The initial search yielded in total 5278 papers (1783 and 3495 hits, respectively, of which 55 duplicates). 4665 papers were excluded according to the title and/or the abstract and 451 were excluded based on the full text. The remaining 104 papers were scored of which 29 papers were considered of high quality (5 or 6 points) and presented in this review. Two of these 29 papers focused on both ADHD and ASD, and are therefore listed in both tables (see Fig. 1).
Table 1 presents the papers that studied the association between ASD and medical disorders: 5 papers on immunology, 6 papers on gastroenterology, 1 paper on neurology and 2 papers on other medical disorders (see Table 1). In Table 2, the papers are listed that studied ADHD and medical disorders: 12 papers on immunology, 1 paper on neurology and 4 papers on other medical disorders (see Table 2).
ASD and immunology
With regard to a possible association between ASD and immunological disorders, most papers studied allergic disease or autoimmune disease. Jyonouchi et al. evaluated whether one could clinically distinguish a subset of children with ASD and immunological disorders from other ASD children based on the frequency of infections . In this sample, no significant differences were found considering the prevalence of atopy, asthma, food allergy, primary immunodeficiency between children in the ASD test group and controls (ASD controls, non-ASD controls with food allergy, non-ASD controls with frequent infections and normal controls).
Chen et al. concluded, however, that the presence of any atopic disease in early childhood increased the risk of developing ASD (hazard ratio: (HR) 3.40) in later life . Greater numbers of atopic comorbidities (4 comorbidities HR: 4.29) were significantly related to a greater risk of developing ADHD and ASD.
Gentile et al. found similar rates of contact with Herpes Simplex Virus 1 and Herpes Simplex Virus 2 between children with ASD and healthy controls .
The study of Puig-Alcatraz et al. found that the increase in homocysteine concentration, suggestive for disorders of the immune system, was significantly correlated with the severity of the deficit in communication skills in children with ASD, but was unrelated to deficit in socialization or repetitive/restricted behavior compared to typically developing children .
Contrary to the study of Jynouchi et al., Zerbo et al. reported that allergies and autoimmune diseases were diagnosed significantly more often among children with autism than among controls (allergy: 20.6 vs. 17.7%, crude odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.13–1.31; autoimmune disease: 1 vs. 0.76%, OR = 1.36, 95% CI 1.01–1.83), and asthma was diagnosed significantly less often (13.7 vs. 15.9%; OR = 0.83, 95% CI 0.76–0.90) . Furthermore, psoriasis was seen more often in cases than in controls (0.34 vs. 0.15%; OR = 2.35, 95% CI 1.36–4.08).
ASD and gastroenterology
The study of Valicenti et al. found that children with ASD had a significantly higher rate of gastro-intestinal (GI) symptoms than children with either typical development or other developmental disabilities (history of GI symptoms 70 vs 28 vs 42%, abnormal stool pattern 18 vs 4 vs 2%, food selectivity 60 vs 22 vs 36%) . There was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
The longitudinal population-based study of Mouridsen et al. found no evidence that patients with infantile autism (IA) were more likely than controls to have defined gastro-intestinal diseases during a 30.3-year observation period (30.5% against 30.7%) . Only diseases of oral cavity (dental problems) were significantly associated with IA (20.3 vs 1.2%, p value < 0.0001).
In the study of Wang et al., parents retrospectively reported significantly more GI problems in children with ASD (249/589; 42%) compared with their unaffected siblings (20/163; 12%) (p < 0.001) . The 2 most common gastro-intestinal problems in children with ASD were constipation (20%) and chronic diarrhea (19%). Next, individuals with ASD were grouped into 3 autism severity groups (Full Autism, Almost Autism, and Spectrum) based on their Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale scores. Increased autism symptom severity was associated with higher odds of gastro-intestinal problems (AOR for trend = 2.63, 95% CI: 1.56–4.45).
The increased prevalence of GI symptoms was also found by Chandler et al. In this study, 46.5% of children with ASD had at least one individual lifetime GI symptom compared with 21.8% of typically developing children and 29.2% of the children with special educational needs . No association was found between GI symptoms and intellectual ability, ASD severity, ASD regression or a faddy diet (arbitrary and often unusual likes and dislikes about food).
The study of Mouridsen et al. compared prevalence rates of gastro-intestinal tract diseases (esophagus, stomach, duodenum, gall bladder, biliary tract, pancreas, liver, peritoneum, intestines) in patients with PDD-NOS. In this study, conducted with data from the Danish National Hospital Register, the difference in prevalence of children with autism (24.7% (22/88)) and at least one diagnosis of any disease of the gastro-intestinal tract was not statistically significant (control group 18.2% (47/258)) (p = 0.22; odds ratio = 1.5; 95% confidence interval = 0.8–2.6). Interestingly, only hernia was significantly associated with autism 11.2 vs 4.7% (p = 0.04; OR = 2.6; 95% CI = 1.08–6.2). There were no children with inflammatory GI diseases, such as Crohn’s disease or ulcerative colitis in the autism group. Hence, in this study people with autism had about the same frequency of gastric, intestinal and hepatic diseases as had controls .
The study of Von Gontard et al. showed increased rates of nocturnal enuresis (30.0 vs 0%) and daytime urinary incontinence (25.0 vs 4.7%) in children with ASD compared to controls. Furthermore, ASD children had more lower urinary tract symptoms (LUTS) especially urgency and postponement, and they needed a longer time to become dry and continent .
ASD and neurology
Mouridsen et al. studied the prevalence of epilepsy among patients with Asperger’s syndrome using the Danish National Hospital Register . In a follow-up period of 4–18 years, patients with Asperger’s syndrome were more likely to have epilepsy (3.9% in 4180 cases) in comparison with the estimated prevalence of 2% in the general population.
ASD and other medical disorders
Van Tongerloo et al. investigated the presence of characteristic complaints of children with ASD presenting to the general practitioners’ practice, in order to enhance early detection and reduce the delay in diagnosing ASD. This study found that children with ASD presented with more traumata (luxations and distortions) (OR 6.57, p-value < 0.01) compared to controls. Also, they were more likely referred to the physiotherapist/ergotherapist (OR 12.63, p-value < 0.05), speech therapist (OR 7.07, p-value < 0.05) and ear–nose–throat specialist (OR 5.54, p-value < 0.05) .
Using data from the Swedish Patient Register, Butwicka et al. studied the prevalence of ASD in men with hypospadias (n = 9626) . Hypospadias is associated with autism (OR 3.20; 95% CI 2.8–3.8) compared to full brothers (n = 4936) and the control group (n = 463,100).
In Table 2, the papers are listed that studied ADHD and medical disorders: 12 papers on immunology, 1 paper on neurology and 4 papers on other medical disorders (see Table 2).
ADHD and immunology
This review includes 12 papers on the association between ADHD and immunological disorders. The study of Leslie et al.  showed that prior streptococcal infection was associated with obsessive–compulsive disorder, tic disorders, major depressive disorder. Studies have suggested a link between Group A beta-hemolytic streptococcal (GABHS) infections and the onset or worsening pediatric obsessive–compulsive disorder (OCD), Tourette’s syndrome (TS) and tic disorder. The prepubertal onset of OCD, TS, or tic disorder with abrupt symptom exacerbation after streptococcal infection has been termed PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). Furthermore, this study showed that some patients prior to their initial diagnosis of ADHD were more likely to have had a diagnosis of streptococcal infection in the previous year than controls (OR 1.20, 95% CI 1.06–1.35) . Although ADHD is frequently comorbid with TS, tic disorders, and OCD, comorbidity of ADHD with TS, tic disorders and OCD were excluded. It remains unclear whether this is the result of a nonspecific stress response or secondary to an activation of the immune system.
The study of Sanchez et al. indicated that frequency of anti-basal ganglia antibodies (ABGA) in children with ADHD (non-comorbid with obsessive–compulsive disorder or tics) does not differ from that in matched controls (4 vs 4%), despite the fact that our ADHD patients had had more recent pharyngeal group A beta-hemolytic streptococcus GABHS infections than the controls (51 vs 14%, p-value = 0.007) .
With regard to atopy, the study of Schmitt et al. found a prevalence of ADHD among patients with atopic eczema (AE) of 5.2 and 3.4% among controls. Allergic comorbidities (asthma, allergic rhinitis) were not significantly associated with ADHD .
The study of Suwan et al. showed significantly increased rates of allergic sensitization (p-value = 0.0048) and allergic rhinitis in children with ADHD (p-value = 0.008) . On the other hand, no differences were observed regarding other allergic diseases, asthma, eczema, allergic conjunctivitis, food allergy and urticarial (p-value > 0.05).
In a population-based study of Tsai et al. allergic rhinitis patients were more likely to have ADHD than the general population (p-value < 0.001) .
The association between allergy and ADHD was also found by Shyu et al. In their study, allergic children have a higher risk for developing ADHD in comparison with the general population (p-value < 0.001) . Allergic rhinitis was found to be the most important contributing factor for the development of ADHD compared to the impact of bronchial asthma and atopic dermatitis.
Chen HJ et al. found a significant association between previously diagnosed diabetes mellitus type 2 and ADHD in children aged 5–15 years (OR 2.75, 95% CI = 1.82–4.16) . There was no association between diabetes type 1 and ADHD.
Using the National Health Insurance Research Database, Chen MH et al. showed that patients with dual diagnoses of ADHD and tic disorder had a significantly higher prevalence of allergic diseases including allergic rhinitis, asthma, atopic dermatitis, allergic conjunctivitis than the ADHD alone group, the tic alone group, and the control group (allergic rhinitis 43 vs. 28.4 vs. 33.6 vs. 19.7%, p-value < 0.001, asthma (27.5 vs. 17.2 vs. 18.2 vs. 11.9%, p-value < 0.001, atopic dermatitis 10.6 vs. 8.4 vs. 7.0 vs. 5.9%, p-value < 0.001, allergic conjunctivitis 55.6 vs. 34.7 vs. 43.5 vs. 26.3%, p-value < 0.001) .
The study of Tsai et al. found a higher rate of allergic disease in children with ADHD compared to controls, particularly allergic rhinitis (OR 1.80 95% CI 1.69–1.93), and allergic conjunctivitis (OR 1.69; 95% CI 1.58–1.81 . Children with atopic dermatitis (OR 1.80; 95% CI 1.58–2.05) and asthma (OR 1.48; 95% CI 1.24–1.78) were also at higher risk of ADHD. The risk of ADHD increased with numbers of allergic disease and age.
The study of Bekdas et al. presented that patients with ADHD displayed significantly higher positivity for measles IgG (80 vs. 60%, p-value = 0.044) . When patients with ADHD were classified according to their pubertal status, adolescents with ADHD displayed higher positivity for mumps.
Chen MH et al. found that the presence of any atopic disease in early childhood increased the risk of developing ADHD (HR: 1.97) in later life . Greater numbers of atopic comorbidities (4 comorbidities HR: 2.53) were significantly related to a greater risk of developing ADHD.
ADHD and neurology
Using data from the Neurodevelopmental Genomics Cohort Study, Merikangas et al. showed that children with central nervous system conditions (seizures and epilepsy) were significantly more likely to have ADHD (OR 1.30, p-value < 0.001) . There was no significant association between ADHD and gastroenterological, immunological, autoimmune, cardiology, hematology, nephrology, endocrine disorders.
ADHD and other medical disorders
The study of DeMaso et al. found that adolescents with d-transposition of the great arteries showed increased rates of attention deficit/hyperactivity disorder compared to healthy controls (19 vs. 7%, p-value = 0.03) . In the study of Dillon et al. 27.8% of the children that underwent adenotonsillectomy had ADHD, whereas only 7.4% of the control group had ADHD . Among the 22 children diagnosed with ADHD before surgery, 50% no longer met diagnostic criteria after adenotonsillectomy.
The population-based study of Silva et al. showed that children under 4 years with ADHD were 70% more likely to be admitted to a hospital compared with controls . Admissions for head injuries, burns, poisons, all other injuries, diseases of the tonsils and adenoids, asthma and early infections were all more common in children with ADHD.
Next to ASD, Butwicka et al. also studied the prevalence of ADHD in men with hypospadias, and found an increased risk of ADHD in men with hypospadias (OR 1.50; 95% CI 1.3–1.9) .