Periodic Fever and Hyperimmunoglobulin D Syndrome in a Boy with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Group A β-Hemolytic Streptococcus

Case Report

E, a 9-year-old boy, presented to our Child and Adolescent Psychiatry Department with hyperactivity, stuttering, and compulsive behaviors such as cleaning, checking, not touching any surfaces, and sniffing his hands. His mother reported that he did not touch any surface, and that he used a handkerchief for touching everything. The patient was in third grade and had poor academic performance. Additionally, his academic skills were much lower than those of his peers, for example, he could not remember his tasks and refused to do homework, and he generally needed help with his homework. He had been teased by peers because of stuttering in school.

The patient was born prematurely following 28 weeks of gestation because of early membrane rupture; he weighed 750 g and was hospitalized for 1.5 months. Since birth, the patient's serum level of C-reactive protein (CRP) had always been above normal. He had undergone left eye surgery for strabismus when he was 16 months old. He had had restrictive eating behavior since infancy. When he was 30 months old, he began to have attacks of fever (38–40°C). The attacks would last for 4–5 days and occurred every 3–4 weeks. The frequency of attacks was reduced to every 4–6 weeks by the time he was 6 years of age. He underwent tonsillectomy at the age of 7 years. Since 7 years of age, he has been followed up because of symptoms of stuttering and poor academic performance. His current weight was 27 kg (10th percentile) and height was 130 cm (25th percentile).

E's mother, a 38-year-old homemaker, had OCD, and a history of acute rheumatic fever (ARF) complicated by rheumatic heart disease (RHD). His father was a police officer 40 years of age, who did not have any autoimmune and/or psychiatric diseases. The patient's 14-year-old sister had been treated for OCD in our department for 1 year. E's maternal grandmother also had a 10 year history of ARF and rheumatoid arthritis (RA). Additionally, his maternal aunt had a 2 year history of RA. The family history was negative for other autoimmune-related diseases and psychiatric disorders. There was no family history of stuttering.

During the mental status examination, the patient seemed younger than 9 years old, and was small for his age. There were no dysmorphic features. Eye contact was normal, but he exhibited avoidant behaviors. His speech was not fluent, and he exhibited restlessness and motor hyperactivity without stereotypy. He had no hallucinations. His mood was normal, but his affect was irritable and anxious.

His Wechsler Intelligence Scale for Children Revised Version (WISC-R) full-scale score was 95. According to current examination of the patient, Yale-Brown Obsessive Compulsive Scale (C-YBOCS) (Scahill et al. 1997) obsession and compulsion scores were 15 and 12, respectively, and his clinical severity was moderate. His Yale-Brown Global Tic Severity Scale (YGTSS) (Leckman et al. 1989) motor tic score was 10, his phonic tic score was 4, his impairment score was 20, and his total severity score was 34.

According to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria (American Psychiatric Association 1994), the boy was diagnosed as having OCD and ADHD combined type, speech disorder, and TD.

Because of periodic fever attacks and for exclusion of any periodic fever syndromes, E was referred to our rheumatology-immunology department. Laboratory and genetic analyses were performed in the rheumatology-immunology department. His serum anti-streptolysin O (ASO) titer was 539 IU/L (prior to tonsillectomy) and 226 IU/L (after the tonsillectomy). During an attack, his white blood cell count (WBC) was 11.000 mm^–3; his erythrocyte sedimentation rate (ESR) was 27 mm/h; and his CRP was 9.81 mg/dL. Between two attacks, his WBC was 8860 mm^–3, his ESR was 2 mm/h, his CRP was 0.801 mg/dL, his IgD was 72.5 mg/L (radial immunodiffusion [RID], n 5–50), and his IgA was 107 mg/dL. No mutation was found in the Mediterranean fever gene (MEFV) (DNA sequencing for exon 2 and exon 10); MVK gene homozygote c.769–38 C>T mutation was determined. (The exonic regions and exon–intron junction sites of these genes were amplified by polymerase chain reaction [PCR]/sequence-based typing technique using specific primers). Pharyngeal culture was negative for bacterial growth. Abdominopelvic ultrasonography and posterior-anterior lung radiography revealed normal findings. His cerebral magnetic resonance imaging (MRI) and electroencephalography (EEG) were normal.

The boy's parents were asked to determine whether there were exacerbations of psychiatric symptoms in association with infectious diseases and/or fever attacks. According to the parents, for the past year, during fever attacks, the patient exhibited motor restlessness, and physical examination showed motor tics, such as eye blinking, head jerking, shoulder shrugging, and vocal tics, including humming. Subsequently, we recognized two typical exacerbation periods as a consequence of pharyngotonsillitis attacks. Cold chills, cervical lymphadenopathy, headache, abdominal pain, arthralgia in the knees, vomiting, diarrhea, and erythematous skin lesions accompanying the attacks. Serum ASO titers were found as high as ≥500 titers at each visit. Consequently, the patient was considered to have a diagnosis of PANDAS. Because of these findings and a family history of ARF, prophylactic benzathine penicillin (1.2 mU every 3 weeks, intramuscular) was started. E did not respond to antibiotherapy, and ASO titers remained high throughout the follow-up period.

In the rheumatology-immunology department, the patient was also given the diagnosis of HIDS because of fever associated with chills, sore throat, cervical lymphadenopathy, abdominal pain and MVK gene mutation (single-nucleotide polymorphism [SNP]). He was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) during his fever attacks. Corticosteroid infusion during the attacks was recommended, but his family declined.

Sertraline 25 mg/day was started then titrated up to 50 mg/day to treat obsessive-compulsive symptoms. After 2 months of sertraline treatment the patient's compulsive cleaning, checking, and sniffing symptoms partially decreased. After ∼4 months, sertraline was reduced to 25 mg/day and was stopped 3 weeks later. C-YBOCS obsession and compulsion scores were reduced to 8 and 6, respectively, and the patient's clinical severity was reduced to mild. His YGTSS motor score was reduced to 7, his phonic score was reduced to 2, impairment score was reduced to 10, and his total score was reduced to 19. We stopped sertraline treatment and gave atomoxetine 40 mg/day, because OCD symptoms were significantly controlled, but ADHD symptoms continued, and caused marked functional impairments. At the time of this report, E was being treated with atomoxetine 40 mg/day and no side effects were observed. In the second months of this treatment, a partial reduction in ADHD symptoms was observed. In addition, although there was no severe recurrence of OCD symptoms, checking and cleaning compulsions and motor tics were observed more severely after the fever attacks, and there were subthreshold cleaning obsessions at 8 month follow-up.

Discussion

The presented case highlights that the similar pathophysiologic mechanisms for PANDAS and HIDS may have substantial overlap. To date, there have been no published reports on HIDS and PANDAS coexistence.

MVK deficiency (MKD) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the gene coding for MVK. From HIDS to mevalonic aciduria, the degree of disease severity varies. According to a case series, as compared to HIDS, mental retardation, epilepsy, and cerebellar ataxia are more common in patients with mevalonic aciduria (Simon et al. 2004). The patient presented here did not have mental retardation, but did have ADHD; however, it should be noted that his ADHD may be related to natal complications, which included premature birth and low birth weight, in addition to HIDS. Moreover, it has been suggested that OCD, ADHD, and TD are associated with a common brain region such as basal ganglia (Murphy et al. 2010). The patient presented here had characteristics similar to those of Palumbo's developmental basal ganglia syndrome hypothesis; accordingly, we may speculate that HIDS and MVK gene mutation may have affected the neurodevelopment course of PANDAS. According to this, a variety of genetic and environmental factors interfering with basal ganglia development can produce a wide range of neuropsychiatric symptoms (Palumbo 1997). There is marked overlapping between this theory and PANDAS, such as multiple diagnoses, prepubertal age of onset, a relapsing/remitting symptom course, temporal relationship between exacerbations and immune system responses (i.e., streptococcal infections or fever attacks), and variability of prominent clinical features, possibly determined by developmental stage and environmental contributors, which may explain the phenomenon that occurred in our patient.

It was reported that the siblings of PANDAS patients have a tendency to develop autoimmune diseases (Lewin et al. 2011). As reported in this article, it is suggested that HIDS could be included in the autoimmune diseases that were previously reported to be associated with PANDAS.

Additionally, there have been some overlap of clinical features between PANDAS and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPP) as follows:

1. Periodicity and/or waxing and vaning of symptoms

Conclusions

HIDS may constitute a special subgroup of PANDAS, in terms of some prominent symptoms, including comorbidity, treatment response, or family history of psychiatric diseases and/or autoimmune diseases. A detailed personal and familial history of recurrent infections and autoimmune diseases should be obtained. Consequently, we suggest that HIDS, as a subtype of periodic fever syndrome, and/or the observed defect in the isoprenoid pathway, may have caused the neuropsychiatric symptoms in the presented case (Kurup 2003). In addition to psychopharmacologic intervention, prospective controlled studies are warranted to determine if augmentation of immune treatments (i.e., corticosteroid, intravenous immunoglobulin, colchicine, simvastatin, and anakinra) would be beneficial.