Misdiagnosed Aicardi Goutières Syndrome Patient: A Case Report

Document Type : Case report

Authors

1 Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Next Generation Genetic Polyclinic, Mashhad, Iran. Department of Modern Sciences and Technologiesm Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Next Generation Genetic Polyclinic, Mashhad, Iran. Honorary Researcher, University of Manchester, UK

4 Pediatric Neurology Department, Ghaem hospital, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Aicardi Goutiere’s syndrome is an autosomal recessive neurodegenerative disorder. Its clinical signs usually mimic TORCH-like clinical signs; which makes the differential diagnosis difficult. Here, we report a case with one homozygous pathogenic mutation c.529G>A p.Ala177Thr on RNASEH2B gene (NM_024570) that relates to Aicardi-Goutieres syndrome type 2  that had been misdiagnosed in about 5 years.

Keywords


Introduction
Aicardi Goutiere’s syndrome (AGS) is an autosomal recessive neurodegenerative disorder. Its clinical signs usually include basal ganglia calcification encephalopathy, white matter abnormalities, congenital problems, high levels of interferon alpha, and TORCH-like clinical signs. The similarity between TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex virus) and AGS makes diagnosis difficult (1–4).
so the disease can be simply missed without a reasonable index of suspicion, especially in RNASEHB2 mutations. Late onset and absence of typical symptoms In RNASEHB2 variant make the diagnosis difficult (5). 

Although there is no cure for the disease, with proper diagnosis; we can prevent born of siblings with the same problem. we hereby report a case that had been misdiagnosed in about 5 years.

Case report 
An 8 years old girl of consanguineous parents was presented with developmental delay. She did not have any birth complications. She could sit in 7 months and walk with help in 18 months. In 24 months, her parents noted that she has developmental delay and abnormal movements. Her axial brain CT (figure 1) revealed bilateral basal ganglion calcification but other  parts (pons, midbrain, base skull, petromastoids region, internal auditory canals, cerebellopontine angles, cisternal spaces, posterior fossa, cerebellum, sella turcia, hypophysis, third and lateral ventricle, white and grey matter) were normal.

 

 

 

 


Figure 1. Brain CT scan at the age of 2 years shows the calcification of basal ganglia (specially globus pallidus 
and putamen), arrows present calcification area.
In 24 months her physical examination revealed exaggerated deep tendon reflexes, irritability, normal auditory brainstem response, mild dystonia, and head circumference of 46 centimeters; consequently, she was diagnosed and treated as a TORCH patient. When she was 3 years old, the intensity of the symptoms reduced.  There was no similar problem in her family history. Findings of CT scan (calcification of only basal ganglia) and normal indexes of growth at birth (normal birth weight (3250 gr) and head circumference (35 cm)) indicated that she might be suffering from other diseases; so when she was 8 years old, we re-assessed her and ordered MRI. 
basal ganglion calcification and white matter engagement (figure 2) along with history lead us to Aicardi Goutieres syndrome. her parents didn’t let us perform lumbar puncture, so we directly referred her to genetic laboratory.

 

 

 

 

 

Based on history, medical geneticist described the disease and pattern of inheritance in the family (figure 3). 

 

 

 


years old, we re-assessed her and ordered MRI. basal ganglion calcification and white matter engagement (figure 2) along with history lead us to Aicardi Goutieres syndrome. her parents didn’t let us perform lumbar puncture, so we directly referred her to genetic laboratory. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Based on history, medical geneticist described the disease and pattern of inheritance in the family (figure 3). Molecular testing detected one homozygous pathogenic mutation c.529G>A p.Ala177Thr on RNASEH2B gene (NM_024570) which related to Aicardi-Goutieres syndrome type 2. Both parents were heterozygous for the variant. Since mother was pregnant (14 weeks), for prenatal diagnosis, chorionic villus sampling (CVS) was performed. After DNA extraction, the candidate variant was assessed through PCR and sequencing analysis. This variant had not been detected in the fetus which indicated that the fetus may not suffer from AGS (figure 4). Following the comprehensive genetic assessment, the patient received conservation therapy. After one year follow up, now she goes to school, and her visual and auditory functions are normal and she doesn’t have any thrombocytopenia, however, dystonia is still positive.

Discussion
Common discovered neurological signs in AGS cases include dystonic posturing, peripheral spasticity, truncal hypotonia, poor head control. One of the differences in RNASEH2B variant of AGS with other mutations (TREX1, RNASEH2C, or RNASEH2A) is the late onset of symptoms that appear after normal development growth at the age of 12 mo or beyond (5).
Our patient presented symptoms is in 24 months. Another difference of AGS variants is the severity of intellectual and physical functions, in which is totally absent in RNASEH2B cases. Unlike other variants, in RNASEH2B head circumference is normal. As a result, limited spectrum of signs in RNASEH2B cases is another challenge, besides TORCH mimicking in diagnosing patients (4,5) .
Radiologic finding includes calcifications in basal ganglia engagement of cerebellum, thalamus, dendate, cerebellar white matter, brainstem, striatum could be found in some cases respectively (6).

conclusion
The similarities between AGS and TORCH makes the diagnosis of the patient very difficult and problematic. Therefore, Children with AGS syndrome usually remain unrecognized until the second child is born, So the importance of recognizing the disease is to prevent another child from being born with the same problem. Thus, it’s important to consider the possibility of AGS in absence of clear evidence of infection, because the disease can be simply missed without a reasonable index of suspicion.

Acknowledgements
We thank Sajad Sahab Negah and Amirhossein Heidari for comments. This work was supported by the Neuropediatric section of Ghaem Hospital, Mashhad, Iran and Next Generation Genetic Polyclinic, Mashhad, Iran.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

literature review 
 is a hospital based prospective study done in a tertiarycentre. Thirty patients with tibial plateau fractures who were operated with locking plates between 2015 and 2016 were followed for 18 months.Consent was taken from each patient before their participation in the study. 
After proper evaluation in the emergency department all patients underwent Xrays and CT scan for proper delineation of fracture site.Patients of either sex above 18 years with radiological evidence of tibial plateau fractures were considered for the study. Patients who had pre-existing arthritis of knee, congenital anomalies of knee, any previous surgery of the same knee, open trauma, those with compartment syndrome of the ipsilateral leg and polytrauma patients were not included in the study.
Patients who had pre-existing arthritis of knee, congenital anomalies of knee, any previous surgery of the same knee, open trauma, those with
compart ment syndrome of the ipsilateral leg and polytrauma patients were not included in the study.
Depending on the fracture type and site, two aplowing surgery, knee range of motions was started as soon as pain subsided usually after 2nd post op day.Postoperatively all patients were assessed after discharge at 2 weeks. Then four weekly till bony union occurred and after that three monthly till last follow up at 18 months.The functional outcome was evaluated using Rasmussen Functional Knee Score (Table 1) which was further graded according to score into Excellent, Good, Fair and Poor6.Post traumatic arthritic changes were graded according to Kellgren Lawrence grading. At 18 months all patients were checked clinically for limb malalignment.
Patients were also interviewed at 18 months regarding return to work. Sample size was 30. Chi square test and ANOVA test was used to calculate p-value depending on categorical and numerical data. Any p-value calculated < 0.05 was taken to be significant. Standard statistical analysis was done using SPSS version 18.

Results
This prospective study was conducted at Central Institute of Orthopaedics, Safdarjung Hospital, New Delhi, India during the period of January 2015 to June 2017. Thirty patients withaverage age 42.4yearswith tibial plateau fractures were enrolled for the study which were fixed with open reduction and internal fixation with locking compression plates (Figure 1).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Discussion
The present study showed that the prevalence of febrile seizures was associated with gender, living place, temperature, family history of seizure, and the serum level of zinc. In this regard, the frequency of zinc deficiency was higher in patients with febrile seizures compared to febrile patients without seizure, before and after adjusting for gender. 
Zinc plays a vital role in the neuronal terminals of the hippocampus and amygdala by producing pyridoxal phosphate and affecting glutamatergic, gamma-aminobutyric acidergic (GABAergic), and glycinergic synapses (13).
Glutamic acid decarboxylase (GAD) acts as a major inhibitory neurotransmitter in the synthesis of gamma-aminobutyric acid (GABA) (14). A study by Ganesh R. and Janakiraman L. on 38 children with febrile convulsion and 38 children as a control group, aged between 3 months and 5 years, indicated that a serum zinc deficiency was significantly more prevalent in their case group than in the control group (15). Another study has reported that there is a correlation between disruption in Zn2+ homeostasis and fever seizure (16).
In studies by Papierkowski A., Mollah M.A., and Gündüz Z. et al., the mean serum zinc level in the febrile convulsion group was significantly lower than in the control group, which indicates the role of zinc in febrile seizure. Comparing the groups in terms of age and gender, no significant difference was found, similar to our study (17-19). Abdel Hameed Z.A. et al. (20), in a study on 100 infants in Egypt, observed that temperature had no significant difference between the case and control groups. But Berg A.T. (21), Ahmed B.W. (22), and our study showed the importance of temperature in febrile seizure. The geographic area can be the cause of this difference. Duangpetsang J. in a study from 2014 to 2017 reported that a high fever with electrolyte disturbance hyponatremia has an important role in FS (23). Sharifi R. et al., in a study in 2007-2014, showed the importance of family history in febrile seizure (24), which is similar to our results.

Conclusion
The findings of this study show that zinc deficiency is significantly associated with the occurrence of febrile seizures. Zinc supplementation in children can therefore be helpful for the prevention and treatment of FS.

Conflict of interest
The authors declare no conflicts of interest.

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