Operative Management of Y-Shaped Metatarsal with Biphalangeal Sixth Toe.

BACKGROUND: In the literature, there is no consensus regarding the surgical management of postaxial polydactyly, and few cases of polymetatarsia with polydactyly have been reported. Treatment of the complete deformity will prevent further foot and gait disorders. OBJECTIVE: To identify literature relevant to the operative management of Y-shaped metatarsal with biphalangeal sixth toe and related skin and wound care to improve surgical treatment protocols from a clinical experience perspective. DATA SOURCES: The authors searched several electronic databases in December 2022 for articles related to postaxial polysyndactyly in the feet and polymetatarsia. Databases searched included PubMed, SciELO, ScienceDirect, Cochrane Database of Systematic Reviews, and Google Scholar gray literature. STUDY SELECTION: Two independent researchers conducted the searches and read the article titles and abstracts. Studies were included if they were narrative reviews, case studies, or observational studies; written in English or Spanish; and published between 2012 and 2022. Nonhuman studies were excluded. Studies that met the inclusion criteria were fully evaluated. Disagreements between reviewers were resolved by consensus, and when there was no consensus, a senior researcher was consulted. DATA EXTRACTION: The following data were extracted from the included studies using a standardized form: author and year of publication, study type, number of participants, sex, polydactyly location, polymetatarsia, type of polydactyly, participants' history of hereditary associated diseases or malformations, treatment, removal criteria, and timing of surgery. DATA SYNTHESIS: Authors evaluated 11 studies of postaxial polydactyly that included a total of 153 participants (64 men, 89 women). They also document their clinical experience with a surgical technique used in cases of bilateral postaxial polydactyly of the foot with a Y-shaped metatarsal with biphalangeal sixth toe. CONCLUSIONS: Surgical correction with lateral removal of the sixth toe is a resolutive treatment to improve the functionality of the foot, its aesthetic appearance, and the patient's quality of life. Case-specific treatment should be applied and tailored to meet the individual needs. The biomechanics of gait and shoe problems in these patients improve with surgical treatment, without presenting secondary aesthetic problems in skin care.

[Research progress of genetic research on Char syndrome].

Char syndrome is a rare autosomal dominant genetic disorder characterized by patent ductus arteriosus, facial dysmorphism, and dysplasia of fingers/toes. It may also be associated with multiple papillae, dental dysplasia, and sleep disorders. TFAP2B has proven to be a pathogenic gene for neural crest derivation and development, and several variants of this gene have been identified. Bone morphogenetic protein signaling plays an important role in embryonic development by participating in limb growth and patterning, and regulation of neural crest cell development. TFAP2B is an upstream regulatory gene for bone morphogenetic proteins 2 and 4. Variants of the TFAP2B gene may lead to abnormal proliferation of neural crest cells by affecting the expression of bone morphogenetic proteins, resulting in multiple organ dysplasia syndrome. In addition, TFAP2B variants may only lead to patent ductus arteriosus instead of typical Char syndrome.

An unusual configuration of two anomalies in the extensor digitorum profundus complex in a human.

The extensor digitorum profundus complex underwent degeneration of the ulnar segments during primate adaptation and evolution. This process resulted in the preservation of only the extensor pollicis longus and extensor indicis in some apes, including humans. Consequently, anatomical variations within the digitorum profundus complex in modern humans have been well-documented, with detailed reports on their frequency and patterns in previous studies. Here, we report an unusual arrangement involving two anomalies in the extensor digitorum profundus complex, identified in a 66-year-old Japanese male cadaver. In this cadaver, two accessory muscles differentiated from both the extensor pollicis longus and extensor indicis. Notably, the latter muscle featured a tendon bifurcating towards both the thumb and index fingers, referred to as the extensor pollicis et indicis communis. Under the extensor retinaculum, the tendon of the accessory extensor pollicis longus passed through an independent compartment, whereas that of the extensor pollicis et indicis communis traversed a compartment shared by the extensor indicis and the extensor digitorum communis. Both muscles were innervated by the posterior interosseous nerve. Previous studies have reported that the accessory slip of the extensor pollicis longus and extensor pollicis et indicis communis appear at frequencies of 0.6% and 0.4-1.4%, respectively. However, to the best of our knowledge, a configuration in which both appear simultaneously has not been reported. The data from this case could provide essential insights into the variations in the extensor digitorum profundus complex in humans and non-human primates.

Macrocephaly and Finger Changes: A Narrative Review.

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.

2D/4D Finger Length Ratio in the Screening of Developmental Dysplasia of the Hip.

OBJECTIVE: To investigate whether there is a relationship between the 2nd finger and 4th finger length measurement ratios and developmental dysplasia of the Hip (DDH). STUDY DESIGN: Cross-sectional observational study. Place and Duration of the Study: Department of Orthopaedics and Traumatology, Meram Faculty of Medicine Hospital, Konya, Turkiye, from January 2020 to May 2023. METHODOLOGY: Infants were screened for DDH with Graff method for the ultrasounds of both hips. Lengths of the 2nd and 4th fingers of both hands were measured and recorded. Patients with additional risk factors for developmental dysplasia of the hip (breech birth, family history, oligohydramnios, swaddling) were excluded. RESULTS: Two hundred and fifty-six babies were screened including 55.1% (n = 141) girls and 44.9% (n = 115) boys. Their mean age was 2.51 ± 0.80 months. The average lengths were 31.73 ± 3.05 mm, for the left 2nd finger and 34.26 ± 3.48 mm for the left 4th finger. In the hip USG measurements, the mean alpha angles were 62.91 ± 3.12° for the right hip and, 63.20 ± 3.55° for the left hip. Eighteen (7%) of babies who underwent hip ultrasound (USG) had unilateral or bilateral DDH. Among these cases, 2.7% (n = 7) had right, 2.3% (n = 6) had left, and 2% (n = 5) had bilateral DDH. There was no statistically significant correlation between the ratios of right 2/4 finger lengths and the right alpha angle (rs = 0.051; p = 0.421). There was a statistically positive and statistically significant correlation between the ratios of left 2/4 finger lengths and the left alpha angle (rs = 0.154; p = 0.013). CONCLUSION: Only the left-hand finger ratio among the parameters in the model had a statistically significant effect on DDH. Therefore, the left hand 2D/4D finger length may be of value in screening for DDH. KEY WORDS: Developmental dysplasia of the hip, Second to fourth finger digit ratio, Ring finger, Digit ratios.

Prenatal diagnosis of ROR-2 related Robinow syndrome presenting with fetal ultrasound findings of mesomelia, vertebral, digital and genital abnormalities.

Autosomal recessive ROR2-Robinow syndrome is caused by pathogenic variants in the ROR2 gene. Fetal ultrasound done on our patient at 24 + 3/7 weeks gestation showed macrocephaly, brachycephaly, flat face, prominent forehead, mild frontal bossing, lower thoracic hemivertebrae, digital abnormalities and micropenis. Fetal trio whole exome sequencing done on amniocytes showed two pathogenic compound heterozygous variants in the ROR2 gene, c.1324 C > T; p.(Arg442*) maternally inherited and c.1366dup; p.(Leu456Profs*3) apparently de novo. c.1324 C > T; p.(Arg442*) is a nonsense variant resulting in protein truncation reported to be associated with RRS3. c.1366dup; p.(Leu456Profs*3) is a frameshift variant predicted to result in protein truncation reported to segregate with the disease in multiple affected individuals from a single large family with distal symphalangism of the fourth finger. Fetal autopsy following pregnancy termination showed a large head with low-set ears, facial abnormalities, mesomelic bone shortening, hemivertebra, fused S3 and S4 vertebral bodies, several fused rib heads and short penis with buried shaft.

PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.

The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.

Cohen syndrome combined with psychiatric symptoms: a case report.

BACKGROUND: Cohen syndrome (CS) is a rare autosomal recessive inherited condition characterized by pathological changes affecting multiple systems. The extensive clinical variability associated with CS poses a significant diagnostic challenge. Additionally, there is limited documentation on the co-occurrence of CS with psychiatric symptoms. CASE REPORT: We report a case of a 30-year-old patient exhibiting characteristic physical features and psychiatric symptoms. Whole exome sequencing identified two heterozygous variants, a nonsense variation c.4336 C > T and a missense mutation c.4729G > A. Integrating clinical manifestations with genetic test results, we established the diagnosis of CS combined with psychiatric symptoms. CONCLUSIONS: This case introduces a novel missense variant as a candidate in the expanding array of VPS13B pathogenic variants. Its clinical significance remains unknown, and further investigation may broaden the spectrum of pathogenic variants associated with the VPS13B gene. Early diagnosis of CS is crucial for the prognosis of young children and holds significant importance for their families.

Cis-regulatory control of mammalian Trps1 gene expression.

TRPS1 serves as the causative gene for tricho-rhino phalangeal syndrome, known for its craniofacial and skeletal abnormalities. The Trps1 gene encodes a protein that represses Wnt signaling through strong interactions with Wnt signaling inhibitors. The identification of genomic cis-acting regulatory sequences governing Trps1 expression is crucial for understanding its role in embryogenesis. Nevertheless, to date, no investigations have been conducted concerning these aspects of Trps1. To identify deeply conserved noncoding elements (CNEs) within the Trps1 locus, we employed a comparative genomics approach, utilizing slowly evolving fish such as coelacanth and spotted gar. These analyses resulted in the identification of eight CNEs in the intronic region of the Trps1 gene. Functional characterization of these CNEs in zebrafish revealed their regulatory potential in various tissues, including pectoral fins, heart, and pharyngeal arches. RNA in-situ hybridization experiments revealed concordance between the reporter expression pattern induced by the identified set of CNEs and the spatial expression pattern of the trps1 gene in zebrafish. Comparative in vivo data from zebrafish and mice for CNE7/hs919 revealed conserved functions of these enhancers. Each of these eight CNEs was further investigated in cell line-based reporter assays, revealing their repressive potential. Taken together, in vivo and in vitro assays suggest a context-dependent dual functionality for the identified set of Trps1-associated CNE enhancers. This functionally characterized set of CNE-enhancers will contribute to a more comprehensive understanding of the developmental roles of Trps1 and can aid in the identification of noncoding DNA variants associated with human diseases.

TRPS1 modulates chromatin accessibility to regulate estrogen receptor alpha (ER) binding and ER target gene expression in luminal breast cancer cells.

Common genetic variants in the repressive GATA-family transcription factor (TF) TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over 80 percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes estrogen receptor alpha (ER) to redistribute in the genome. ER redistribution leads to both repression and activation of dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the genomic distribution of ER, both activating and repressing transcription of genes related to cancer cell fitness.

Use of Multiple Machine Learning Approaches for Selecting Urothelial Cancer-Specific DNA Methylation Biomarkers in Urine.

Diagnosing urothelial cancer (UCa) via invasive cystoscopy is painful, specifically in men, and can cause infection and bleeding. Because the UCa risk is higher for male patients, urinary non-invasive UCa biomarkers are highly desired to stratify men for invasive cystoscopy. We previously identified multiple DNA methylation sites in urine samples that detect UCa with a high sensitivity and specificity in men. Here, we identified the most relevant markers by employing multiple statistical approaches and machine learning (random forest, boosted trees, LASSO) using a dataset of 251 male UCa patients and 111 controls. Three CpG sites located in ALOX5, TRPS1 and an intergenic region on chromosome 16 have been concordantly selected by all approaches, and their combination in a single decision matrix for clinical use was tested based on their respective thresholds of the individual CpGs. The combination of ALOX5 and TRPS1 yielded the best overall sensitivity (61%) at a pre-set specificity of 95%. This combination exceeded both the diagnostic performance of the most sensitive bioinformatic approach and that of the best single CpG. In summary, we showed that overlap analysis of multiple statistical approaches identifies the most reliable biomarkers for UCa in a male collective. The results may assist in stratifying men for cystoscopy.

Successful topical minoxidil treatment for hair density and length in trichorhinophalangeal syndrome type 1.

A 9-year-old girl presented with slow hair growth and hair thinning since birth. Additionally, she had short stature and abnormally short fingers; genetic testing confirmed the diagnosis of trichorhinophalangeal syndrome (TRPS) type 1. After 4 months of topical minoxidil treatment, hair density and length significantly improved diffusely throughout the scalp without evidence of hypertrichosis. This case underscores the therapeutic potential of topical minoxidil for TRPS, paving the way for improved patient quality of life.

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families.

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3), Limb-mammary syndrome (LMS), Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT), Rapp-Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

A Comparative Evaluation of TRPS1 and GATA3 in adenoid cystic, secretory, and acinic cell carcinomas of the breast and salivary gland.

GATA3 is the most used marker to determine tumors' breast origin, but its diagnostic value in triple-negative breast cancer (TNBC) is limited. The newly identified TRPS1 is highly sensitive and specific for breast carcinoma, especially TNBC. Here, we compared the utility of TRPS1 and GATA3 expression in a subset of salivary gland-type breast tumors (including adenoid cystic, acinic cell, and secretory carcinomas [AdCC, ACC, and SC, respectively]), and we compared TRPS1 and GATA3 expression of such tumors with head and neck (H&N) and AdCC of upper respiratory tumors. TRPS1 was strongly expressed in basaloid TNBC and AdCCs with solid components, including 100 % of mixed and solid breast AdCCs. However, TRPS1 was positive in only 50 % cribriform AdCCs. Expression patterns of TRPS1 in H&N and upper respiratory AdCC were similar. TRPS1 was positive in 30 % of H&N cribriform AdCCs but was strongly expressed in mixed AdCC (67 %) and solid AdCC (100 %). In the upper respiratory AdCCs, TRPS1 was positive in 58.4 % of cribriform AdCCs and positive in 100 % of AdCCs with solid components. On the contrary, GATA3 was negative in predominant AdCCs of the breast, H&N, and upper respiratory tract. These data show that GATA3 and TRPS1 expression varies AdCCs. In addition, TRPS1 and GATA3 expression patterns were similar SC and ACC of breast and H&N. Both markers were positive in SC and negative in ACC. Therefore, TRPS1 and GATA3 cannot be used to differentiate salivary gland-type carcinomas of breast origin from those of upper respiratory or H&N origin.

Whole genome resequencing reveals candidate genes for postaxial polydactyly in Large White pigs.

Polydactyly is a genetic abnormality that affects both pig welfare and industry profits. Despite efforts to explore the genetic basis of pig polydactyly, progress remains limited. In this study, we analyzed a group of Large White pigs with postaxial polydactyly, including 29 cases and 79 controls from 24 families. High-depth sequencing was performed on 20 pigs, while low-depth sequencing was improved through imputation for the remaining pigs. A genome-wide association study (GWAS) and genetic differentiation were conducted using the resequencing dataset, resulting in the identification of 48 significantly associated SNPs and 27 candidate regions. The genetic differentiation regions on chromosomes 5 and 18, which harbored GWAS-identified SNPs, were delineated as confidence regions. The confidence region at Chr18: 1.850-1.925 Mb covers the fifth intron of LMBR1, a gene that contains an important regulatory element for SHH, known as ZRS. Mutations in this ZRS have been found to cause polydactyly in animals and humans. Therefore, we propose LMBR1 as a prospective candidate gene for postaxial polydactyly. These findings emphasize the importance of exploring the role of ZRS within LMBR1 in the pathogenesis of polydactyly in pigs.

Molecular Genetic Analysis and Growth Hormone Treatment in a Three-Generation Chinese Family with Tricho-Rhino-Phalangeal Syndrome I.

INTRODUCTION: Tricho-rhino-phalangeal syndrome (TRPS) is a rare genetic disorder characterized by craniofacial and skeletal abnormalities, which is caused by variants in the TRPS1 gene. METHODS: Clinical information and follow-up data were collected. Whole-exome sequencing (WES) was performed for variants and validated by Sanger sequencing. Bioinformatic analysis was performed to predict the pathogenicity of the identified variant. Moreover, wild-type and mutated TRPS1 vectors were constructed and transfected into human embryonic kidney (HEK) 293T cells. Immunofluorescence experiments were performed to assess the localization and expression of the mutated protein. Western blot analysis and RT-qPCR were used to detect the expression of downstream genes. RESULTS: The affected family members had typical craniofacial phenotype including sparse lateral eyebrows, pear-shaped nasal tip, and large prominent ears, plus skeletal abnormalities including short stature and brachydactyly. WES and Sanger sequencing identified the TRPS1 c.880_882delAAG variant in affected family members. In vitro functional studies showed that the TRPS1 variant did not affect the cellular localization and the expression of TRPS1, but the transcriptional repression effect of the TRPS1 on the RUNX2 and STAT3 was disturbed. The proband and his brother have been treated with growth hormone (GH) for 2 years until now, and we have observed the improvement of the linear growth in both. CONCLUSIONS: The variant of c.880_882delAAG in TRPS1 was responsible for the pathogenesis of the Chinese family with TRPS I. The treatment of GH could be beneficial for the height outcome in TRPS I patients, and earlier initiation and longer duration of the therapy in prepubertal or early pubertal stage could be associated with better height outcomes.