Childhood Disintegrative Disorder

Updated: Jun 28, 2016
  • Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD  more...
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Overview

Practice Essentials

Childhood disintegrative (or disintegration) disorder, also known as Heller syndrome, is characterized by a loss of previously acquired language and social skills and results in a persistent delay in these areas. For example, a child previously able to speak in 2- or 3-word phrases gradually or abruptly loses the ability to communicate using words or can use only fragments.

Social and emotional development also regress, resulting in an impaired ability to relate with others. For example, a child who was previously able to accept reassurance from his or her parent (eg, a hug) loses the ability to be consoled and may even withdraw from human (tactile) contact.

Childhood disintegrative disorder occurs in about 2 per 100,000 children and thus is much rarer than either autistic disorder, which affects 20 per 10,000 children, or pervasive developmental disorder, not otherwise specified (PDD-NOS), which occurs in 30 per 10,000 children. [1] Childhood disintegrative disorder generally manifests by the fourth year of life, after a period of at least 2 years of normal development.

Overall, the social, communicative, and behavioral features of childhood disintegrative disorder resemble those of autistic disorder. Affected children have distinct qualitative impairments in social interaction and communication. In addition, restricted, repetitive, or stereotyped patterns of behavior, interests, and activities occur. Previously acquired motor skills are lost (eg, a child who was toilet-trained begins to soil during the day and night, or a child who was able to pedal a tricycle or draw shapes can no longer do so).

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Background

Childhood disintegrative (or disintegration) disorder may be associated with lysosomal storage disorders such as late-onset Tay-Sachs disease(LOTS). A recent case report of a patient with symptoms of childhood disintegrative disorder at age 4 years determined that the patient had a sialylation deficiency and an increase of asialo-core fucosylated bisected N-glycans, aberrant N-glycan structures of CSF even though there were no changes of total plasma N-glycan strucutres of CSF proteins. [2]

Additional symptoms of childhood disintegrative disorder may include the onset of difficulty in the transition to waking from sleep. Social interactions become compromised (as manifested by aggressiveness, tantrums, or withdrawal from peers), as does motor function, resulting in poor coordination and possible awkwardness of gait. [3]

Family home movies can be very helpful in early identification of autistic spectrum disorders (ASDs), including childhood disintegrative disorder. [4]

Illustrative case

A 3-year-old boy is referred for evaluation because his behavior has recently gotten him “expelled” from daycare. He screams, throws tantrums, and no longer accepts hugs from his daycare teacher, with whom he was previously familiar. He has lately become destructive to his toys and does not use them to interact with his peers. His parents report that he was doing “okay” up until the past 3 months. They do not report that he had had any language delays.

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Pathophysiology

It was long held, erroneously, that “refrigerator mothers” (a term coined on the basis of the presumed emotional frigidity of such mothers toward their children) caused ASDs in their children. This flawed theory has caused unnecessary psychological pain in countless families. However, current research has yet to reveal a clear-cut pathophysiology for childhood disintegrative disorder, and there remains considerable debate within the developmental disabilities field regarding the long-term outcomes of children with this condition.

Some researchers hypothesize that genetic predispositions combined with environmental stressors (eg, virus exposure or birth trauma) result in brain deposition of amyloid and disruption of synaptic transmissions, possibly involving interleukin-1 (IL-1) or beta-endorphins. Provision of enriched environmental experiences during critical periods of development may restore brain plasticity and thus mitigate genetic predispositions. However, earlier disruption of psychosocial development can result in even more severe developmental consequences.

Several researchers have theorized that altered or inappropriate immune responses, potentially involving abnormal B-cell activation and neuronal function, may play a role in the pathophysiology. In this regard, some studies have found that lithium and hyperbaric oxygen [5] reduce oxidative stress and may increase blood flow to the brain, lending some support to the idea that a possible endophenotype leads to oxidative stress and neuronal injury. [1, 6, 7, 8] A much smaller subset of children with ASD who show onset of symptoms or behavioral deterioration after viral or infectious insults may have this response due to a specific polysaccharide antibody deficiency (SPAD) that may respond to treatment with IV immunoglobulin. [9]

Autoantibodies to myelin basic protein (MBP) in children with childhood disintegrative disorder appear to differ from those in children with nonregressive forms of autism; however, this finding has not yet been shown to correlate with disease severity or prognosis. [6]

No gene has yet been isolated as the cause of childhood disintegrative disorder; however, a gene that codes for elongator protein complex 4 (ELP4) has been identified on human chromosome 11 and appears to be associated with centrotemporal spikes (CTS), the electroencephalographic (EEG) feature typical of rolandic epilepsy (RE).

ELP4 is one component of the elongator complex, a group of 6 genes that function in transcription and modification of transfer RNA (including regulating the actin cytoskeleton, cell motility, and migration) and that seem to play a critical role in influencing genes important to neuronal migration, axon growth, motility of growth cones, and related activities. [10]

ELP4 may also play a critical role in the transcription and modification of transfer RNA. Interference with necessary migration, synaptogenesis, and division in the central nervous system (CNS) before adolescence may result from disruption of transcriptional regulatory and translational modification roles and may render dendrites unable to make the proper neuronal connections. [11]

ASDs, including PDD, are generally associated with an increased incidence of seizures. Other idiopathic focal epilepsies occur during sleep. In addition, other epilepsy syndromes are associated with impaired frontal lobe and language function, potentially leading to continuous epileptiform discharges during sleep. [12]

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Etiology

No single causative factor for childhood disintegrative disorder has been identified. Research suggests that a combination of genetic susceptibility, including possibly abnormal autoimmunity, and prenatal (or environmental) stress may explain the pathophysiologic findings of higher-than-expected brain deposition of amyloid and disruption of synaptic transmission.

As the child experiences developmental departure from normality, the diminished preferential attention to the eyes of others has cascading detrimental effects, decreasing further socialization. The child’s attention focuses on aspects (eg, point sounds, lights, and lip motions), leading to further impairment of appropriate social interaction (mediated by eye contact and facial expression). [13]

Environmental risk factors for childhood disintegrative disorder include the following:

  • Viral exposure (and possibly bacterial infectious exposure for some vulnerable children; however, the more common pathway is usually intrauterine transmission) - Toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex (TORCH)
  • Birth trauma
  • Toxin exposure
  • Teratogenicity
  • Association of increased risk of ASD with in utero exposure to antiepileptic drugs: Meador and Loring in a recent review found up to an 8-fold increased risk of ASD associated with in utero exposure to valproate such that the American Association of Neurology has recommended avoidance of valproate during pregnancy whenever possible

Research directions include the possible association of ophthalmologic malformations with ASDs resulting from the teratogenicity of thalidomide and misoprostol [14]

Genetic factors include the following:

  • Possible susceptibility to chromosomal breakage or disruption
  • Family history of autism or Asperger disorder
  • Family history of RE, with or without CTS – RE commonly affects prepubescent children aged 3-12 years, occurring in about 1 per 500 children (60% of whom are boys); seizures in RE typically begin as groaning noises (in the larynx) that interfere with speech and then may present as sensorimotor activity; seizures in benign RE (BRE) occur at night and during sleep, possibly because sleep is associated with a lowered seizure threshold [15, 16]
  • CTS are also associated with attention deficit/hyperactivity disorder (ADHD), speech disorders, and developmental coordination disorder; in many cases, CTS due to RE are missed because the child’s history of falls can be mistakenly attributed to poor coordination [16]
  • A specific polysaccharide antibody deficiency (SPAD) [9]

Disorders associated with childhood disintegrative disorder include the following:

  • Autoimmune disorders [17]
  • Allergies (eg, food sensitivity reactions) and gastrointestinal (GI) disorders, which may show differences in GI bacterial composition in individuals with autism (Recent work on the microbiology of autism subjects’ stool specimens show that the presence of Desulfovibrio species and the impact of penicillins and cephalosporins, including clindamycin, can predispose to the overgrowth of Clostridium difficile. This may eventually lead to a role of probiotics for those individuals with prominent GI symptoms. [18, 19] ) and which may include asthma [20]
  • Insomnia [21]
  • Vitamin B-12 deficiency [22]
  • Hyperhomocysteinemia [22]
  • Anti – NMDA-receptor encephalitis [23, 24]
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Epidemiology

In the United States, childhood disintegrative disorder is very rare (affecting 2 per 100,000 children), much rarer than autistic disorder (which affects 20 per 10,000 children). [1] No current studies are large enough to determine the international frequency of childhood disintegrative disorder.

Childhood disintegrative disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), occurs only after a period of at least 2 years of normal development, when the child is younger than 10 years. [25, 1] Onset generally occurs in children aged 3-4 years and may be insidious or abrupt. The average age at diagnosis is 3.9 years, comparable to that of autistic disorder (average age, 3.1 years; range, 4.1-5.5 years in some studies). [1]

Childhood disintegrative disorder is slightly more common in males than in females. [1] No studies have shown childhood disintegrative disorder to be any more or less common in any particular race or culture.

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Prognosis

The prognosis of childhood disintegrative disorder has been considered guarded; because the disorder is so rare, more data are needed. [3] Children with moderate-to-severe mental retardation or lack of communicative language have a worse prognosis than those with usual intelligence and communicative language. [3, 26] The disorder is lifelong, and the social, communicative, and behavioral difficulties tend to impair function throughout life. [3, 27]

No mortality or morbidity is directly attributable to childhood disintegrative disorder. Indirectly, a comorbid medical condition, such as a neurodegenerative disorder, may increase the risk of mortality and morbidity. The clinician should be alert to the possibility of Landau-Kleffner syndrome (LKS). [28, 29]

LKS is a rare condition of unknown etiology that is more common in boys. LKS generally presents with more severe language impairment and later than childhood disintegrative disorder; LKS has a mean age of onset of 5.5 years. Excluding this syndrome is important because it is generally associated with seizure disorder and may respond to treatment with anticonvulsants such as valproic acid or steroids. [28, 29]

The risk of seizures increases with age and peaks at adolescence. Concomitant administration of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and low-dose high-potency neuroleptics such as haloperidol tends to lower the seizure threshold (as does alcohol), which may increase the likelihood of seizures. [30]

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