The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia due to 21-hydroxylase deficiency

doi:10.1016/S0378-3782(02)00073-7

Early Human Development

Volume 70, Issues 1–2, December 2002, Pages 47-54

https://doi.org/10.1016/S0378-3782(02)00073-7 Get rights and content

Abstract

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in excessive androgen exposure in the gestational period and various degrees of masculinization of the external genitalia in female foetuses. Intrauterine gonadal steroids are not only essential for the development of the genital organs but also affect some other extragenital organ development.

The second to fourth digit (2D/4D) ratio shows a sexually dimorphic pattern with longer fourth digit from second digit in men compared to women. A low 2D/4D ratio is associated with high sperm count, testosterone levels and reproductive success in men. A high 2D/4D ratio is associated with high oestrogen levels in women. Second and fourth digit ratio has also found to be correlated with sexual orientation, left hand preference autism and some adult onset diseases such as breast cancer and myocardial infarction.

We found lower 2D/4D ratio in female patients with 21-hydroxylase deficiency compared to healthy girls (p=0.000) and equal 2D/4D ratio for female patients when compared to male controls. Male patients with 21-hydroxylase deficiency had significantly lower 2D/4D ratio than female and male controls in the right hand. Healthy boys had lower 2D/4D ratio than healthy girls.

It is concluded that 2D/4D ratio established by intrauterine androgen levels influences the sexually dimorphic digit pattern.

Introduction

Congenital adrenal hyperplasias (CAH) are a group of autosomal recessive disorders of steroidogenesis that result in high levels of androgens beginning in early gestational period and continuing until treatment is initiated. Disorders of 21-hydroxylation account for over 95% of patients with CAH, with a wide spectrum of clinical manifestations. The classical form of the disease includes the simple virilizing form and the salt-wasting form, the symptoms are present as early as the foetal period. Girls with 21-hydroxylase deficiency have varying degrees of virilization of external genital organs. The appearance of the clitoris resembles the penis because of excessive phallic growth, the urethra becomes enclosed and tends to open on the base of the phallus, the vagina internalizes and may have a shared opening with the urethra [1], [2], [3]. The nonsalt-losing form of 21-hydroxylase deficiency may be diagnosed in the neonatal period in boys with the presence of family history or the diagnosis may be made at a later age with increasing masculinization, which is inappropriate for their age [1]. The salt-losing form of classic 21-hydroxylase deficiency is usually diagnosed during the first few days and weeks of life and may be fatal if it is not diagnosed [2]. The nonclassical form of the disease is characterised by the extra uterine onset of symptoms such as masculinization, premature adrenarche, or phallic growth for each gender [3].

It has been known for some time that the ratio between the length of the second and fourth digits (2D/4D) is sexually dimorphic. Males have on average longer fourth digits relative to their second digits than do females [4], [5]. The 2D/4D ratio may be used as a predictor of fertility and the expression of a number of adult onset diseases [5], [6]. In men, low 2D/4D ratio is associated with high sperm counts, high level of testosterone and elevated levels of fertility, high 2D/4D ratios are correlated with low sperm counts, low testosterone and high oestrogen concentrations. In women, oestrogen is positively related to 2D/4D ratio [5], [6], [7]. Low 2D/4D ratios in men have been found not only to be associated with reproductive success [7] but also associated with ability in sports [8], [9], and left-hand preference [10]. The 2D/4D ratios are also correlated with sexual orientation [11] and some adult onset diseases such as breast cancer [6], [12]. The male-like pattern of the finger lengths has also been demonstrated in homosexual women [13].

It was recently suggested that the sexually dimorphic pattern of the digits may correlate with prenatal androgens and relative lengths of the digits is set before birth [5]. Recent research on 2D/4D had been summarized by Manning [14].

The aim of this study was to measure second- and fourth-digit lengths in children with CAH (caused by 21-hydroxylase deficiency) to compare them with healthy children in an attempt to the prenatal androgen effects on the sexually dimorphic finger-length pattern.

Section snippets

Material and methods

The patient group was composed of 26 children with CAH due to 21-hydroxylase deficiency that were followed up at the Karadeniz Technical University, Medical School, Paediatric Endocrinology Department, Trabzon, Turkey. The patients were aged between newborn and 13.3 years (mean±S.D.: 4.6±4.2 years) and they were diagnosed with 21-hydroxylase deficiency. Their mean age at the diagnosis was 1.5±2.5 years (range: newborn to 8.3 years). According to their chromosomal analysis, 9 children had 46XY

Results

One of the patients had complete virilization with penile urethra considered as Prader 5 (4%). The other patients had clitoral hyperplasia, hypospadias and only one urogenital sinus opening and considered as Prader 3.

Hand preferences were generally right. Only two children were left-handed, one of them was in the CAH group, another was in the control group.

The digit lengths, which were obtained from the palm photocopies, showed significantly lower 2D/4D ratios in 52 healthy boys compared to 52

Discussion

Intrauterine exposure to sex hormones is crucial for development and differentiation of the genital organs. Normally, a male foetus is exposed to testosterone from two sources, the foetal testes and the foetal adrenal glands. Prenatal oestrogen appears to be the aromatase conversion of testosterone from the adrenal glands and the placenta. The adrenal gland is the main source of male sex hormone in the female foetus [16], [17].

Adrenal 21-hydroxylase activity is mediated by cytochrome P450c21

References (30)

D.K. Edmonds
Congenital malformations of the genital tract
Obstet. Gynecol. Clin. North Am.
(2000)
J.T. Manning et al.
The ratio of 2nd and 4th digit length: a new predictor of disease predisposition?
Med. Hypotheses
(2000)
J.T. Manning et al.
The 2nd and 4th digit ratio, sexual dimorphism, population differences, and reproductive success: evidence for sexually antagonistic genes?
Evol. Hum. Behav.
(2000)
J.T. Manning et al.
Second to fourth digit ratio and male ability in sport: implications for selection in humans
Evol. Hum. Behav.
(2001)
S.J. Robinson et al.
The ratio of 2nd to 4th digit length and male homosexuality
Evol. Hum. Behav.
(2000)
J.T. Manning et al.
2nd to 4th digit ratio and age at presentation of breast cancer
Breast
(2001)
H. Merchant-Larios et al.
Onset of sex differentiation: dialog between genes and cells
Arch. Med. Res.
(2001)
A.D. Carlson et al.
Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment
J. Steroid Biochem. Mol. Biol.
(1999)
S.A. Berenbaum et al.
Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia
Psychoneuroendocrinology
(1997)
S.A. Berenbaum
Effects of early androgens on sex-typed activities and interests in adolescents with congenital hyperplasia
Horm. Behav.
(1999)

J.J. Nora et al.

Congenital abnormalities and first-trimester exposure to progestagen/oestrogen

Lancet

(1976)

M.I. New

Diagnosis and management of congenital adrenal hyperplasia

Annu. Rev. Med.

(1998)

W.L. Miller

Genetics, diagnosis and management of 21-hydroxylase deficiency

J. Clin. Endocrinol. Metab.

(1994)

J.T. Manning et al.

The ratio of 2nd and 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen

Hum. Reprod.

(1998)

J.T. Manning et al.

The 2nd and 4th digit ratio and autism

Dev. Med. Child Neurol.

(2001)

Cited by (271)

Patients with developmental dysplasia of the hip shows higher digit ratio (2D:4D)
2023, Early Human Development
Developmental dysplasia of the hip (DDH) encompasses a range of hip disorders, from dysplasia to dislocation. One key factor is sex, with women being four to eight times more susceptible to DDH than men. However, there have been no studies investigating the second-to-fourth digit ratio (2D:4D), a biomarker of prenatal sex steroid exposure, in DDH patients. This study aimed to explore whether there is an association between the 2D:4D ratio and DDH.
Digital calipers were used to measure the second and fourth finger lengths of 250 patients treated for DDH and 200 patients in the healthy control group between January 2020 and January 2023. The Mann-Whitney U test was used for non-normally distributed variables and two-way analysis of variance to assess differences in measurements between DDH patients based on sex, side, and the interaction of sex and side. The intraclass correlation coefficient (ICC) was used to assess measurement repeatability.
The median (min-max) age was 10.00 (6–16) years in the DDH group, 12.00 (6–16) years in the control group, and 10 (6–16) years for the whole cohort. There was no significant difference in terms of age between the patient and control groups (p = 0.083). When comparing the DDH group with controls the former showed higher right 2D:4D and Δ2D:4D and these differences were significant in both males and females. Among the patients, controlling for side of dysplasia did not affect right 2D:4D, left 2D:4D or Δ2D:4D.
There was a significant association between higher 2D:4D ratios (both right and left hands) and DDH in both men and women. This indicates that the 2D:4D ratio, a marker of intrauterine estrogen/testosterone balance, is associated with DDH.
Direct and radiographic digit ratio (2D:4D) measurements of Tuvan children and adolescents from Southern Siberia: Sex differences and skeletal maturation
2023, Early Human Development
In Mongolian-origin ethnic groups digit ratio (2D:4D; a proxy for prenatal sex-steroids) is sexually dimorphic (males < females), as reported for other ethnicities. Most studies measured 2D:4D from soft tissue (directly from the digits, or indirectly from hand scans), or from radiographs. Evidence on the correspondence of 2D:4D measurements from soft tissue with measurements from radiographic images is scarce and has not been reported for a Mongolian-origin sample. In addition, previous research has not considered relationships between 2D:4D and measures of skeletal maturity.
To examine (i) associations between 2D:4D measured directly from the palms with those obtained from radiographic images of the same individuals in a sample of children and adolescents from the Tuvan population in Siberia (Russian Federation), and ii) associations between 2D:4D measurements with chronological and skeletal age.
Participants were Tuvan boys and girls aged 7 to 18 years. 2D:4D of the right and left hand was measured from soft tissue (directly from the palm) and compared with radiographic images (left hand only). In addition to finger length 2D:4D, we examined 2D:4D of the phalanges from measurements of radiographs. Skeletal age was assessed using the Tanner-Whitehouse method.
Sex differences (boys < girls) in measurements of 2D:4D from soft tissue and radiographs were found for total finger length and phalanges. In addition, 2D:4D measurements from radiographs correlated positively and significantly with those obtained from soft tissue. Sex predicted 2D:4D measurements from soft tissue and radiographs, but no effects of chronological/skeletal age and body height were detected. In girls (but not in boys), earlier skeletal maturity (relative to chronological age) was associated with higher 2D:4D in soft tissue measurements of both hands, radiographic 2D:4D, and 2D:4D of the proximal phalanges.
Consistent with reports from other ethnic groups, 2D:4D in young Tuvans was sexually dimorphic, with boys having lower 2D:4D than girls. For girls, higher 2D:4D was found for participants whose skeletal age was more advanced than chronological age. This finding was obtained from direct soft tissue and indirect radiographic measurements. Age and body height were not associated with 2D:4D, which suggests differences in hormone developmental trajectories for 2D:4D and height.
Digital biomarker 2D:4D as a predictor of cancer: A systematic review
2022, Early Human Development
The digital ratio between the second and fourth digits of the hands, known as 2D:4D, is sexually dimorphic. It has been suggested that a low 2D:4D indicates high exposure to prenatal testosterone and low estrogen exposure while a high 2D:4D indicates the inverse. The 2D:4D may be predictive of cancer susceptibility, and this may be particularly true in cancers that show differences between sexes in their occurrence.
To conduct a systematic review of published epidemiological literature examining the association between 2D:4D and cancer.
This review was carried out according to criteria recommended for the systematic review of Statement PRISMA. We enrolled 25 papers involving eleven cancer topographies with 4,569 cases and 19,416 controls from Europe, America, Asia and Australia.
We noticed variations and discrepancies in the results of the association between 2D:4D and cancer among the studies, either in those that had evaluated the same or different types of cancer, or in the same or distinct lateralities. However, a high 2D:4D was considered a likely predictor of cancer risk in 11 of 25 studies, a low 2D:4D was suggested as a predictor of risk in eight papers, and five of the twenty-five studies did not demonstrate any association.
Although this biomarker has the advantage of being easy to measure, it is noted that its relationship with sex hormone levels at specific stages of life has not yet been well quantified, and it has still been questioned. Hence, it is suggested that those findings from studies involving 2D:4D as a proxy for foetal hormone exposure should be interpreted with caution, as well as those studies which claim its association with cancer. Thus, this review shows the need for a greater number of epidemiological studies using more homogeneous methodology and techniques to better investigate the strength of the findings.
2D:4D does not predict economic preferences: Evidence from a large, representative sample
2021, Journal of Economic Behavior and Organization
The digit ratio (2D:4D) is considered a proxy for testosterone exposure in utero, and there has been a recent surge of studies testing whether 2D:4D is associated with economic preferences. Although the results are not conclusive, previous studies have reported statistically significant correlations between 2D:4D and risk taking, altruism, positive reciprocity, negative reciprocity and trust. However, most previous studies have small sample sizes gathered from university students and there is also no consensus on the type of analysis (e.g., which hand to analyze or subgroup to focus on) or the preference elicitation method. We present results from a pre-registered large sample study testing if 2D:4D is associated with economic preferences. Data were collected in a representative sample of adults in the German Socioeconomic Panel-Innovation Sample (SOEP-IS), in a sample of about 3450 respondents (about 5 times larger than the previously largest study in this field). Using experimentally validated survey questions, we find no statistically significant association between 2D:4D and economic preferences in the largest study to this date on the topic.
No evidence for a difference in 2D:4D ratio between youth with elevated prenatal androgen exposure due to congenital adrenal hyperplasia and controls
2021, Hormones and Behavior
The second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: β = −0.001 (−0.008, 0.006); females: β = −0.004 [−0.015, 0.007]; males: β = 0.001, [−0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.
Digit ratio (2D:4D) and congenital adrenal hyperplasia (CAH): Systematic literature review and meta-analysis
2020, Hormones and Behavior
Citation Excerpt :
However the difference between d and g is negligible, so it does appear that newer studies have produced smaller estimates of difference. Another potential explanation for the disparity in findings between our study and that of Hönekopp and Watson (2010) is that the latter treated the infant and young toddler sample of Ökten et al. (2002) as independent from their larger sample. As these samples appear unlikely to have been independent (i.e. although not entirely clear within the article, the smaller sample appears to be comprised of participants present in the larger sample), they should not have been included in the same meta-analysis.
The ratio of length between the second and fourth fingers (2D:4D) is commonly used as an indicator of prenatal sex hormone exposure. Several approaches have been used to try to validate the measure, including examining 2D:4D in people with congenital adrenal hyperplasia (CAH), a suite of conditions characterised by elevated adrenal androgen production secondary to defective steroidogenesis. We present a systematic review and meta-analysis that examines the relationship between these two variables. Twelve articles relating to nine CAH cohorts were identified, and 2D:4D comparisons have been made between cases and controls in eight of these cohorts. Altogether, at least one 2D:4D variable has been compared between n = 251 females with CAH and n = 358 unaffected females, and between n = 108 males with CAH and n = 204 unaffected males. A previous meta-analysis (Hönekopp and Watson, 2010) reported lower right hand (R2D:4D) and left hand (L2D:4D) digit ratios in patients with CAH relative to sex-matched controls. Our meta-analysis showed the same pattern, with medium effect sizes for R2D:4D and small effect sizes for L2D:4D. Differences of small magnitude were also observed for M2D:4D, and no significant effects were observed for D_[R-L]. Notably, the only effects that remained statistically significant when stratified by sex were R2D:4D in males and L2D:4D in females, and the average effect size had reduced by 46.70% since the meta-analysis of Hönekopp and Watson (2010). We also found that individual comparisons in this literature were considerably underpowered, and that patterns of sexual dimorphism in 2D:4D were similar in CAH samples as in typically developing populations. Findings are discussed in relation to the prenatal androgen hypothesis as well as alternative explanations.

View all citing articles on Scopus

View full text

The ratio of second- and fourth-digit lengths and congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Abstract

Introduction

Section snippets

Material and methods

Results

Discussion

Obstet. Gynecol. Clin. North Am.

Med. Hypotheses

Evol. Hum. Behav.

Evol. Hum. Behav.

Evol. Hum. Behav.

Breast

Arch. Med. Res.

J. Steroid Biochem. Mol. Biol.

Psychoneuroendocrinology

Horm. Behav.

Lancet

Diagnosis and management of congenital adrenal hyperplasia

Annu. Rev. Med.

Genetics, diagnosis and management of 21-hydroxylase deficiency

J. Clin. Endocrinol. Metab.

The ratio of 2nd and 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen

Hum. Reprod.

The 2nd and 4th digit ratio and autism

Dev. Med. Child Neurol.