Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder caused by heterozygous mutations in the genes encoding transforming growth factor-β receptor type 1 or 2. It is typically characterized by a triad of hypertelorism, cleft palate or bifid uvula, and arterial tortuosity with aneurysm or dissection. Characteristic vascular abnormalities such as tortuosity, aneurysms, dissections, and stenosis are the most severe complications of LDS and can occur in the neurovascular system. We report a 5-year-old boy who presented with headaches and neurovascular abnormalities and was diagnosed with LDS with a novel mutation of the
Loeys-Dietz syndrome (LDS, OMIM 609192) is a connective tissue disease characterized by the triad of hypertelorism, cleft palate or bifid uvula, and arterial tortuosity with aneurysm or dissection. LDS was first described by Loeys in 2005 as an autosomal dominant disorder caused by a heterozygous mutation in the gene encoding transforming growth factor-β receptor type 1 (
The most severe abnormality in LDS, and the leading cause of death, is aortic aneurysm and dissection. In LDS, aortic dissection often occurs at a younger age, when aortic diameters are smaller, than in other connective tissue disorders.2, 3) The mean onset age of aortic dilatation is in the teens. Due to the aggressive nature of the aortic pathology in LDS, early surgical intervention is recommended. 3) In addition to the risks of aortic aneurysm, neurovascular involvement can cause dissections and intracranial hemorrhages that affect morbidity and mortality.1-3) Here, we report a case of LDS, diagnosed by a novel mutation of
A 5-year-old boy was referred to our hospital for evaluation of headache, tortuous intracranial arteries and vertebral arteries found up on brain magnetic resonance angiography. The patient’s family history was unremarkable for any genetic disease. He was born at 39 weeks of gestation by spontaneous vaginal delivery without complications. His birth weight was 3,580 gm. At 3 years of age, he was diagnosed with an inguinal hernia that was repaired surgically. At 4 years of age, he underwent surgical intervention for exotropia. His weight was 17 kg (50-70th percentile) and his height was 109.5 cm (50-70th percentile). His head circumference was 53 cm (97th percentile). On physical examination, bifid uvula, pectus carinatum, joint laxity, and borderline macrocephaly were noted; however, he had no definite facial dysmorphisms except mild hypertelorism and no specific ocular abnormalities. His neurologic examination was normal. For evaluation of the headache, he underwent electroencephalography (EEG) and brain magnetic resonance imaging (MRI) with magnetic resonance angiography (MRA). EEG showed a few generalized slow wave bursts interspersed with sharp wave discharges. Brain MRI/MRA revealed multiple T2 hyperintense lesions in the frontal and parietal subcortical white matter and diffuse, dilated, and tortuous intracranial arteries, including the vertebral artery, the basilar artery, and both the middle and posterior cerebral arteries (Fig. 1). With suspicion of systemic vascular disease, echocardiography and abdomen computed tomography (CT) was performed. Echocardiography showed normal cardiac anatomy but a markedly enlarged aortic sinus and annulus, which measured 50.2 mm (Z-value=17.99) and 22.8 mm (Z-value = 8.1), respectively (Fig. 2). Abdomen CT revealed a prominent celiac trunk and tortuosity of the abdominal aorta (Fig. 3). LDS was suspected based on clinical and imaging findings, including bifid uvula, multiple artery tortuosities, and aneurysm. Molecular genetic testing of the
At 7 years of age, valve-sparing aortic root replacement was performed because of a significantly enlarged aortic sinus. The postoperative clinical course was uneventful. After a 17 month follow-up period, a brain MRI/MRA showed no changes in the multiple T2 hyperintense lesions in both cerebral hemispheres and dilated, tortuous intracranial and vertebral arteries. In spite of his intermittent headaches, he has not developed any new neurological symptoms.
In 2005, Loeys et al., Dietz, and others described LDS as an autosomal dominant connective tissue disorder with multiple systemic involvement.1) LDS is characterized by the triad of arterial tortuosity and aneurysm, hypertelorism, and a bifid uvula or a cleft palate. Two subtypes of LDS have been described. LDS type 1 patients present with craniofacial manifestations, including cleft palate, craniosynostosis, or hypertelorism. Approximately threequarters of LDS patients present with typical facial dysmorphic features and are considered LDS type 1. LDS type 2 refers to patients with isolated bifid uvula and at least two of the clinical features associated with vascular Ehlers-Danlos syndrome (visceral rupture, easy bruising, wide and atrophic scars, joint laxity, and translucent and/or velvety skin).2)
The most severe abnormality in LDS is aneurysmal dilatation of the aortic root, which is present in 98% of LDS patients. It can result in aortic dissection and rupture, causing death at an early age.2) In addition to aortic root aneurysm, patients with LDS show several abnormal manifestations, including cardiac anomalies (patent ductus arteriosus, ductus aneurysm, bicuspid aortic valve, bicuspid pulmonary valve, arterial septal defects, mitral valve prolapse, and coronary artery aneurysm), craniofacial anomalies (craniosynostosis, malar hypoplasia, retrognathia and high arched palate, and dolichocephaly/scaphocephaly), and musculoskeletal anomalies (scoliosis, pectus deformity, dolichostenomelia, arachnodactyly, and camptodactyly).2, 4, 5) Neuroradiologic abnormalities are also commonly seen in patients with LDS. Previous studies have reported neuroradiologic features such as craniosynostosis, intracranial artery tortuosity, aneurysm, dissection and stroke, Chiari 1 malformation, and hydrocephalus, accompanied by neurocognitive symptoms such as developmental delays, sensory hearing loss, and headaches.2, 6)
A diagnosis of LDS is based on characteristic clinical findings and can be confirmed by molecular genetic testing of
The LDS phenotype may resemble other connective tissue disorders such as Marfan syndrome (MFS), Shprintzen-Goldberg syndrome (SGS), and vascular Enlers-Danlos syndrome (EDS). MFS is caused by mutations in the
The patient whom we described in this report was diagnosed with LDS because of clinical findings such as a bifid uvula, aortic aneurysm, and tortuosities of multiple arteries, and this diagnosis was confirmed by the detection of a novel mutation of
LDS is an aggressive aortic and distal arterial aneurysm syndrome predisposed to dissection and rupture earlier than other connective tissue diseases; therefore, early diagnosis and appropriate intervention are essential to prevent life-threatening complications. Since neurovascular abnormalities also can be accompanied by LDS, patients with any suspicion of LDS should be evaluated by imaging modalities such as brain MRA, and appropriate interventions should be taken to prevent neurologic complications.
Brain MRI/MRA revealed diffusely dilated, elongated, and tortuous intracranial arteries, cervical internal carotid arteries (ICA), and vertebral arteries (VA) (A, B), as well as multiple T2 hyperintense lesions in the frontal and parietal subcortical white matter (C).
Echocardiography and heart CT showed aortic root aneurysm. The aortic sinus and annulus measured 5.02 cm (Z-value=17.99) and 2.28 cm (Z-value=8.1), respectively.
Abdomen computed tomography demonstrates a prominent celiac trunk and superior mesenteric artery (SMA), and a tortuous abdominal aorta.