused by mutations in Tgfbr1 or Tgfbr2. Nat Genet 2005;37:275–81. 10.1038/ng1511 [DOI] [PubMed] [Google Scholar]
- 9. Loeys BL, Dietz HC. Loeys-Dietz syndrome. In: Adam MP, Mirzaa GM, Pagon RA, eds. GeneReviews®. Seattle (WA): University of Washington, 2008. [Google Scholar]
- 10. MacCarrick G, Black JH, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genetics in Medicine 2014;16:576–87. 10.1038/gim.2014.11 [DOI] [PMC free article] [PubMed] [Google Scholar]