Loeys–Dietz syndrome, a rare autosomal dominant disorder caused by heterozygous mutations in the TGFBR1
genes, is characterized by vascular, skeletal, and craniofacial abnormalities. Affected individuals demonstrate vascular fragility leading to aortic aneurysms and dissections similar to those seen in patients with Marfan syndrome and Ehlers–Danlos syndrome type IV (OMIM 130050). Owing to this predisposition to hemodynamic compromise, the median survival for patients with LDS is only 37 years, with the most common cause of death being thoracic aortic aneurysm rupture [Loeys et al., 2005
]. Early diagnosis of LDS is essential as patients benefit from increased vascular surveillance and medical management to optimize hemodynamic parameters. In addition to life-threatening abnormalities of the vascular system, many patients with LDS also have characteristic findings of craniosynostosis, hypertelorism, downward slanting palpebral fissures, strabismus, highly arched palate, cleft palate or bifid uvula, micro-/retrognathia, malar hypoplasia, pectus deformity, scoliosis, arachnodactyly, and joint laxity. Less common findings that are rare in the general population include blue sclera, velvety or transparent skin, camptodactyly, patent ductus arteriosus, and atrial septal defects [Loeys et al., 2006
]. A minority of affected individuals have developmental delay, which is more likely to be present in association with craniosynostosis and/or hydrocephalus [Loeys et al., 2005
haploinsufficiency as a mechanism for LDS has been argued against in the literature because immunohistochemical staining of pathological surgical sections revealed an increase in downstream effectors of TGF-β signaling in vascular tissue and because of the wide repertoire of documented missense mutations [Dietz, 2010
Thus, the identification of a TGFBR2
deletion in a 20-month-old girl presented us with the clinical dilemma of having no precedent to guide clinical surveillance. In consultation with our cardiology colleagues, we chose to perform cardiac MRI and MRA studies of the arterial tree of the neck, chest, and abdomen, as well as MRA of the cerebral vasculature in our patient. Although, no arterial or cardiac abnormalities were detected, the risk of aortic dilatation and vascular fragility is undetermined in this individual. We have recommended repeat surveillance, as patients with LDS benefit from medical management and surgical repair of aortic aneurysms [Loeys et al., 2006
We were unable to definitively verify a diagnosis of craniosynostosis because X-ray or CT imaging would not have altered our clinical management since surgical intervention was not a consideration.
Recently, a patient with a large (~14 Mb) duplication CNV, including the entire TGFBR1
gene was reported to have an LDS-like phenotype [Breckpot et al., 2010
]. The 17-year-old boy presented with bifid uvula, pubertas tarda, camptodactyly, and dysmorphic features. Similarly, a patient harboring a large duplication of 3p21.3-3p25 (containing the TGFBR2
gene) was identified [Zhang and Wang, 1984
]. The 7-year-old boy presented with developmental delay, brachycephaly, micrognathia, and other dysmorphic features. Both of these patients have CNVs including a multitude of potentially dosage sensitive genes. Nonetheless, it appears that mammals are exquisitely sensitive to dosage variations in TGF-β signaling pathways, and thus it is reasonable to suggest that both phenotypes are at least partially caused by variation in dosage of TGF-β receptors.
Another rational conclusion might be to attribute our patient’s microcephaly and prematurely closed fontanels to a failure of brain development (suggesting a secondary craniosynostosis), especially given the abnormalities detected on brain MRI. Whereas, mutation of the TGFBR2 gene has been associated with primary craniosynostosis, developmental abnormalities of the nervous system are usually not observed in the affected individuals.
gene, encoding a glutamate decarboxylase-like protein 1, is also located within this patient’s deleted region (), but cytosolic enzymes are not typically dosage dependent [Phadnis and Fry, 2005
The PCR finding of mosaicism in this patient’s father, undetectable by traditional diagnostic FISH, raises the question of the clinical significance of such somatic mosaic CNVs. Previous studies have reported TGFBR2
mosaicism; the father of a severely affected child was found to harbor low levels of a missense mutation, suggesting mosaicism [Loeys et al., 2006
] and the father of another individual with LDS was more thoroughly investigated and found to have TGBFR2
mutations in multiple cell lineages [Watanabe et al., 2008
]. In both of these cases, the fathers had clinical manifestations to provoke investigation. In contrast, our patient’s father appears asymptomatic.
The relatively recent observation of CNV somatic mosaicism suggests that a meaningful number of CNVs can occur during mitosis [Notini et al., 2008
; Piotrowski et al., 2008
]. In our patient’s father, cells with the genomic rearrangement were too rare to be detected by peripheral blood FISH, but the CNV was nonetheless transmitted to his daughter. The importance of this observation lies in its impact on genetic counseling. Standard interpretation of the CGH and FISH results presented here would have suggested a near-zero recurrence risk. The recurrence risk for this father is higher based on our studies, and these observations have broader applicability for patients and counselors alike.
In summary, we present a first case of TGFBR2 deletion in a patient with microcephaly, mild dysmorphic features, and global developmental delay. Our findings suggest that TGFBR2 haploinsufficiency is insufficient to cause LDS but may have clinical consequences. The identification of additional patients with TGFBR2 haploinsufficiency and documentation of their natural history will be critical to demonstrate the full spectrum of phenotypes associated with alterations in the TGFBR2 gene and to guide clinical care and surveillance.