Moyamoya syndrome in a patient with Aicardi-Goutières syndrome associated with a SAMHD1 mutation: a case report

Aicardi‒Goutières syndrome is a rare, early-onset, autoinflammatory, genetically determined encephalopathy belonging to the interferonopathy family [1]. The syndrome results from multiple protein deficiencies involving nine major genes whose pathogenic variants lead to an alteration in nucleic acid metabolism, leading to uncontrolled production of interferon-α and chronic inflammation pathology. The diagnosis is established by clinical examination, analysis of cerebrospinal fluid, brain imaging, and genetic analysis [1].

In its classic form, Aicardi-Goutières syndrome starts in the neonatal period or in infancy in a patient born at term with a normal neonatal head circumference. Aicardi-Goutières syndrome is characterized by severe encephalopathy (irritability, feeding difficulties, psychomotor delay or regression, and seizures) with progressive microcephaly and nonneurological symptoms (glaucoma, sterile pyrexia, chilblains, inflammatory arthropathy, short stature, and hypothyroidism). Presence of the radiological features of Aicardi-Goutières syndrome is a clue for diagnosis, and the most common abnormalities are leukodystrophy, basal ganglia and white matter calcifications, striatal necrosis, deep white matter cysts, and supra- and infratentorial atrophy [2].

A girl born at full term to parents of Turkish origin, first cousins, presented with congenital glaucoma, congenital hypothyroidism (normal anti-TPO and anti-thyroglobulin antibody levels), and a deep sacrococcygeal dimple. At birth, her head circumference was 31.5 cm (3rd percentile). At 6 months of age, strabismus appeared. From 11 months of age, the patient presented with axial hypotonia and numerous episodes of irritability. At 15 months of age, she was referred for neuropaediatric evaluation. Neurological examination revealed progressive microcephaly (head circumference below the first percentile), speech delay, pyramidal syndrome with severe axial hypotonia, and peripheral hypertonia leading to motor difficulties. Hearing was normal.

Cerebrospinal fluid analysis and blood tests revealed no signs of prenatal infection. The interferon signature could not be obtained because of a technical problem. Cardiac and abdominal ultrasonography findings were normal.

The girl underwent successive brain imaging. At 15 months of age, the spinal-cord magnetic resonance imaging (MRI) findings were normal, and brain MRI revealed delayed myelination and T₂ hypersignals in the periventricular white matter (Fig. 1). At 2 years and 6 months of age, brain MRI additionally revealed symmetrical clusters of hyposignals on susceptibility-weighted images, suggesting calcifications in the periventricular frontal white matter. Therefore, brain computed tomography (CT) was performed (at the age of 3 years and 2 months), and the findings confirmed the scattered calcifications in the periventricular frontal white matter and in the lenticulate nuclei (Fig. 2). These results suggested Aicardi-Goutières syndrome or pseudo-TORCH syndrome; however, TORCH infections were excluded. Trio-based whole-genome sequencing revealed a homozygous p.Arg290 Cys variant in the SAMHD1 gene (Chr20(hg38):g.36917034G>A;NM_015474.4:c.868 C>T). Each parent was heterozygous for the variant. This variant has previously been reported in a patient with interferonopathy and was considered pathogenic (class 5 according to the American College of Medical Genetics and Genomics) [3]. This finding led to the performance of another brain MRI with 3D time-of-flight (TOF) angiography at 4 years and 3 months of age, which revealed severe stenosis of the left middle cerebral artery origin, with a dilated collateral arterial network (moyamoya syndrome); long stenosis of the right posterior cerebral artery; and mild narrowing of the right internal carotid artery (Fig. 3). No ischaemic lesions were detected on diffusion-weighted, T₁-weighted, or T₂-weighted images. Even retrospectively, no obvious intracranial arterial stenosis was visible on conventional MRI sequences. Retrospectively, brain CT revealed mild hypoplasia of the right carotid canal at the level of the petrous bone (Fig. 2). The narrowing of the right internal carotid artery was considered a congenital anomaly (i.e., hypoplasia) rather than an acquired process (i.e., stenosis).

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Physiotherapy and occupational therapy were started, and clinical and MRI monitoring were instituted. To date, no vascular surgery has been planned.

Interferonopathies are a subgroup of recently described autoinflammatory diseases characterized by a dysregulated inflammatory innate immune response. These diseases are caused by gain-of-function mutations in protein components of complex signalling pathways, resulting in excessive and inappropriate secretion of type I interferon in the blood and cerebrospinal fluid. This overproduction leads to excessive activation of the Janus kinase/signal transducer and activator of transcription (STAT) pathway [4].

Aicardi-Goutières syndrome represents a group of monogenic interferonopathies that affect mainly the brain and skin and are caused by variants in nine different genes (TREX1, RNASEH2 A, RNASEH2B, RNASEH2 C, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1) [1]. The spectrum of phenotypes is wide due to the multiple genes involved and their variable expressivity, even among siblings.

A diagnosis of Aicardi-Goutières syndrome is suggested on the basis of a constellation of clinical signs and symptoms, such as progressive microcephaly, loss of acquired skills, seizures, irritability, feeding difficulties, glaucoma, hypothyroidism, cardiomyopathy, and cutaneous manifestations (the most common being systemic lupus erythematosus) [3]. In addition, biological tests can be performed to help exclude TORCH infection, and their findings can be indicative of a diagnosis of Aicardi-Goutières syndrome, as these tests reveal normal viral serology findings, elevated lymphocyte counts and interferon-α levels in the cerebrospinal fluid (during the first years of life), and the overexpression of interferon-stimulated genes (interferon gene signatures) in peripheral blood cells.

On cerebral imaging, the classic pattern is well known as “pseudo-TORCH syndrome” because it resembles prenatal infection owing to the presence of leukodystrophy, basal ganglia and white matter calcifications, deep white matter cysts, striatal necrosis, and supra- and infratentorial atrophy. More misleading findings are mass-like lesions and haemorrhagic lesions [2].

Genetic analysis, whole-exome or whole-genome sequencing, can confirm and specify the diagnosis [3]. Most cases of Aicardi-Goutières syndrome are due to a biallelic mutation and, more rarely, a monoallelic mutation (e.g., some pathogenic variants in TREX1, ADAR, and IFIH1). For this reason, consanguinity is commonly observed, as in our patient, whose parents are first cousins of Turkish origin. Notably, in the literature, a pathogenic variant of the SAMHD1 gene has been reported in patients of Ashkenazi Jewish ancestry and Old Order Amish families [3, 5].

The identification of a homozygous variant of the SAMHD1 gene was clinically significant because this variant is frequently associated with multiple vascular anomalies, including stenoses, particularly of the distal portion of the internal carotid artery (moyamoya syndrome), aneurysms, and calcifying microangiopathy [2, 5, 6]. This finding led us to perform an additional MRI, including 3D TOF angiography, which enabled the identification of multiple intracranial arterial stenoses before the occurrence of ischaemic lesions.

The patient described here has a rare new cause of moyamoya syndrome. The most common causes of moyamoya syndrome in children are sickle cell disease and other haemoglobinopathies, Down syndrome, and neurofibromatosis type 1. Rarer causes include genetic causes (homocystinuria, microcephalic osteodysplastic dwarfism, ACTA2-related disease, Schimke immuno-osseous dysplasia, morning glory disc anomaly, and glycogen storage disease type 1a) and other causes (radiation therapy, meningitis, HIV infection, and emboligenic heart disease) [3]. In Aicardi-Goutières syndrome, intracranial large-artery stenosis, possibly multifocal and including moyamoya syndrome, has been described mainly in cases of SAMHD1 mutation but also in cases of TREX1 mutation [7] and RNASEH2 A mutation [8]. Therefore, including arterial MR angiography is crucial when performing brain MRI in a patient with a proven diagnosis of an interferonopathy (whatever the precise genetic mutation) or with lesions suggesting TORCH infection or an interferonopathy. MR angiography should be included in initial and follow-up brain imaging for the detection large intracranial artery stenosis, aneurysms, and ischaemic/haemorrhagic lesions. Early identification of this specific radiological pattern of Aicardi-Goutières syndrome is essential for establishing appropriate medical care, especially for the prevention of ischaemic/haemorrhagic brain injury, since new therapies are available. Janus kinase inhibitors, which block interferon pathway activation by inhibiting Janus kinase, have been successfully administered, resulting in a very promising targeted therapy [4].