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Severity of minor physical anomalies as a possible trait marker in schizophrenia/Sizofrenide olasi bir isaretleyici olarak minor fiziksel anomalilerin siddeti.


Schizophrenia is a chronic, severe mental disorder with high heritability. Although there has been important advances in the treatment of this disorder, outcome is stil not very favorable. Therefore, it is very important to detect markers that can be used to identify individuals at risk. These risk markers are traits--which can be biological, neuropsychological, or physical- (1), and they reflect the phenotypic reflection of the tendency to develop schizophrenia. One of these markers is minor physical abnormalities (MPAs), a heterogenous group of morphological markers indicating subtle abnormalities in neurodevelopment (2). Neuronal and craniofacial development occurs simultaneously during gestation, a period sensitive to environmental exposures (3). MPAs are structural aberrations that are believed to associated with abnormal neurodevolepment (2,4) The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia: the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration (2,4,5).

Symptom-based characterization of schizophrenia has been found to be inadequate to delineate the underlying neurobiologic substrate of this complex disorder, and therefore, researchers have recently turned their attention to neuroanatomical, soft neurologic, neuropsychologic, electrophysiologic, brain morphometric, and other biologic indices that are reliably associated with this condition. Study of these endophenotypes is expected to facilitate understanding schizophrenia (6).

Several studies have compared the frequency of MPAs in patients with schizophrenia, their first-degree non psychotic relatives, and healthy individuals. These studies have shown that MPAs were more common in patients with schizophrenia when compared with both healthy controls and their unaffected relatives (7,8). While some studies reported that unaffected first-degree relatives had higher MPAs than healthy controls (9), a recent showed that the difference was not statistically significant (10). However, some questions remain to be answered. One study investigated the association of MPAs and neurological soft signs with schizotype in first degree relatives (11). Most of the studies included a mixed population of siblings and parents. It has been shown that the risk of having schizophrenia is lower in parents than siblings. Besides, since schizophrenia most commonly emerges in young adulthood, most of the parents have passed the highest risk periods, and therefore may be low risk carriers. Another less intensively investigated issue is the association of depression and anxiety symptoms with MPAs in the schizoprenia patients and their siblings. Previous studies have produced inconsistent findings regarding MPAs in unipolar depression (12).

In this study, our aims were to investigate, 1- whether there are differences among subjects with schizophrenia, their siblings and healthy controls regarding MPA levels, 2- whether psychotic and affective symptom ratings were associated with MPAs in patients with schizophrenia.



This study is part of a larger study investigating possible endophenotypes in schizophrenia. The sample included 38 subjects with schizophrenia, their 34 unaffected siblings and 38 healthy controls. The schizophrenia subjects were recruited from consecutive addmissions to Public Mental Health Center at Bolu, a day-care treatment center for chronic, stable schizophrenia patients. Inclusion criteria were having DSM-IV schizophrenia diagnosis, being 18 to 65 years of age and giving consent to the study. Exclusion criteria were; having substance abuse other than smoking, mental retardation, pervasive developmental disorders, chronic medical conditions and head trauma that resulted in unconciousness. The control group were recruited from volunteers working at the hospital. Institutional review board approved the study and written informed consent was obtained from each participant.


Structered Clinical Interview for Diagnostic and Statistical Manuel of Mental Disorder-fourth edition (DSM-IV) (SCID-I) (13,14) was used to make schizophrenia diagnosis and screen other DSM-IV diagnoses. Patients with comorbid substance abuse, affective psychosis and head trauma were excluded from the study. The siblings and healthy controls were also screened with SCID-I. Siblings and healthy controls with any of the DSM-IV Axis I diagnosis were excluded from the study. Healthy controls were excluded if they endorsed any personal or family history (in first- or second-degree relatives) of psychotic or mood disorders. A total of 5 subjects with schizophrenia, 7 first-degree relatives and 1 healthy control were excluded from the study. We used Positive and Negative Symptoms Scale (PANNS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) to evaluate psychotic, depressive and anxiety symptoms, respectively, in the schizophrenia group (15,16,17,18,19,20).

MPAAs Assessment: We used a modified version of Waldrop scale to evaluate "informative morphogenetic variants". The Waldrop Physical Anomaly Scale is currently the most widely used instrument for assessment of dysmorphic features (21). Lane et al proposed new scale assesment of anomalies (22). The reliability (internal consistency) of the Waldrop scale has been low (5) and trixler and associates argued that the original Waldrop scale was not adequate to make a distinction between minor malformations and phenogenetic variants (23). Therefore, the authors expanded the original scale with additional informative morphogenetic variants by the pediatricians, resulting in 56 items. This modified version was reported to be reliable. the Waldrop Scale contains only 18 informative morphogenetic variants, but more than 50 informative morphogenetic variants have been listed in the pediatric literature (23). We used to Using a list of informative morphogenetic variants containing 56 minor signs established by pediatric researchers (24) A kappa coefficient above 75% was found in 34 of the 56 informative morphogenetic variants compared to alcohol dependent and schizophrenia (23). But MPA s found high some psychiatric disorders (especially bipolar affective disorder) (25).

Statistical Analysis

We used analysis of variance with post-hoc Tukey test to compare the PANNS, BDI, BAI and Waldrop scores of patients with schizophrenia, their unaffected siblings and healthy controls. We used Pearson correlation test to find the association of PANNS, BDI and BAI scores with Waldrop scores in the schizophrenia group. Two tailed test results are reported (alpha = 0.05). Statistical analysis was performed using SPSS 15.0 for Windows.


The mean age was 37.0 [+ or -] 11.5, 34.5 [+ or -] 11.4 and 31.2 [+ or -] 5.2 in schizophrenia, siblings and controls groups, respectively. Regarding the gender distribution 36.8%, 47.1%, 48.6% of the subjects were females in subjects with schizophrenia, their siblings and controls. There were no significant differences among the groups regarding age and gender.

PANNS, BDI, and BAI scores were summarized in Table 1. MPAs were significantly different among the groups (F = 68.1; p < .001). Post hoc analysis revealed that schizophrenia group had the highest MPA followed by the siblings group. Healthy control group had significantly lower MPA than both other groups.

According to the Spearman's correlation analysis, MPAs score was not significantly correlated with PANNS (rho = .30, p = .06), BDI (rho = .07, p = .67), and BAI (rho = -.11, p = .49) scores in the schizophrenia group.


The results of the present study showed that the three groups were alligned in a hierarchical order for the severity of MPAs with schizophrenia group having the highest, siblings having intermediate and the healthy controls having the lowest. Second, in the schizophrenia group the association between psychotic and affective symptom ratings were not significant. Our first finding was consistent with the previous studies showing that patients with schizophrenia had higher MPAs when compared with their unaffected first-degree relatives and controls (8,26,27,28). The lack of a significant association between symptom ratings and MPAs was also consistent with some research results (6). Whether MPAs are increased in the unaffected first-degree relatives is a controvertial issue (6). Our results showed that unaffected siblings on the schizophrenia probands had significantly higher MPAs. This was consistent with some of the previous studies although there are several negative reports as well (9,29,30,31). The inconsistencies in these previous studies might be due to differences in sample selection. The gene pool shared between the siblings is larger than that shared between the parents and their offsprings (31,32). Therefore, previous studies which included mixed samples of parents and siblings in the first-degree relative groups might have underestimated the frequency of MPAs as a risk marker for schizophrenia.

Our results might support that the degree of MPAs might be a trait marker (MPAs were more common in unaffected siblings of the patients when compared with healthy controls) and the degree of MPAs were not significantly correlated with symptom severity. Therefore, MPAs fulfill some of the criteria for endophenotypes (33); they are associated with illness in the population and are also state independent (6). Our results supported the previous findings that they are found in unaffected relatives more frequently than controls, providing additional support for MPAs being an endophenotype.

The principal limitation of the study was the clinical nature of the sample, therefore, the results may not be valid for population samples.

In summary, in a more homogeneous sample consisting only of unaffected siblings; our results showed that patients with schizophrenia had higher MPAs then their siblings who had higher MPAs then healthy controls. These results argue in favor of MPAs as traitmarkers for schizophrenia.

DOI: 10.4274/npa.y6148

Conflict of interest: The authors reported no conflict of interest related to this article.

Cikar catismasi: Yazarlar bu makale ile ilgili olarak herhangi bir cikar catismasi bildirmemislerdir.


This study was supported by Abant Izzet Baysal University BAP funds.


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Mehmet Hamid BOZTAS [1], Ekrem GUNEY [1], Ozden ARISOY [1], Mustafa SERCAN [1], Hulya ENSARI [2]

[1] Abant Izzet Baysal University Medical Faculty, Department of Psychiatry, Bolu, Turkey

[2] Bolu Izzet Baysal Mental Health and Diseases Hospital, Psychiatry Clinic, Bolu, Turkey

Correspondence Address/Yazisma Adresi: Mehmet Hamid Boztas MD, Abant Izzet Baysal University Medical Faculty, Department of Psychiatry, Bolu, Turkey

Gsm: +90 533 460 52 57 E-mail: Received/Gelis tarihi: 25.04.2011 Accepted/Kabul tarihi: 08.08.2011
Table 1. Clinical psychometrcis scales relations with in
schizophrenia, siblings and control

 Age Gender

Schizophrenia 37.0 [+ or -] 11.5 36.8%
Siblings 34.5 [+ or -] 11.4 47.1%
Control 31.2 [+ or -] 5.2 48.6%

 Waldrop *,** PANSS *

Schizophrenia 4.47 [+ or -] 1.466 84.39 [+ or -] 19.390
Siblings 3.18 [+ or -] 1.623
Control .84 [+ or -] .928

 BDI * BAI *

Schizophrenia 14.42 [+ or -] 9.596 12.68 [+ or -] 8.761
Siblings 6.21 [+ or -] 5.835 6.06 [+ or -] 7.236
Control 5.86 [+ or -] 5.628 5.38 [+ or -] 6.020

control groups, * : Schizophrenia group > Siblings and Healthy
Controls; **: Siblings > Healthy Controls.
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Article Details
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Title Annotation:Research Article/Arastirma Makalesi
Author:Boztas, Mehmet Hamid; Guney, Ekrem; Arisoy, Ozden; Sercan, Mustafa; Ensari, Hulya
Publication:Archives of Neuropsychiatry
Article Type:Report
Date:Sep 1, 2012
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