Phenotypic Overlap between Infantile Systemic Lupus Erythematosus and Aicardi-Goutières Syndrome

Sir,

we have read with great interest Rasmussen et al.'s report of two sisters with Aicardi-Goutières syndrome (AGS) with cerebral thrombotic microangiopathy, one of whom had antiphospholipid antibodies [[1]]. As the authors pointed out, their observation adds to a previous similar report of two siblings [[6]].

We would like to describe a further patient with clinical and biological signs of systemic lupus erythematosus (SLE) and an AGS-like picture that improved markedly on corticosteroids and her sister with similar features consistent with AGS.

The propositus presented at seven months with a skin rash and feeding difficulties. She was born at 37 weeks gestation from healthy consanguineous parents from Pakistan. Birth weight was 2700 g, height was 47.5 cm, and head circumference 33 cm. She has two healthy older brothers, a brother with a poorly documented history of severe developmental delay who died in status epilepticus at the age of 19 months, a brother with congenital cardiomyopathy and squamous skin lesions of unknown etiology, and one sister described below. Investigations and availability of information regarding the other family members have been limited by poor parental collaboration. At presentation, she had failure to thrive including microcephaly, poor interaction, quadriplegia with spasticity and generalized dystonia, chronic otorrhea, interstitial pneumopathy, and scaly erythematous plaques extending over the whole body. The following investigations were normal: hemogram, liver enzymes, serum lactate, plasma and urine aminoacids, urine organic acids, karyotype, toxoplasma, Rubella and herpes simplex serology, biotinidase, arylsulfatase and cerebroside-β-galactosidase activities and isoelectrofocussing of sialotransferrins. Total IgG levels were 1.9 g/dL (0.3 - 1.7 g/dL) and IgM 1.0 g/dL (0 - 0.2 g/dL). Cerebrospinal fluid cell count, protein level, and electrophoresis, glucose, and lactate were normal as well as neurotransmitters. Magnetic resonance imaging (MRI) performed at eight months showed diffuse hypomyelination. Skin biopsy showed monocytic inflammation in the superficial dermis. Cultured fibroblasts showed normal growth under UV exposure. Additional immunological investigations obtained at the age of two years showed antinuclear factor titer at 1 : 2500, anti-mDNA antibody 1 : 80, anti-double stranded DNA 1 : 140, anti-nucleosome 6.4 BI, negative anti-RNP, anti-RO, anti-LA, anti-SCL70, and antimyelin antibodies. Anticardiolipin antibodies, and complement were normal. Repeat brain MRI showed cortical atrophy, hypomyelination, and abnormal signal in putamina (Fig. [1]) corresponding to the calcifications seen on computed tomography (Fig. [2]).

Fig. 1 a - c MRI of the index case at six years of age showing cortical atrophy, hypomyelination, and abnormal signal in putamina. a T₂-weighted image; b FLAIR sequence; c recovery inversion.

Fig. 2 CT of index case at 3 years of age showing bilateral basal ganglia calcifications.

She received prednisolone (1 mg/kg/d) and azathioprin (2 mg/kg/d). On this treatment, the skin rash disappeared, otorrhea resolved, and pulmonary function markedly improved with disappearance of radiographic interstitial infiltrate. Concomitantly, there was marked improvement in interaction and motor control, with the emergence of social smile, vocalizing, and eye pointing, voluntary axial righting, improvement of muscle tone, and the emergence of manipulation skills. However, head growth profile remained subnormal, with aggravating microcephaly (e.g., 45.5 cm at five years). Incidental treatment discontinuation was associated with resumption of the rash, pneumopathy, and neurological deterioration. At the age of six, while she was on immunosuppressive treatment, she presented acutely with severe hemolytic anemia (Hb 2.9 g/dL). Direct Coombs test and cold agglutinins were positive. Reticulocyte level was 35 %. Continuing hemolysis was noted following blood transfusion. After prednisolone increase to 2 mg/kg/d, hemoglobulinemia stabilized at normal values. Interferon-alpha levels measured at six years of age while the patient was receiving corticosteroids were very high in the serum and cerebrospinal fluid (199 and 121 pg/mL, respectively; normally undetectable in the cerebrospinal fluid).

The patient's sister was followed up from birth. Birth weight and height were normal but she had microcephaly, which became more marked as she grew (e.g., 44 cm at 28 months). She showed ichthyosis, irritability, and severe hypotonia. This was gradually replaced by quadriplegia with both spastic and dystonic features. She had mild oculomotor apraxia. Investigations performed in the neonatal period showed severe thrombocytopenia, normal liver enzymes, serum lactate, amino acids, acylcarnitine profile, urine organic acids, and mucopolysaccharides, no antinuclear antibodies, normal complement, markedly increased serum interferon-alpha (250 pg/mL), interventricular septal hypertrophy on echocardiography, linear hyperechogenic areas in the basal ganglia, and diffuse hyperechogenicity of the periventricular white matter on cerebral ultrasound. MRI showed diffuse swelling of the frontal and parieto-occipital white matter bilaterally. At the age of one year, she has marked developmental delay with severe axial hypotonia and mixed-type quadriplegia, and has shown little developmental change since then. Cerebrospinal fluid examination showed normal cell count. Repeat MRI performed at the age of 17 months showed cortico-subcortical atrophy, delayed myelination, and abnormal signals in the caudates and putamina consistent with calcifications (Fig. [3]).

Fig. 3 a - d Sister's MRI performed at the age of 17 months showing cortico-subcortical atrophy, delayed myelination and abnormal signals in the caudates and putamina. a Proton density; b T₂-weighted image; c, d recovery inversion.

The index patient fulfils the diagnostic criteria for SLE, including pneumopathy, hemolytic anemia, and the typical autoimmune profile with anti-mDNA, anti-double stranded DNA, and anti-nucleosome antibodies. However, the familial character of the disease, its very early onset and the clinical and imaging features differ from those reported in both neonatal and infantile SLE. After excluding other causes of encephalopathy with intracranial calcifications, the diagnosis of AGS can be proposed. AGS is a rare neurogenetic condition characterized by early onset, progressive encephalopathy with basal ganglia calcifications, white matter changes, increased interferon-alpha levels in the blood, and cerebrospinal fluid, cerebrospinal fluid lymphocytosis, and scaly erythematous rash. Reports since Aicardi's and Goutières' original description [[1]] have revealed some clinical heterogeneity. Both our patients presented early with severe motor and intellectual developmental impairment, spasticity, brain atrophy, bilateral basal ganglia calcifications, and dysmyelination. The skin lesions found in the index case share some characteristics with those classically described in AGS [[3], [13]], although they are much more widespread. They are different from the typical pigmented atrophic lesions with telangiectasia seen in neonatal SLE [[10]]. To our knowledge, those seen in the sister, i.e., ichthyosis, have not been described in AGS. Similarly, although heart abnormalities have been reported in AGS [[12]], these did not include septal hypertrophy as seen in the sister.

Dale et al. previously reported two brothers with progressive encephalopathy associated with SLE [[6]]. In the same issue of Neuropediatrics, Aicardi's and Goutières' editorial commentary suggested that it could correspond to AGS [[2]]. A body of evidence suggests that AGS results from a primary genetic defect in interferon-alpha metabolism. Transgenic mice receiving astrocyte-targeted interferon-alpha develop a progressive encephalopathy with calcifications of the basal ganglia and vasculitis that recapitulates the neuropathological findings observed in AGS [[4]]. Serum levels of interferon-alpha are also raised in SLE [[8]]. In particular, interferon-alpha levels increase during neurological exacerbations of SLE, concomitantly with an inducing factor of interferon in the serum [[9]]. Moreover, therapy with interferon-alpha can induce clinical and immunological features of SLE, pointing to possibly shared pathophysiology between SLE and AGS [[5], [7], [14]].

Rasmussen's report and ours add further evidence to this hypothesis. We speculate that an initial immune dysfunction with raised interferon-alpha evolved into a picture of SLE. We noted clinical improvement in our first patient after the beginning of immunomodulatory treatment given in this picture of SLE. It is not presently clear whether such treatment may affect the natural history of this condition. However, our observation, like those of Rasmussen et al. and Dale et al., suggest that, at least in some cases, AGS and SLE are closely related diseases and that it may be of interest to search for autoantibodies in patients with a phenotypic expression of AGS.

References

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