Sec23IP recruits VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation.

VPS13B/COH1 is the only known causative factor for Cohen syndrome, an early-onset autosomal recessive developmental disorder with intellectual inability, developmental delay, joint hypermobility, myopia, and facial dysmorphism as common features, but the molecular basis of VPS13B/COH1 in pathogenesis remains largely unclear. Here, we identify Sec23 interacting protein (Sec23IP) at the ER exit site (ERES) as a VPS13B adaptor that recruits VPS13B to ERES-Golgi interfaces. VPS13B interacts directly with Sec23IP via the VPS13 adaptor binding domain (VAB), and the interaction promotes the association between ERES and the Golgi. Disease-associated missense mutations of VPS13B-VAB impair the interaction with Sec23IP. Knockout of VPS13B or Sec23IP blocks the formation of tubular ERGIC, an unconventional cargo carrier that expedites ER-to-Golgi transport. In addition, depletion of VPS13B or Sec23IP delays ER export of procollagen, suggesting a link between procollagen secretion and joint laxity in patients with Cohen disease. Together, our study reveals a crucial role of VPS13B-Sec23IP interaction at the ERES-Golgi interface in the pathogenesis of Cohen syndrome.

Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.

[Surgical treatment of polydactyly]. / Chirurgische behandeling van polydactylie.

This clinical lesson addresses the treatment options for polydactyly, emphasizing the lack of consensus in the Netherlands regarding the timing and method of intervention. The study aims to provide evidence-based recommendations for the management of post-axial polydactyly type B. Two cases are presented, each illustrating different approaches to surgical intervention for post-axial polydactyly type B in a 1-year-old boy (Patient A) and a newborn girl (Patient B). Patient A undergoes surgical removal of an extra digit under general anesthesia after waiting for a year, while Patient B undergoes prompt surgical removal under local anesthesia. Both procedures are successful with no complications, demonstrating positive outcomes for early surgical intervention under local anesthesia. The study advocates for revising outdated national guidelines, recommending surgical removal under local anesthesia within the first three months after birth for post-axial polydactyly type B. Delaying intervention increases stress, risks, and costs without apparent benefits. This clinical lesson calls for optimizing care for children with post-axial polydactyly type B through guideline updates.

Congenital malformations of the hand and fingers.

Congenital anomalies of the upper limb are in Denmark estimated to have an incidence of around 20 in 10,000 live births. This covers a wide array of conditions summarised in this review. At the time of referral, the patient is thoroughly examined, and a treatment plan is discussed with the family. In some cases, no treatment is needed, in others there might be a need for surgery, night splinting, or an upper limb prosthesis. In case an underlying syndromatic cause is suspected, the patient is referred for paediatric evaluation at specialized centre.

[Clinical characteristics and genetic analysis of a child with Char syndrome caused by TFAP2B gene variant].

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Char syndrome. METHODS: A child who was presented at the Department of Child Health, Henan Children's Hospital in February 2022 was selected as the study subject. Clinical data of the child was collected, and peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child had mainly manifested facial dysmorphism, patent ductus arteriosus, growth retardation, curving of fifth fingers and middle toes. Whole exome sequencing revealed that she has harbored a heterozygous c.944A>C (p.Glu315Ala) variant of the TFAP2B gene, which was verified to be de novo by Sanger sequencing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated to be likely pathogenic (PM1+PM2_Supporting+PM6+PP3). CONCLUSION: The heterozygous c.944A>C (p.Glu315Ala) variant of the TFAP2B gene probably underlay the Char syndrome in this child. Above finding has expanded the mutational and phenotypic spectra of the TFAP2B gene, which has facilitated early identification and diagnosis of Char syndrome.

Trichorhinophalangeal Syndrome Orthopaedic Manifestations and Management: A Systematic Review.

Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant genetic malformation disorder which is best characterized by both its craniofacial and skeletal abnormalities. The purpose of this paper is to identify the various orthopedic manifestations and management in patients with TRPS. A systematic search of PubMed, Ovid MEDLINE, and Cochrane Library was conducted. They were each individually searched for primary articles yielding information on the orthopedic manifestations and management of patients with TRPS. The goals and results of each of the included studies were described. Data regarding the demographics, orthopedic condition, treatment strategy, and outcomes were extracted and analyzed. 221 unique articles were retrieved, with 13 articles being included in the study. 26 patients with TRPS were identified. Trials of conservative management were reported for 14 patients, and surgical intervention was pursued for 8 patients. The mean age for surgery was 14.1 years. The most common orthopedic manifestations of TRPS are clinodactyly, Perthes-like changes, and coxa magna. Early identification and maintenance of TRPS is important for being able to monitor musculoskeletal health of the patients in order to prevent detrimental outcomes. Additional high-quality research is required regarding the orthopedic manifestations and treatment of this patient population.

An extremely rare case of absent extensor digitorum communis of the right index finger.

The hand is a unique structure in human body performing complex activities of daily life making it prone to injuries. While operating on zone VI extensor tendon injury, a surprising entity was observed. The extensor digitorum to the right index finger was absent. This is an extremely rare entity in the literature. Also, all previous studies on the extensor digitorum are cadaveric. Our findings are first of its kind intraoperative, incidental, and confirmed on MRI. Thus, it becomes a case report of special worth mentioning in literature.

Spontaneous Resolution of Congenital Insufficiency of the Extensor Tendon Central Slip.

BACKGROUND: The congenital insufficiency of the extensor tendon central slip of the fingers is a relatively rare condition, with only a few reported cases in pediatric patients, as described in 2 clinical series. In this study, we aimed to present the natural history of a significant number of untreated patients with this deformity. METHODS: This study has received institutional review board approval, and parents provided informed consent following the Declaration of Helsinki guidelines for biomedical research involving humans. A retrospective analysis of children with this deformity, ranging from June 2008 to July 2021, was collected by 1 surgeon. The inclusion criteria included children with a supple PIP flexion deformity, characterized by MP hyperextension and PIP extension lag, which had been present since birth. Complete passive PIP extension and the absence of volar skin webbing differentiated this condition from camptodactyly. RESULTS: The mean age of 24 children with 57 involved digits at diagnosis was 7 months (range, 1 to 17) and the mean follow-up was 6 years to 9 months (2 yr to 1 mo to 13 yr). Six patients had an incorrect previous diagnosis of camptodactyly.Active PIP extension recovered progressively. At the final follow-up, complete PIP extension occurred in all except 4 cases in which a residual 10° extension lag. The mean time for a complete active PIP extension was 2 years to 7 months (20 mo to 3 yr to 9 mo). Nineteen cases (79%) showed a mild FDS contracture of the involved digits at the final follow-up.The deformity was bilateral in 15 children (62.5%) and involved only 1 finger (unilaterally or bilaterally) in 15 cases (62.5%), and 2 fingers in 6 (25%). Little and ring fingers were most commonly involved. In 7 cases, there was a family history of finger deformity. CONCLUSIONS: Congenital insufficiency of the extensor tendon central slip typically resolves spontaneously within the first 4 years of life. Literature suggests that splinting can expedite the correction of the deformity and thus, if possible, it can be used. In most cases, a residual, clinically insignificant FDS contracture may be present. This condition is often misdiagnosed as camptodactyly. LEVEL OF EVIDENCE: IV.

Deletion of Trps1 regulatory elements recapitulates postnatal hip joint abnormalities and growth retardation of Trichorhinophalangeal syndrome in mice.

Trichorhinophalangeal syndrome (TRPS) is a genetic disorder caused by point mutations or deletions in the gene-encoding transcription factor TRPS1. TRPS patients display a range of skeletal dysplasias, including reduced jaw size, short stature, and a cone-shaped digit epiphysis. Certain TRPS patients experience early onset coxarthrosis that leads to a devastating drop in their daily activities. The etiologies of congenital skeletal abnormalities of TRPS were revealed through the analysis of Trps1 mutant mouse strains. However, early postnatal lethality in Trps1 knockout mice has hampered the study of postnatal TRPS pathology. Here, through epigenomic analysis we identified two previously uncharacterized candidate gene regulatory regions in the first intron of Trps1. We deleted these regions, either individually or simultaneously, and examined their effects on skeletal morphogenesis. Animals that were deleted individually for either region displayed only modest phenotypes. In contrast, the Trps1Δint/Δint mouse strain with simultaneous deletion of both genomic regions exhibit postnatal growth retardation. This strain displayed delayed secondary ossification center formation in the long bones and misshaped hip joint development that resulted in acetabular dysplasia. Reducing one allele of the Trps1 gene in Trps1Δint mice resulted in medial patellar dislocation that has been observed in some patients with TRPS. Our novel Trps1 hypomorphic strain recapitulates many postnatal pathologies observed in human TRPS patients, thus positioning this strain as a useful animal model to study postnatal TRPS pathogenesis. Our observations also suggest that Trps1 gene expression is regulated through several regulatory elements, thus guaranteeing robust expression maintenance in skeletal cells.

A novel homozygous FAM92A gene (CIBAR1) variant further confirms its association with non-syndromic postaxial polydactyly type A9 (PAPA9).

Polydactyly is a very common digit anomaly, having extra digits in hands and/or toes. Non-syndromic polydactyly in both autosomal dominant and autosomal recessive forms are caused by disease-causing variants in several genes, including GLI1, GLI3, ZNF141, FAM92A, IQCE, KIAA0825, MIPOL1, STKLD1, PITX1, and DACH1. Whole exome sequencing (WES) followed by bi-directional Sanger sequencing was performed for the single affected individual (II-1) of the family to reveal the disease causative variant/gene. 3D protein modeling and structural molecular docking was performed to determine the effect of the identified mutation on the overall protein structure. WES revealed a novel biallelic missense variant (c.472G>C; p.Ala158Pro) in exon 6 of the FAM92A gene. The identified variant segregated perfectly with the disease phenotype using Sanger sequencing. Furthermore, Insilco analysis revealed that the variant significantly changes the protein secondary structure, and substantially impact the stability of FAM92A. We report the second FAM92A disease-causing mutation associated with recessive non-syndromic postaxial polydactyly. The data further confirms the contribution of FAM92A in limb development and patterning.

Digital mucous cyst.

Mucous cyst is a benign but recurrent lesion. It is located on the dorsal surface of the digital extremity between the distal interphalangeal joint and the base of the nail. The nail is often affected by the cyst because of its topographical proximity. Nail plate deformity may even be the first obvious abnormality indicating the presence of a small mucous cyst or subungual cyst. Mucous cyst is associated with osteoarthritis of the joint, osteophytes probably being the main contributing factor. Surgical treatment by joint debridement and cyst removal is the most effective way of preventing recurrence.

Congenital Flexor Contracture of Ulnar Digits Masquerading as Volkmann Ischemic Contracture.

ABSTRACT: Congenital flexion contracture of ulnar digits is a rare entity with few cases reported in medical literature. This condition is often misdiagnosed as Volkmann ischemic contracture as both have similar presentation. The patient history, physical examination, radiological investigation, and intra-operative findings can differentiate these 2 conditions clearly. A 14-year-old female presented to a tertiary care hospital with flexion deformity of the left long, ring, and little fingers without neurological deficit since she was 3 years old. Patient had decreased handspan with difficulty in grasping daily life objects. Finger flexion deformity was also not aesthetically acceptable due to social stigma. Patient finger contracture was managed with flexor pronator slide (Max-Page) operation. The muscle slide operation was done using concealed medial incision. Aesthetic and functional correction was achieved with no recurrence at subsequent follow-ups.

A novel missense variant located within the zinc finger domain of the GLI3 gene was identified in a Vietnamese pedigree with index finger polydactyly.

BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly. METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members. RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species. CONCLUSION: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.

[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.

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.

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.