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Digit length pattern in schizophrenia suggests disturbed prenatal hemispheric lateralization

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Abstract

The differentiation of the human brain is triggered by sexual steroid hormones in the fetus. The development of both the urogenital system and the appendicular skeleton are under common control by the HOX genes. Generally men have longer ring fingers than index fingers, whereas in women these fingers are close to equal. The inborn digit pattern may reflect fetal estrogen/androgen influences on hemispheric brain specialization. Reduced hemispheric asymmetry has been found in schizophrenia. Gender differences in schizophrenia also suggest a possible endocrine component in the complex pathogenesis of the illness. To test this hypothesis the authors have measured the relative digit lengths of patients with schizophrenia and healthy comparison subjects. The distance of the tip of the index and ring finger was measured from the tip of the third digit in 80 male and 80 female, right-handed patients with DSM-IV diagnosis of schizophrenia and in 80 right-handed healthy comparison men and women. Schizophrenic men and women showed a more “feminine” phenotype of the index and ring fingers in both hands than same-sex controls. This finding implies that low fetal androgen/estrogen ratio may have a predisposing role in the development of schizophrenia and points toward involvement of endocrine factors in the disturbed hemispheric lateralization attributed to the illness.

Introduction

Several studies support the presence of significant gender differences in schizophrenia ranging from the interplay of sex hormones to neurodevelopmental, clinical and psychosocial sex differences Flor-Henry, 1990, Leung and Chue, 2000. Men have an earlier age of onset and poorer outcome. Male patients seem to be more prone to a poor-prognosis, neurodegenerative subtype of schizophrenia than female patients Castle and Murray, 1991, Salem and Kring, 1998. The production of testicular hormones (mostly testosterone) in early fetal age, around the third month, is fundamental in the differentiation of the male brain. A pubertal “second hit” of hormonal influence contributes to the process of progressive hemispheric specialization in the same brain areas that are critical for the development of language. The left hemispheric predominance of the planum temporale, a key language area, is the most pronounced human brain asymmetry (Geschwind and Galaburda, 1985). Magnetic resonance morphometry showed a stronger leftward-biased planum temporale asymmetry in girls than in boys, independently of age, in children aged 3 to 14 years (Preis et al., 1999). Schizophrenic patients show less hemispheric asymmetry than the population as a whole, and their symptoms may be associated with a “dominance failure” for language (Crow, 1997). Patients with chronic as well as first-episode schizophrenia showed left planum temporale gray matter volume reduction compared to both healthy controls and patients with bipolar manic psychosis (Hirayasu et al., 2000).

The typical onset of schizophrenia is after adolescence (with a second peak around menopause in females) and the illness very rarely occurs before or after the reproductive age, implicating a disturbed balance of sex hormones as a possible contributory component in the pathogenesis of schizophrenia. It is justified to assume that a combination of the genetic and early fetal brain adverse effects interacting with late (reproductive age) pathogenic factors (humoral, neurochemical, psychosocial) may result in the development of the full-blown clinical manifestations of schizophrenia (Keshavan and Hogarty, 1999).

Several lines of evidence suggest that the inborn pattern of digit formation may reflect fetal estrogen/androgen balance Manning and Bundred, 2000, Williams et al., 2000. The differentiation of the urogenital system and the appendicular skeleton is under the control of HOX genes (Kondo et al., 1997). The relationship between gonad differentiation and the formation of fingers and toes led to the suggestion that patterns of digit and toe morphology may correlate with gonad function in the fetus and adult Manning et al., 1998, Manning, 2002. According to the hypothesis of Manning and Bundred (2000) the ratio of the index (second digit, or 2D) and ring finger (fourth digit, or 4D) length (2D:4D), may be used as an indicator and predictive factor in a variety of disorders associated with a disturbed testosterone/estrogen hormone balance. The typical pattern in right-handed human males is shorter index finger than ring finger, a “masculine pattern,” while in human females 2D and 4D are more often close to equal, a “feminine pattern.” Prenatal imbalances of reproductive hormones have been implicated in infertility, autism, dyslexia, left- (“mixed”) handedness, migraine, stammering, immune dysfunction, myocardial infarction and breast cancer Manning and Bundred, 2000, Manning et al., 2001. The fetal sex steroids may influence gender identity and sexual orientation Green, 2000, Williams et al., 2000. Lower 2D:4D ratio, an indicator of higher fetal testosterone levels, has been found associated with male and female homosexuality and male physical competitiveness Robinson and Manning, 2000, Williams et al., 2000, Manning and Taylor, 2001.

Based on these hypotheses, the authors investigated the lengths of 2D and 4D relative to the middle finger in patients with schizophrenia. The goal of the study was to provide evidence for an endocrine component in the development of incomplete brain hemispheric specialization associated with schizophrenia.

Section snippets

Methods

Eighty male and 80 female patients with DSM-IV (American Psychiatric Association, 1994) schizophrenia, under the long-term care of one of the investigators, and 80 healthy, male and female comparison subjects were included in this investigation after obtaining written informed consent. The age range was from 18 to 60 years, with the mean age (±S.D.) being similar in the schizophrenia group (males=41.4±11.3, females=40.4±11.1 years) and in the comparison group (males=38.3±11.0,

Results

Table 1 shows the finger pattern data of schizophrenic patients and comparison subjects. After analyzing the r2Dr4D measure, the following group differences have emerged. The variable was significantly smaller for both hands in healthy and schizophrenic females as compared to the male members of the same group: mean±S.D. of controls: left hand 1.5±4.0 vs. 4.9±4.0 mm (t=5.3, P<.01), right hand 1.2±4.3 vs. 3.9±4.8 mm (t=3.7, P<.01); mean±S.D. of patients: left hand 0.3±3.7 vs. 2.9±4.3 mm (t=3.9,

Discussion

With the finding of 2D lengths closer to 4D lengths in women as compared to men, this study supports the sexual dimorphism of finger pattern described by Manning et al. (1998). In addition, it was found that schizophrenic patients, both males and females, had a more “feminine” phenotype of the 2D and 4D in both hands than same-sex controls. Estrogen is thought to increase the length of 2D and testosterone the length of 4D (Manning, 2002). Since female patients had longer 2D than healthy women,

Conclusions

This study was the first to investigate the relative digit lengths in schizophrenia and to reveal a “feminine digit pattern” in the illness. The pattern indicates a low androgen/estrogen ratio in the fetus who later in life, usually after puberty, develops schizophrenia. This finding is consistent with the possibility of an endocrine component in the development of schizophrenia, or at least in a subgroup of schizophrenic patients.

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    Part of this study was presented at the International Congress on Schizophrenia Research, Whistler, BC, Canada, April 28–May 2, 2001.

    Deceased.

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