Prenatal diagnosis of familial 2p15 microduplication associated with pulmonary artery stenosis, single umbilical artery and left foot postaxial polydactyly on fetal ultrasound.

OBJECTIVE: We present prenatal diagnosis of familial 2p15 microduplication associated with pulmonary artery stenosis, single umbilical artery and left foot postaxial polydactyly on fetal ultrasound. CASE REPORT: A 34-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed the karyotype of 46,XX. Prenatal ultrasound examination at 21 weeks of gestation showed pulmonary artery stenosis, single umbilical artery and left foot postaxial polydactyly. Repeat amniocentesis was performed at 22 weeks of gestation and array comparative genomic hybridization (aCGH) analysis on the DNAs extracted from amniocytes revealed the result of arr 2p15 (61, 495, 220-62,885,679) × 3.0 [GRCh37 (hg19)] with a 1.391-Mb 2p15 duplication encompassing seven Online Mendelian Inheritance in Man (OMIM) genes of USP34, XPO1, FAM161A, CCT4, COMMD1, B3GNT2 and TMEM17. aCGH analysis on the DNAs extracted from parental bloods confirmed a familial transmission from a normal carrier mother who had no phenotypic abnormality. A 3270-g female baby was delivered at term with mild pulmonary artery stenosis and left foot postaxial polydactyly. The infant had normal physical and psychomotor development when follow-up at age of one year. CONCLUSION: Prenatal diagnosis of fetal structural abnormalities should include aCGH analysis in addition to conventional cytogenetic analysis.

Decreased second to fourth digit ratios in female multiple sclerosis patients.

BACKGROUND: Sex-related differences in multiple sclerosis (MS) suggest a possible role of prenatal sex hormones in the pathogenesis. The aim of this study was to investigate whether the 2D:4D ratio, considered a predictor of prenatal hormonal exposure, in MS patients differ from that in healthy controls. METHODS: Two hundred MS patients and one hundred seventy healthy control subjects with similar age and sex distribution enrolled. All participants were right-handed. The right hands of all participants were scanned using a digital scanner. Measurements of second and fourth digit lengths were made from digital scans. The 2D:4D ratio was calculated by dividing the length of the second digit by the length of the fourth digit. RESULTS: A total of 171 MS patients' and 159 healthy controls' digit scans included in the study. The MS group consisted of 94 females (mean age 38.32 ± 10.5) and 77 males (mean age 42.06 ± 11.8) and the control group of 86 females (mean age 40.24 ± 9.7) and 73 males (mean age 38.49 ± 11.6). 2D:4D ratios of female MS patients were significantly lower than those of healthy females (p=0.004). Although 2D:4D ratios of male patients with MS were lower than those of healthy males, this difference was not statistically significant (p=0.33). There was no significant correlation between the 2D:4D ratio, EDSS levels or duration of the disease in male or female MS patients (p<0.05). CONCLUSION: Although our results suggest that a prenatal hormonal balance in favor of androgenic activity may be a risk factor for MS, complex factors mediating the actions of sex hormones on target cells should always be considered when evaluating the effects of sex hormones.

A multidisciplinary review of triphalangeal thumb.

Despite being a rare congenital limb anomaly, triphalangeal thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of triphalangeal thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, triphalangeal thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the triphalangeal thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of triphalangeal thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies.

The development of human digital Meissner's and Pacinian corpuscles.

Meissner's and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner's and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner's corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner's corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner's and Pacini's corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.

Pacinian Corpuscles in the Human Fetal Finger and Thumb: A Study Using 3D Reconstruction and Immunohistochemistry.

The detailed distribution of Pacinian corpuscles was evaluated by viewing the transverse sections of all fingers and thumbs, including the interdigital areas, from eight hands of five fetuses of gestational age 28-33 weeks (crown-rump length 230-290 mm). Among the 40 fingers and thumbs, serial sections were prepared for 3D reconstructions of nerve elements in the distal and middle phalangeal segments of three fifth fingers; in these three fingers, the distal segment contained 45-75 Pacinian corpuscles. These Pacinian corpuscles were 0.2-1.0 mm in length and 0.05-0.3 mm in thickness, oriented along the proximodistal axis and arranged along the palmar digital nerve branches. Other than beneath the digital skin, small corpuscles (<0.1 mm in thickness) were observed within the tendon sheath of the flexors in the middle or distal segment of five fetuses and in the nail beds of four fetuses. Clusters of 5-20 corpuscles formed bouquet- or tree-like arrangements along neurovascular bundles in the fingers, thumbs and interdigital areas. Because the space beneath the skin was thick and loose in the interdigital area, trees in the interdigital area were up to 2 mm long. Regardless of site, the central core of each corpuscle was positive for S100 protein, while the core and parts of the capillaries in the corpuscle were weakly positive for nestin. Because corpuscles in the tendon sheath and nail bed, as well as bouquet- and tree-like arrangements of corpuscles, have not been reported in adults, these morphologies are likely specific to fetuses. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:154-165, 2018. © 2017 Wiley Periodicals, Inc.

Self-Amputation of the Extra Digit in a Fetus with Polydactyly: First Ultrasound Demonstration.

We herein report the first ultrasound evidence of the self-amputation of an extra digit in case of fetal polydactyly. The prenatal evidence of fetal polydactyly is not always followed by postnatal confirmation. This is not always due to ultrasound misdiagnosis, but often to an in utero self-amputation phenomenon. We demonstrate that there is the detachment of part of the digit, leading to the evidence of a neonatal bump on the site of the prenatal extra digit. This demonstration has been possible by the direct visualization of the remnant by ultrasound.

Polydactyly: A Review.

Polydactyly, also known as hyperdactyly, is a common congenital limb defect, which can present with various morphologic phenotypes. Apart from cosmetic and functional impairments, it can be the first indication of an underlying syndrome in the newborn. Usually, it follows an autosomal dominant pattern of inheritance with defects occurring in the anteroposterior patterning of limb development. Although many mutations have been discovered, teratogens have also been implicated in leading to this anomaly, thus making it of multifactorial origin. There are three polydactyly subtypes (radial, ulnar, and central), and treatment options depend on the underlying feature.

Self-organization in the limb: a Turing mechanism for digit development.

The statistician George E. P. Box stated, 'Essentially all models are wrong, but some are useful.' (Box GEP, Draper NR: Empirical Model-Building and Response Surfaces. Wiley; 1987). Modeling biological processes is challenging for many of the reasons classically trained developmental biologists often resist the idea that black and white equations can explain the grayscale subtleties of living things. Although a simplified mathematical model of development will undoubtedly fall short of precision, a good model is exceedingly useful if it raises at least as many testable questions as it answers. Self-organizing Turing models that simulate the pattern of digits in the hand replicate events that have not yet been explained by classical approaches. The union of theory and experimentation has recently identified and validated the minimal components of a Turing network for digit pattern and triggered a cascade of questions that will undoubtedly be well-served by the continued merging of disciplines.

Male infants with hypospadias and/or cryptorchidism show a lower 2D/4D digit ratio than normal boys.

BACKGROUND: In humans the ratio of the index finger to the ring finger is sexually dimorphic, with the mean ratio being larger in women than in men. It has been suggested that this difference is related to prenatal androgen exposure. This has been further demonstrated in children with congenital adrenal hyperplasia. Normal development of the male external genitalia is linked to androgen-mediated events during gestation. We therefore wanted to determine if the 2D:4D digit ratio was normal in boys with cryptorchidism or hypospadias. METHODS: We prospectively enrolled all prepubertal patients seen in the outpatient clinic for cryptorchidism or hypospadias between September and December 2012. We then compared their 2D:4D digit ratio with two control groups made up of normal boys and normal girls. Interobserver and intraobserver variability was evaluated. RESULTS: We included 57 boys with hypospadias and/or cryptorchidism, 79 boys without genital abnormalities and 25 girls without genital abnormalities. The mean 2D:4D ratio for both hands was significantly different between the three groups, with the digit ratio for boys with genital anomalies being lower than for normal boys and normal girls (p<0.0001). CONCLUSIONS: It appears that boys with genital abnormalities (cryptorchidism and/or hypospadias) have a lower 2D:4D digit ratio than boys without genital anomalies.

[Assessment of sexual dimorphism of finger length ratio (2D:4D) ]. / Ocena dymorfizmu plciowego wskaznika dlugosci palców (2D:4D).

INTRODUCTION: Studies on many populations have shown that the length of the second finger (2D) compared to the fourth (4D), expressed as the finger length ratio (2D:4D), might be characteristic for sexual dimorphism. It was also found that the values of 2D:4D differ significantly between examined populations. It is thought that the value of 2D:4D is determined in early foetal life under the influence of genetic factors and the strong influence of sex hormones. It has been proven that the values of 2D:4D are related to, for instance, sexual orientation, and artistic and sporting ability. Recently, increasing interest in the clinical signifi- cance of finger length ratio in the diagnosis of somatic and mental disorders has been observed. For example, it was found that values of 2D:4D in individuals suffering from congenital adrenal hyperplasia or autism were significantly lower compared to healthy subjects. The aim of the study was to determine sexual dimor- phism in finger length ratio among representatives of the Polish population. MATERIALS AND METHODS: The study group comprised 115 people (57 females and 58 males). Anthropometric meas- urements were taken from the second and fourth finger of the right and left hands - from the point of dactylion (da) to pseudophalangion (pph) using analogue callipers. We calculated the significance of differences in 2D:4D between males and females separately for the right and left hands. RESULTS: In both hands mean 2D:4D values were lower in males than in females. The difference in the right hand reached the statistical significance level with p < 0.05. CONCLUSIONS: Among the subjects from the examined population the 2D:4D ratio shows trends characteristic for sexual dimorphism.

[Application of free flap pedicled with supracarpal cutaneous branch of ulnar artery in repairing of finger replantation].

OBJECTIVE: To evaluate clinical application and clinical outcomes of free flap pedicled with supracarpal cutaneous branch of ulnar artery in repairing of finger replantation with skin defect. METHODS: From April 2007 to March 2013,25 patients affected by finger amputation with skin defect were replanted and repaired by free flap pedicled with supracarpal cutaneous branch of ulnar artery. Among them, 18 patients were male and 7 were female,with an average age of 31.5 years old (ranged 16 to 58). The time of trauma to admission ranged from 45 to 210 min (averaged 105). Fifteen patients were complete separted, and 10 patients were non-complete separated. The area of flaps ranged from 3.5 cm x 2.0 cm to 4.5 cm x 3.0 cm, and the vessels were anastomosed through end-to-end. The functional evaluation standard of finger replantation was used to evaluate the postoperative function. RESULTS: Twenty-four cases were finally survived. Two flaps occurred vascular crisisin within 48 h after operation, one of which was survived after anti-vasospasm treatment and changing dressing,another was replanted finger for failed to survive. One had infection and healed after changing dressing. Twenty-four cases were followed up from 3 to 38 months with an average of 16.5 months. The appearance and texture of flaps were satisfactory, and the superficial senses of pain and touch were recovered,and two-point discrimination was 5.5 to 11 mm (averaged 7.4 mm). According to functional evaluation standard finger replantationissued by Hand Surgery Association of Chinese Medical Association, 8 cases got excellent results, 14 good and 2 poor. CONCLUSION: The free flap pedicled with supracarpal cutaneous branch of ulnar artery can be used in complex finger replantation with skin and vessels defect, which can extend operation indications, recover function and appearance for maximum.

Embryology of familial (non-syndromic) brachydactyly of the hand.

Isolated familial non-syndromic brachydactyly is interesting from the embryological point of view because the phenotypes of isolated brachydactyly are frequently overlapping, yet they are caused by different gene mutations and the ring finger is frequently relatively preserved. We review the embryology of isolated familial brachydactyly with special attention to these two features.

Preaxial polydactyly of the upper limb viewed as a spectrum of severity of embryonic events.

Preaxial polydactyly (PPD) is a common congenital abnormality and its classification varies among geneticists and hand surgeons. For example, the triphalangeal thumb, preaxial polysyndactyly, and the mirror hand deformity are considered as forms of PPD only in the genetics literature. Preaxial polydactyly is an error in the anteroposterior axis of the development of the upper limb. In this paper, the development of this axis is detailed and all molecular events that are known to lead to PPD are reviewed. Finally, based on the review, PPD is viewed as a spectrum of severity of embryonic events.

The pathogenesis of ulnar polydactyly in humans.

The pathogenesis of ulnar polydactyly in humans is not known. There are numerous syndromes that are associated with ulnar polydactyly. We have noted that the genetic defects in these syndromes lead to a disturbance of the normal balance between the two forms of the Gli3 protein (the active and repressor forms of Gli3, which are known as Gli3-A and Gli3-R, respectively), leading to a relative increase in the Gli3-R protein. We offer the hypothesis of a unified pathogenesis of ulnar polydactyly through the relative predominance of Gli3-R.

Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys.

A smaller length ratio for the second relative to the fourth finger (2D:4D) is repeatedly associated with fetal male-typical testosterone (T) and is implicated as a biomarker for a variety of traits and susceptibility to a number of diseases, but no experimental human studies have been performed. The present study utilizes the rhesus monkey, a close relative of humans, and employs discrete gestational exposure of female monkeys to fetal male-typical T levels for 15-35 days during early-to-mid (40-76 days; n = 7) or late (94-139 days; n = 7) gestation (term: 165 days) by daily subcutaneous injection of their dams with 10 mg T propionate. Such gestational exposures are known to enhance male-typical behavior. In this study, compared to control females (n = 19), only early-to-mid gestation T exposure virilizes female external genitalia while increasing 2D:4D ratio in the right hand (RH) by male-like elongation of RH2D. RH2D length and 2D:4D positively correlate with androgen-dependent anogenital distance (AG), and RH2D and AG positively correlate with duration of early-to-mid gestation T exposure. Male monkeys (n = 9) exhibit a sexually dimorphic 2D:4D in the right foot, but this trait is not emulated by early-to-mid or late gestation T exposed females. X-ray determined phalanx measurements indicate elongated finger and toe phalanx length in males, but no other phalanx-related differences. Discrete T exposure during early-to-mid gestation in female rhesus monkeys thus appears to increase RH2D:4D through right-side biased, non-skeletal tissue growth. As variation in timing and duration of gestational T exposure alter male-like dimensions of RH2D independently of RH4D, postnatal RH2D:4D provides a complex biomarker for fetal T exposure.

2D:4D finger ratio in Slovak autism spectrum population.

Previous studies have revealed that autism may arise as the result of exposure to high concentrations of prenatal testosterone. Ratio of second and fourth digits (2D:4D) is usually used as a proxy for prenatal testosterone. In this study, 2D:4D in 56 boys with ASD and in 32 control boys was measured. We found that the 2D:4D in ASD boys were lower than the ratio in control boys. These findings are discussed with reference to the "extreme male-brain" theory of autism. Results achieved in this interdisciplinary research are valuable in further biological and psychological approaches in neurocognitive research and diagnostics of children from ASD (Tab. 1, Ref. 38).

Digit ratio (2D:4D), salivary testosterone, and handedness.

The length of the index finger relative to that of the ring finger, the 2D:4D ratio, has been taken to be a marker of the amount of testosterone (T) that was present in the foetal environment (Manning, Scutt, Wilson, & Lewis-Jones, 1998). It has also been suggested (Geschwind & Galaburda, 1987) that elevated levels of foetal T are associated with left-handedness and that adult levels of circulating T might relate to foetal levels (Jamison, Meier, & Campbell, 1993). We used multiple regression analyses to investigate whether there is any relationship between either left or right hand 2D:4D ratio and handedness. We also examined whether adult levels of salivary T (or cortisol, used as a control hormone) predict digit ratio and/or handedness. Although the 2D:4D ratio of neither the left nor the right hand was related to handedness, the difference between the digit ratios of the right and left hands, D(R-L), was a significant predictor of handedness and of the performance difference between the hands on a peg-moving task, supporting previous findings (Manning & Peters, 2009; Manning et al., 1998; Manning, Trivers, Thornhill, & Singh, 2000; Stoyanov, Marinov, & Pashalieva, 2009). Adult circulating T levels did not predict the digit ratio of the left or right hand; nor was there a significant relationship between concentrations of salivary T (or cortisol) and either hand preference or asymmetry in manual skill. We suggest that the association between D(R-L) and hand preference arises because D(R-L) is a correlate of sensitivity to T in the developing foetus.

Digit ratio (2D:4D) asymmetry and Schneiderian first rank symptoms: implications for cerebral lateralisation theories of schizophrenia.

Schneiderian first rank symptoms (FRS) in schizophrenia have been hypothesised to be secondary to aberrant cerebral lateralisation over the course of human evolution. The ratio of length of second digit to fourth digit (2D:4D) has been put forward as a potential indicator of cerebral lateralisation. This study examined 2D:4D and its asymmetry in antipsychotic-naïve schizophrenia patients (N=79) in comparison with healthy controls (N=75). Psychopathology was assessed using Scales for Assessment of Positive and Negative Symptoms. FRS assessment was performed as per established descriptions. The digit lengths (2D & 4D) were measured using a digital vernier caliper with good inter-rater reliability. Female schizophrenia patients showed significantly lower 2D:4D than female healthy controls. Mean 2D:4D asymmetry index was significantly lower in male schizophrenia patients than male healthy controls. FRS status had significant effect on left 2D:4D as well as 2D:4D asymmetry index, the patients with FRS having the lowest values. Our study findings support association between schneiderian FRS and low 2D:4D as well as low 2D:4D asymmetry index. Since 2D:4D is linked with limbic asymmetry, our study findings offer further support to the cerebral lateralisation theories of schizophrenia.

Genetic and pathologic aspects of retinoic acid-induced limb malformations in the mouse.

Because all-trans retinoic acid (atRA) is teratogenic in all species tested and many of the specific defects induced are common across the phylogenetic spectrum, it would be logical to predict that murine strain differences in teratology to this agent are minimal. However, for specific defects, strain susceptibilities are vastly different. Studies with atRA have shown stark differences between C57BL/6 and SWV mouse strains in susceptibility to postaxial forelimb ectrodactyly and ectopic hindlimb formation, with the C57 strain being more susceptible for both defects. Various approaches were used to determine why these strains differ in susceptibility, but the mechanisms remain unknown. Hindlimb duplications were hypothesized to be caused by the formation of ectopic posterior body axes. For forelimb ectrodactyly, a locus on chromosome 11, Rafar, has linkage to the strain difference, and mRNA localization has shown that specific genes (Fgf8, Dlx3, Bmp4, and Sp8) in the postaxial preAER (prior to formation of the apical ectodermal ridge) of the developing limb bud (the site of the defect) were downregulated hours after atRA administration more in the susceptible C57 than in the SWV strain. Because both atRA and divalent cadmium induce postaxial forelimb ectrodactyly (right-sided predominance) at a high rate in C57BL/6 and low in the SWV strain, there is debate as to whether they share a common mechanism. These teratogens cause a greater-than-additive level of forelimb ectrodactyly when coadministered at low doses, but cadmium does not induce ectopic hindlimb formation. The hypothesis is that these agents have separate molecular pathologic pathways that converge to perturb a common anatomic structure.

Relationships of toe-length ratios to finger-length ratios, foot preference, and wearing of toe rings.

Sexually differentiated digit ratios of the hand (2D:4D and other) are currently widely studied, owing to their presumed role as a retrospective diagnostic window into prenatal androgen action. This study was only the second one (following McFadden & Shubel, 2002) to examine all 6 possible finger-length ratios (excluding the thumb) and all 10 possible toe-length ratios (including the big toe). Data from a sample of 59 male and 69 female Austrian adults (M age = 27 yr., SD = 7.9) were collected. Replicating the prior study, the majority of toe-length ratios exhibited significant sex differences, which was similar to finger-length ratios, but of weaker effect size. Ipsilateral correlations of toe-length and finger-length ratios were largely absent, except for those of corresponding or adjacent length ratios of the right body side among women. However, these associations were directionally opposite, such that among women, feminized finger-length ratios corresponded to masculinized toe-length ratios. Foot preference (among both sexes) and wearing of toe rings (among women) were not correlates of toe-length ratios. Discussed are implications of these findings for digit ratio research, along with ideas for further inquiry on this topic.