Aicardi-Goutières syndrome type 7 in a Chinese child: A case report

Abstract

BACKGROUND

IFIH1 is a protein-coding gene. Disorders associated with IFIH1 include Aicardi-Goutières syndrome (AGS) type 7 and Singleton-Merten syndrome type 1. Related pathways include RIG-I/MDA5-mediated induction of the interferon (IFN)-α/β pathway and the innate immune system. AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. In infancy, most patients present with psychomotor retardation, axial hypotonia, spasticity, and brain imaging changes Laboratory assessments showed increased IFN-α activity with upregulation of IFN signaling and IFN-stimulated gene expression. Some patients develop normally in the early stage, and then have episodic neurological deficits.

CASE SUMMARY

The 5-year-old girl presented with postpartum height and weight growth retardation, language retardation, brain atrophy, convulsions, and growth hormone deficiency. DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation. Heterozygous mutations in the IFIH1 gene were found. Physical examination at admission found that language development was delayed, the reaction to name calling was average, there was no communication with people, but there was eye contact, no social smile, and no autonomous language. However, the child had rich gesture language and body language, could understand instructions, had bad temper. When she wants to achieve something, she starts crying or shouting. Cardiopulmonary examination showed no obvious abnormality, and abdominal examination was normal. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes exist, but pathological reflexes were not elicited.

CONCLUSION

We reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7, which expanded the mutational spectrum of the IFIH1 gene.

Key Words: Aicardi-Goutières syndrome type 7; IFIH1 gene; Children; Case report

Core Tip: We report a 5-year-old girl with Aicardi-Goutières syndrome type 7. The clinical characteristics included postnatal height and weight retardation, delayed language development, brain atrophy, convulsions, and growth hormone deficiency. Whole exome test showed c.1093A>G (p.Lys365Glu) and heterozygous mutation in IFIH1 gene, and the mutation source was her father. This report provides a molecular basis for etiological diagnosis and treatment of the child, as well as for genetic counseling for the pedigree.

INTRODUCTION

Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy[1-4]. Individuals affected with AGS typically suffer from progressive microcephaly associated with severe neurological symptoms, such as hypotonia, dystonia, seizures, spastic quadriplegia[5,6], and severe developmental delay. On brain imaging, AGS is characterized by basal ganglia calcification, white matter abnormalities, and cerebral atrophy cerebrospinal fluid analyses show chronic lymphocytosis and elevated levels of the interferon (IFN)-α[7] and neopterin. AGS-affected individuals are often misdiagnosed as having intrauterine infections, such as Pseudo-TORCH syndrome[8] (Pseudo-TORCH syndrome is a rare, chronic disorder that is characterised by dimorphic features such as microcephaly, intracranial calcification, seizures, mental retardation, hepatosplenomegaly and coagulation disorders), because of the similarities of these disorders, particularly the intracranial calcifications. AGS type 7 (AGS7) is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. Episodic neurological deficits occur after the onset. Therefore, diseases related to mutations at the genetic locus must be diagnosed in the early phase so as to be treated in timely.

CASE PRESENTATION

Chief complaints

She was 3 years old at the time of her first visit and presented on 16 September 2020 due to language delay. She is 5 years old now.

History of present illness

Since age 6 mo, she had had obvious slow growth in height and weight. Language development was delayed. Her response to name calling was normal but there was no communication with people. Her eyes could not be met and there was no social smile. There was no autonomous language, However, the child had rich gesture language and body language, she could understand instructions, had a short temper, and when she wants to achieve something, she starts crying or shouting. She was thin, with a weight of 9 kg and height of 83 cm.

History of past illness

There was no obvious abnormality at birth, weight 3 kg, height 50 cm. She raised her head at 3 mo, crawled at 7 mo, and walked at 15 mo. She had a history of febrile convulsions twice, each lasting about 2 min, which resolved spontaneously, and a 1-year history of ulcerative colitis.

Personal and family history

Both parents were healthy.

Physical examination

Body temperature was 36.2 °C, heart rate 96 beats/min, breathing 24 beats/min, blood pressure 100/60 mmHg, height 83.0 cm and weight 9 kg. There was no special sick face, and cardiopulmonary and abdominal examinations showed no obvious abnormalities. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes were present but pathological reflexes were not elicited.

Laboratory examinations

Routine blood and urine examinations, myocardial enzymes, lactic acid, liver function, renal function, electrolytes, blood glucose, thyroid function, and hematuria showed no obvious abnormalities. The peak growth hormone challenge test was 5.77 ng/mL.

Imaging examinations

Video electroencephalography showed no abnormalities. Magnetic resonance imaging (MRI) of the brain showed mild atrophy.

FINAL DIAGNOSIS

AGS7 caused by a missense mutation in the IFIH1 gene.

TREATMENT

Symptomatic nutritional support and rehabilitation were undertaken.

OUTCOME AND FOLLOW-UP

The child was followed up for 1 year and 9 mo. Her weight increased to 12 kg and height to 90 cm. Language ability improved, and simple conversations could be conducted.

DISCUSSION

Our patient presented with growth retardation, language retardation, brain atrophy and convulsions as the main clinical manifestations. Among the various examination indicators of our patient, we particularly noticed that the peak value of growth hormone was decreased, and MRI of the brain showed brain atrophy, Combined with the patient's clinical symptoms and physical and chemical examination results, we considered the possibility of hereditary metabolic disease or genetic disease. Subsequent genetic metabolic screening for hematuria showed no obvious abnormality.

Whole exome analysis showed that the IFIH1 gene had a c.1093A>G (p.Lys365Glu) heterozygous mutation, and the source of the mutation was her father (Figure 1A-C). IFIH1 gene can cause two diseases, AGS7, and Singleton-Merten syndrome type 1. According to their clinical manifestations, children are more likely to have AGS7[1]. AGS (MIM 615846) is a rare genetic disorder characterized by aberrant type 1 IFN production and systemic, chronic inflammation. IFIH1 gene[2-4] may lead to changes in MDA5[7] and type 1 IFN (Mutations in the IFIH1 gene lead to overproduction of type 1 interferons, resulting in the AGS phenotype). AGS 7 may lead to an increase in type 1 IFN, and there are clinical manifestations caused by elevated type 1 IFN. Our patient had similar manifestations, but due to the patient’s clinical conditions, we did not examine the IFN concentration.

Figure 1 Whole-exome gene sequencing. A: IFIH1 gene of the patient was found to have c.1093A>G (p.Lys365Glu), and heterozygous mutation. B: The source of mutation was her father. C: The sequencing of the patient’s mother.

It has been reported that the IFIH1 gene is inherited in an autosomal dominant manner, with high heterogeneity and incomplete penetrance. Our patient had c.1093A>G (p.Lys365Glu) heterozygous mutation, and the pathogenicity of this variant has been reported previously. The clinical manifestations of the child were consistent with the clinical features of AGS7.

CONCLUSION

In summary, we reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS7, which expanded the mutational spectrum of the IFIH1 gene.