Fetal intracerebral hemorrhage and cataract: think COL4A1

Abstract

The COL4A1 gene encodes the alpha1 chain of type IV collagen, a crucial component of nearly all basement membranes. Mutations in COL4A1 were first associated with cerebral microangiopathy and familial porencephaly. Recently, several authors have reported mutations in COL4A1 as a Mendelian cause of prenatal onset intracranial hemorrhage (ICH). We report two cases of prenatal ICH associated with cataract and suggest that COL4A1 mutation should be envisaged in fetuses with prenatal ICH, especially in the presence of lens abnormalities at ultrasound examination.

Introduction

The COL4A1 gene encodes the alpha1 chain of type IV collagen, a crucial component of nearly all basement membranes including those of the vasculature, renal glomerule and ocular structures. Mutations in COL4A1 were first associated with cerebral microangiopathy (OMIM 607595) and familial porencephaly (OMIM 175780), and then with neonatal and adult intracerebral hemorrhages, aneurysms, ocular manifestations of variable types and nephropathy.¹ Recently, COL4A1 mutations have also been identified prenatally in fetuses with intracranial hemorrhage (ICH).^{2, 3} The two additional prenatal cases we present suggest that the involvement of COL4A1 may be suspected prenatally in fetuses with ICH associated with cataract.

Case

Case 1

A 35-year-old woman (G2P1) without medical history was referred at 23 weeks of gestation (WG) after detection of fetal abnormalities. Ultrasound (US) examination showed left-sided abnormalities including a hyperechogenic lens, a hyperechogenic lesion (3 × 5 × 8 mm) involving basal ganglia and mild ventriculomegaly (10.5 mm; Figures 1a and b). The family history was remarkable for the presence of a congenital bilateral cataract in her first daughter. This girl had been seen by one of us (DB) at the age of 2 years before the mother envisaged a subsequent pregnancy, but the risk of recurrence was considered low. At 32 WG, magnetic resonance imaging confirmed the subependymal hemorrage affecting the left cerebral hemisphere (Figure 1c) and evidenced a cerebellar hypoplasia. Subsequent US examination at 33 WG showed a 5.4 mm-long subependymal hemorrhage in the left cerebral hemisphere, dilated anterior horns of the ventricles, cerebellar hypoplasia and bilateral cataract. After being informed of the neurologic prognosis, the parents opted for termination of the pregnancy (TOP) at 34 WG, as permitted by French law. Histological examination confirmed the hemorrhagic lesions and revealed neuroglial heterotopia with vascular hyperplasia in the brain, hypoplasia of cerebellar peduncles and a few heterotopic Purkinje cells in the cerebellum.

Figure 1

Case 1: ultrasonography at 23 weeks of gestation (WG) showing cataract in the left eye (a) and hyperechogenic lesion involving left basal ganglia (arrow, b). MRI at 32 WG showing left subependymal hemorrage (arrow, c). Case 2: ultrasonography at 31 WG showing hyperechogenic lesion in the left cerebral hemisphere with thalamic echogenicity (d) and right cataract (e). MRI at 32 WG showing left parenchymal hemorrhage and mild left-sided ventriculomegaly (arrow, f).

Case 2

A 26-year-old woman (G2P1), without medical and family history, was referred at 31 WG after fetal detection at US examination of a hyperechogenic lesion in the left cerebral hemisphere with thalamic echogenicity, suggesting calcification (Figure 1d), bilateral hyperechogenic lenses and a hyperechogenic bowel. At 32 WG, magnetic resonance imaging showed a left-sided periventricular parenchymal hemorrhage and mild ventriculomegaly (11 mm), and US examination confirmed the presence of a bilateral cataract (Figures 1e and f). Similarly to Case 1, the parents opted for a TOP at 34 WG. Histological examination of the brain and cerebellum showed numerous foci of calcified necrotic tissue. In both cases, there was no history of trauma during pregnancy and maternal screening for fetal infections, including cytomegalovirus, thrombophilia and alloimmune thrombocytopenia, were negative.

Molecular findings

In both these cases, the involvement of COL4A1 was evoked because congenital cataracts had been previously reported in association with ICH in pediatric cases.⁴ The sequencing of COL4A1 was therefore performed on fetal DNA obtained after TOP and evidenced two heterozygous novel missense mutations c.2317G>A (p.Gly773Arg) and c.3005G>A (p.Gly1002Asp) in fetuses 1 and 2, respectively. Both these mutations are typical of mutations usually reported in collagenopathies, involving highly conserved glycine residues in a triple helical domain of the protein heterotrimer. These mutations were not found in 288 control chromosomes and were absent in the Exome Variant Server and in dbSNP137. In Case 1, the mutation was also found in the asymptomatic mother but was not searched for in the daughter affected with congenital cataract. The asymptomatic parents of Case 2 declined testing for the COL4A1 mutation.

Discussion

Fetal ICH has been reported with a prevalence of 0.9 per 1000 pregnancies and 0.46 per 1000 deliveries. In some cases maternal and fetal risk factors were suspected, but in the majority of cases no etiology was identifiable.⁵ Recently, several authors have reported mutations in COL4A1 as a Mendelian cause of prenatal onset ICH,^{1, 4, 6, 7} but the prevalence in fetal ICH is unknown. COL4A1 mutations were initially described as a cause of perinatal ICH in mice and porencephaly in human and thereafter implicated in a broad spectrum of clinical phenotypes involving most frequently the brain and the eyes, starting from the fetal period until late adulthood.¹ Ophthalmologic features associated with COL4A1 mutations include retinal arteriolar tortuosity, anterior segment dysgenesis and congenital cataract.⁸ Interestingly, congenital cataract, found in three out of four cases in a recently reported pediatric study of early stroke caused by a COL4A1 mutation,⁴ seems to be a frequently associated sign. Although the underlying mechanism of cataract pathogenesis in this condition is still unknown, it has been shown in COL4A1 mutant mice that missassembly of the COL4(A1.A1.A2) heterotrimers leads to the retention of both COL4A1 and COL4A2 in the lens secretory pathway activating the unfolded protein response.⁹

In most cases of COL4A1-related ICH of prenatal onset the diagnosis was made postnatally, but prenatal diagnosis of this condition has been recently reported in two instances.^{2, 3} The two cases reported here show that the COL4A1 mutation should be envisaged in fetuses with prenatal ICH, especially in the presence of lens abnormalities at US examination. Conversely, the presence of a fetal cataract should lead to a thorough search of the family history for stroke, migraine and cataract or other anterior segment defects, as well as US examination for neurological abnormalities. Molecular confirmation of a COL4A1 mutation may indeed have important implications for the outcome of the pregnancy and for genetic counseling.