Periodic Fever and Hyperimmunoglobulin D Syndromein a Boy with Pediatric Autoimmune Neuropsychiatric

Disorders Associated with Group Ab-Hemolytic Streptococcus

Perihan Cam Ray, MD,1 Didem Arslan Tas, MD,2 Gonca Gul Celik, MD,1

Aysxegul Yolga Tahiroglu, MD,1 Aysxe Avci, MD,1 and Eren Erken, MD2

To the Editor:

The importance of the immune system in pediatric psychi-

atric disorders has been known since the 1990s. Swedo et al.

(1998) have reported that obsessive-compulsive disorder (OCD),

tics, and other neuropsychiatric symptoms, such as separation

anxiety, irritability, hyperactivity, and attention and concentration

deficits, are usually triggered by infections, and have reported a

phenomenon known as pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections (PANDAS). The

diagnostic criteria for PANDAS are as follows: 1) Presence of a tic

disorder or OCD; 2) onset by puberty (usually at 3–12 years of age);

3) abrupt symptom onset or episodic course of symptom severity;

4) temporal association between symptom exacerbation and

streptococcal infections; and 5) presence of neurologic abnormal-

ities during periods of symptom exacerbation (Swedo et al. 1998).

To the best of our knowledge, there is no reported case or con-

trolled study describing the psychiatric signs or symptoms ac-

companying hyperimmunoglobulin D syndrome (HIDS). HIDS is

among the periodic fever syndromes that are genetically inherited

and share some common features, including recurrent fever, in-

flammation of serosal membranes, musculoskeletal involvement,

skin rashes, and amyloidosis. HIDS was originally described in

patients of Dutch ancestry by van der Meer et al. (1984). HIDS is

characterized by sustained high fever, lymphadenopathy, abdomi-

nal pain, arthritis, and skin rashes; episode duration is from 4 to 8

weeks. HIDS is caused by mutations in the gene that encodes

mevalonate kinase (MVK), an enzyme involved in the isoprenoid

and cholesterol biosynthesis pathway. The four most prevalent

mutations of MVK (V377I, I268T, H20P/N, and P167L) account

for 71.5% of the known mutations (van der Hilst et al. 2008;

Steichen et al. 2009). The differential diagnosis of HIDS is broad

and includes familial mediterranean fever (FMF), tumor necrosis

factor receptor associated periodic syndrome (TRAPS), periodic

fever adenitis pharyngitis aphthous ulcer (PFAPA), adult-onset

Still’s disease, juvenile idiopathic arthritis, rheumatic fever, and

Behcet’s disease (Long 2005; Steichen et.al. 2009).

Although MVK gene mutations have been suggested to be the

genetic defect responsible for the etiopathogenesis of HIDS, they

were not observed in a substantial proportion of those with the

disease; therefore, the pathophysiology of the disease remains un-

clear. More than 66% of HIDS patients present to physicians within

the first year of life. An earlier study of ours suggested later onset of

the HIDS (Tas et al. 2012). Episodic attacks of fever (lasting 3–7

day) are generally accompanied by chills, cervical lymphadeno-

pathy, abdominal pain, and vomiting or diarrhea. Patients may

also present with headache, arthralgia or arthritis, aphthous ulcer-

ation, rash, and splenomegaly (van Der Hilst et al. 2008). Attacks

may be precipitated by vaccination, viral infection, trauma, and

stress (Drenth et al.1994). Laboratory test results generally show

the presence of characteristic abnormalities such as an Im-

munoglobulin D (IgD) level >100 kU/L, and some patients also

have an elevated immunoglobulin A level.

We report a case with concurrent HIDS and OCD comorbid with

attention-deficit/hyperactivity disorder (ADHD) combined type,

speech disorder (stuttering), and Tourette’s disorder (TD).

Case Report

E, a 9-year-old boy, presented to our Child and Adolescent

Psychiatry Department with hyperactivity, stuttering, and com-

pulsive 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 stut-

tering in school.

The patient was born prematurely following 28 weeks of ges-

tation 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

1Department of Child and Adolescent Psychiatry, Cukurova University, School of Medicine, Adana, Turkey.2Department of Rheumatology-Immunology, Cukurova University, School of Medicine, Adana, Turkey.

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 23, Number 4, 2013ª Mary Ann Liebert, Inc.Pp. 302–304DOI: 10.1089/cap.2012.0129

302

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 de-

partment 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 examina-

tion 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 im-

pairment 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 com-

bined type, speech disorder, and TD.

Because of periodic fever attacks and for exclusion of any pe-

riodic fever syndromes, E was referred to our rheumatology-

immunology department. Laboratory and genetic analyses were

performed in the rheumatology-immunology department. His se-

rum anti-streptolysin O (ASO) titer was 539 IU/L (prior to tonsil-

lectomy) and 226 IU/L (after the tonsillectomy). During an attack,

his white blood cell count (WBC) was 11.000 mm–3; his erythro-

cyte 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 ampli-

fied by polymerase chain reaction [PCR]/sequence-based typing

technique using specific primers). Pharyngeal culture was nega-

tive for bacterial growth. Abdominopelvic ultrasonography and

posterior-anterior lung radiography revealed normal findings. His

cerebral magnetic resonance imaging (MRI) and electroencepha-

lography (EEG) were normal.

The boy’s parents were asked to determine whether there were

exacerbations of psychiatric symptoms in association with infec-

tious diseases and/or fever attacks. According to the parents, for the

past year, during fever attacks, the patient exhibited motor rest-

lessness, and physical examination showed motor tics, such as eye

blinking, head jerking, shoulder shrugging, and vocal tics, includ-

ing humming. Subsequently, we recognized two typical exacer-

bation periods as a consequence of pharyngotonsillitis attacks. Cold

chills, cervical lymphadenopathy, headache, abdominal pain, ar-

thralgia 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, re-

spectively, 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 signifi-

cantly 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 com-

mon 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

HYPERIMMUNOGLOBULIN D AND NEUROPSYCHIATRIC DISORDERS 303

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, phar-

yngitis, and adenitis (PFAPP) as follows:

1. Periodicity and/or waxing and vaning of symptoms

2. Sudden onset of symptoms, and infection-related aggrava-

tion of symptoms

3. Benefiting from penicillin prophylaxis and/or tonsillectomy

for both PANDAS and PFAPP (Alexander et al. 2011;

Snider et al. 2005; Wang et al. 2008).

Conclusions

HIDS may constitute a special subgroup of PANDAS, in terms of

some prominent symptoms, including comorbidity, treatment re-

sponse, or family history of psychiatric diseases and/or autoimmune

diseases. A detailed personal and familial history of recurrent infec-

tions 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 con-

trolled studies are warranted to determine if augmentation of immune

treatments (i.e., corticosteroid, intravenous immunoglobulin, col-

chicine, simvastatin, and anakinra) would be beneficial.

Disclosures

No competing financial interests exist.

References

Alexander AA, Patel NJ, Southammakosane CA, Mortensen MM:

Pediatric autoimmune neuropsychiatric disorders associated with

streptococcal infections (PANDAS): an indication for tonsillec-

tomy. Int J Pediatr Otorhinolaryngol 75:872–873, 2011.

American Psychiatric Association: Diagnostic and Statistical Manual

of Mental Disorders, 4th ed. Washington, DC: American Psychia-

tric Association; 1994.

Drenth JP, Haagsma CJ, van der Meer JW: Hyperimmunoglo-

bulinemia D and periodic fever syndrome: the clinical spectrum in a

series of 50 patients. International Hyper-IgD Study Group. Med-

icine (Baltimore) 73:133–144, 1994.

Kurup RK: Isoprenoid pathway-related membrane dysfunction in

neuropsychiatric disease. Int J Neurosci 113:1579–1591, 2003.

Leckman, JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson

J, Cohen DJ: The Yale Global Tic Severity Scale: Initial testing of a

clinician-rated scale of tic severity. J Am Acad Child Adolesc

Psychiatry 28:566–573, 1989.

Lewin AB, Storch EA, Murphy TK: Pediatric autoimmune neuro-

psychiatric disorders associated with Streptococcus in identical

siblings. J Child Adolesc Psychopharmacol 21:177–182, 2011.

Long S: Distinguishing among prolonged, recurrent and periodic fever

syndromes: Approach of a pediatric infectious diseases subspe-

cialist. Pediatr Clin N Am 52:811–835, 2005.

Murphy TK, Kurlan R, Leckman J: The immunobiology of Tourette’s

disorder, pediatric autoimmune neuropsychiatric disorders associ-

ated with streptococcus, and related disorders: a way forward.

J Child Adolesc Psychopharmacol 20:317–331, 2010.

Palumbo D, Maughan A, Kurlan R: Hypothesis III. Tourette syndrome

is only one of several causes of a developmental basal ganglia

syndrome. Arch Neurol 54:475–483, 1997.

Scahill L, Riddle MA, McSwiggin–Hardin M, Ort SI, King RA,

Goodman WK, Cichetti D, Leckman J: Children’s Yale–Brown

Obsessive Compulsive Scale: Reliability and validity. J Am Acad

Child Adolesc Psychiatry 36:844–852, 1997.

Simon A, Kremer HPH, Wevers RA, Scheffer H, de Jong JG, van der

Meer JWM, Drenth JPH: Mevalonate kinase deficiency: Evidence

for a phenotypic continuum. Neurology 62:994–997, 2004.

Snider LA, Lougee L, Slattery M, Grant P, Swedo SE: Anti-

biotic prophylaxis with azithromycin or penicillin for childhood-

onset neuropsychiatric disorders. Biol Psychiatry 57:788–792,

2005.

Steichen O, van der Hilst J, Simon A, Cuisset L, Grateau G: A clinical

criterion to exclude the hyperimmunoglobulin D syndrome (mild

mevalonate kinase deficiency) in patients with recurrent fever.

J Rheumatol 36:1677–1681, 2009.

Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perl-

mutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK: Pediatric

autoimmune neuropsychiatric disorders associated with strepto-

coccal infections: Clinical description of the first 50 cases. Am J

Psychiatry 155:2, 1998.

Tas DA, Dinkci S, Erken E. Different clinical presentation of the

hyperimmunoglobulin D syndrome (HIDS) (four cases from Tur-

key). Clin Rheumatol 31:889–893, 2012.

van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der

Meer JW, Simon A, International HIDS Study Group. Long-term

follow-up, clinical features, and quality of life in a series of 103

patients with hyperimmunoglobulinemia D syndrome. Medicine

(Baltimore). 87:301–310, 2008.

van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ,

Lobatto S, van Furth R: Hyperimmunoglobulinaemia D and peri-

odic fever: a new syndrome. Lancet 1:1087–1090, 1984.

Wong KK, Finlay JC, Moxham JP: Role of tonsillectomy in

PFAPA Syndrome. Arch Otolaryngol Head Neck Surg 134:16–

19, 2008.

Address correspondence to:

Gonca Gul Celik, MD

Department of Child and Adolescent Psychiatry

Cukurova University School of Medicine

01330, Adana

Turkey

E-mail: goncagulcelik@gmail.com

304 RAY ET AL.