Adducted Thumbs Research Articles

Normative Values for Thumb Length in Central Indian Adult Population.

Introduction This article aims to establish the relative thumb length in comparison to the index finger in central Indian adults. Materials and Methods Five hundred normal adult hands (1,000 thumbs), 316 men and 184 women, mean age 30 years, were included in the study. The relative length of the thumb was measured using the length of the proximal phalanx of the index finger (thumb-proximal phalanx index) and the distance between the proximal digital crease and proximal interphalangeal crease of the index finger (thumb-digital crease index). Results The tip of a normal adducted thumb extends to 69% of the length of the proximal phalanx of the index finger and 38% of the distance between the two proximal creases of the index finger. The tip of a normal adducted thumb extends to 68% for male and 69% for female of the length of the proximal phalanx of the index finger. For the dominant hand the tip of a normal adducted thumb extends to 68%, while for nondominant hand it reaches 71% of the length of the proximal phalanx of the index finger. The difference between the laterality, gender, and hand dominance was not statistically significant. Conclusion The tip of a normal adducted thumb extends to 69% of the length of the proximal phalanx of the index finger and 38% of the distance between the two proximal creases of the index finger. Relative normal thumb length is independent of gender, laterality, or hand dominance.

L1 Syndrome-Associated Phenotypes and a Novel L1CAM Variant: A Clinical Report

AbstractL1 syndrome is a group of X-linked diseases caused by pathogenic variants in the human L1 cell adhesion molecule gene (L1CAM; OMIM 308840). The L1CAM gene is expressed primarily in the nervous system, where it plays important roles in neuronal development, including the guidance of neurite outgrowth, neuronal cell migration, axon bundling, synaptogenesis, myelination, neuronal cell survival, and long-term potentiation. L1 syndrome comprises a group of overlapping phenotypes including partial agenesis of corpus callosum, congenital X-linked hydrocephalus, and mental retardation, aphasia, shuffling gait, and adducted thumbs syndrome. Molecular analysis was performed in four patients with congenital hydrocephalus (CH) and adducted thumbs. Three pathogenic variants were identified in the L1CAM gene, novel c.539dupA (p.Gln181Alafs*46) common to the two siblings, c.791G > A (p.Cys264Tyr) and c.1453C > T (p.Arg485*) variants. A correlation between genotype and phenotype has been reported in L1-related disorders. Two families with intrafamilial variability are presented and a novel pathogenic variant in the L1CAM gene has been reported. L1 syndrome should be considered primarily in patients with CH and adducted thumbs.

Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury.

The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the L1 gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis. Clinicians have observed that recovery post-traumatic brain injury (TBI) varies among the population. This variability may be explained by the genetic differences present in the general population. In this study, we utilized a novel mouse model of L1 syndrome with a mutation at aspartic acid position 201 in the extracellular domain of L1 (L1-201). We assessed the impact of this specific single nucleotide polymorphism (SNP) localized to the X-chromosome L1 gene on recovery outcomes following TBI by comparing the L1-201 mouse mutants with their wild-type littermates. We demonstrate that male L1-201 mice exhibit significantly worse learning and memory outcomes in the Morris water maze after lateral fluid percussion (LFP) injury compared to male wild-type mice and a trend to worse motor function on the rotarod. However, no significant changes were observed in markers for inflammatory responses or apoptosis after TBI.

The Study of Clinical Phenotypes and Analysis of Mutations in L1 Syndrome

The Study of Clinical Phenotypes and Analysis of Mutations in L1 Syndrome

Morphological integration and shape covariation between the trapezium and first metacarpal among extant hominids.

The shape of the trapezium and first metacarpal (Mc1) markedly influence thumb mobility, strength, and the manual abilities of extant hominids. Previous research has typically focused solely on trapezium-Mc1 joint shape. Here we investigate how morphological integration and shape covariation between the entire trapezium (articular and non-articular surfaces) and the entire Mc1 reflect known differences in thumb use in extant hominids. We analyzed shape covariation in associated trapezia and Mc1s across a large, diverse sample of Homo sapiens (n = 40 individuals) and other extant hominids (Pan troglodytes, n = 16; Pan paniscus, n = 13; Gorilla gorilla gorilla, n = 27; Gorilla beringei, n = 6; Pongo pygmaeus, n = 14; Pongo abelii, n = 9) using a 3D geometric morphometric approach. We tested for interspecific significant differences in degree of morphological integration and patterns of shape covariation between the entire trapezium and Mc1, as well as within the trapezium-Mc1 joint specifically. Significant morphological integration was only found in the trapezium-Mc1 joint of H. sapiens and G. g. gorilla. Each genus showed a specific pattern of shape covariation between the entire trapezium and Mc1 that was consistent with different intercarpal and carpometacarpal joint postures. Our results are consistent with known differences in habitual thumb use, including a more abducted thumb during forceful precision grips in H. sapiens and a more adducted thumb in other hominids used for diverse grips. These results will help to infer thumb use in fossil hominins.

Mouse Models of Musculocontractural Ehlers-Danlos Syndrome

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 (CHST14) (mcEDS-CHST14) or dermatan sulfate epimerase (DSE) (mcEDS-DSE). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.g., adducted thumbs, clubfeet, and craniofacial characteristics) and progressive connective tissue fragility-related manifestations (e.g., recurrent dislocations, progressive talipes or spinal deformities, pneumothorax or pneumohemothorax, large subcutaneous hematomas, and/or diverticular perforation). Careful observations of patients and model animals are important to investigate pathophysiological mechanisms and therapies for the disorder. Some independent groups have investigated Chst14 gene-deleted (Chst14-/-) and Dse-/- mice as models of mcEDS-CHST14 and mcEDS-DSE, respectively. These mouse models exhibit similar phenotypes to patients with mcEDS, such as suppressed growth and skin fragility with deformation of the collagen fibrils. Mouse models of mcEDS-CHST14 also show thoracic kyphosis, hypotonia, and myopathy, which are typical complications of mcEDS. These findings suggest that the mouse models can be useful for research uncovering the pathophysiology of mcEDS and developing etiology-based therapy. In this review, we organize and compare the data of patients and model mice.

Decoding Natural Grasping Behaviors: Insights Into MRCP Source Features and Coupling Dynamics.

The effective decoding of natural grasping behaviors is crucial for the natural control of neural prosthetics. This study aims to investigate the decoding performance of movement-related cortical potential (MRCP) source features between complex grasping actions and explore the temporal and frequency differences in inter-muscular and cortical-muscular coupling strength during movement. Based on the human grasping taxonomy and their frequency, five natural grasping motions-medium wrap, adducted thumb, adduction grip, tip pinch, and writing tripod-were chosen. We collected 64-channel electroencephalogram (EEG) and 5-channel surface electromyogram (sEMG) data from 17 healthy participants, and projected six EEG frequency bands into source space for further analysis. Results from multi-classification and binary classification demonstrated that MRCP source features could not only distinguish between power grasp and precision grasp, but also detect subtle action differences such as thumb adduction and abduction during the execution phase. Besides, we found that during natural reach-and-grasp movement, the coupling strength from cortical to muscle is lower than that from muscle to cortical, except in the hold phase of γ frequency band. Furthermore, a 12-Hz peak of inter-muscular coupling strength was found in movement execution, which might be related to movement planning and execution. We believe that this research will enhance our comprehension of the control and feedback mechanisms of human hand grasping and contributes to a natural and intuitive control for brain-computer interface.

P119: Molecular basis of adducted thumbs syndrome in the Old Order Amish community

P119: Molecular basis of adducted thumbs syndrome in the Old Order Amish community

Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM.

Objective:The study aimed to show the clinical characteristics and prognosis of the L1 syndrome in patients with L1CAM mutations in the extracellular region.Materials and Methods:Three affected boys and their siblings and parents from a large family were included in this study. Genetic etiology was investigated by whole-exome sequencing in the index patient. The pathogenic variant was detected by whole-exome sequencing and was validated by Sanger sequencing in 3 patients and other family members.Results:We present 2 brothers and their cousin with prenatal onset hydrocephalus, severe developmental and speech delay, corpus callosum agenesis/hypogenesis, epilepsia, and adducted thumbs. A hemizygous missense mutation NM_024003 (c.A2351G:p.Y784C) on exon 18 of L1CAM gene was found in the 3 patients and their carrier mother. This missense mutation in the conserved region of the second fibronectin type III-like repeats located in the extracellular region of L1CAM resulted in the severe phenotype of X-linked inherited L1 syndrome in the patients.Conclusion:L1 syndrome should be considered in the differential diagnosis of male children with intellectual disability, hydrocephalus, and adducted thumbs. While truncating mutations of L1CAM may cause a more severe phenotype, missense mutations cause milder forms. However, pathogenic missense mutations affecting key amino acid residues lead to severe phenotype likely.

Adducted thumb may not be mandatory for prenatal diagnosis of X-linked hydrocephalus in early second trimester

ObjectiveX-linked hydrocephalus (XLH), the most common genetic hydrocephalus, is caused by mutation of the L1 cell adhesion molecule (L1CAM). A fetus/neonate with this disorder frequently shows an adducted thumb, which has been employed as a helpful finding in the prenatal diagnosis of XLH. Materials and methodsWe describe a male fetus with hydrocephalus without an adducted thumb: the pregnancy was terminated at 21 weeks' gestation on the parents' request. Direct sequencing of the umbilical cord revealed L1CAM mutation, which confirmed the diagnosis of XLH. ResultsOur literature review demonstrated that while an adducted thumb was observed in almost all fetuses with this disorder after 24 weeks' gestation, it was noted in only 57% (8/14) of fetuses/neonates at less than 24 weeks: it was absent in 43%. ConclusionEven if an adducted thumb is not observed, XLH should not be ruled out, especially in early gestation.

Severe phenotypes of B3GAT3-related disorder caused by two heterozygous variants: a case report and literature review

BackgroundLinkeropathies refers to a series of extremely rare hereditary connective tissue diseases affected by various glycosyltransferases in the biosynthesis of proteoglycans. We report for the first time two heterozygous variants of B3GAT3 in a Chinese infant, in whom Marfan syndrome was suspected at birth.Case presentationA 2-month-old boy from a non-consanguineous Chinese family without a family history presented severe phenotypes of joint dislocation, obvious flexion contractures of the elbow, arachnodactyly with slightly adducted thumbs, cranial dysplasia, foot abnormalities and aortic root dilation; Marfan syndrome was suspected at birth. Our patient was the youngest, at the age of 2 months, to experience aortic root dilation. Two B3GAT3 variants, NM_012200.2, c.752T>C, p.V251A and c.47C>A, p.S16*, with heterozygosity were identified in the patient by whole-exome sequencing; the variants were inherited from his parents. During close follow-up, significant changes in the cranial profile and obvious external hydrocephalus were present at the age of 7 months, which differs from previously reported cases.ConclusionWe diagnosed a patient with congenital heart defects at an early age with a B3GAT3-related disorder instead of Marfan syndrome and expanded the spectrum of B3GAT3-related disorders. We also provide a literature review of reported B3GAT3 cases; for at least one of the variants, this is the first report of genotype–phenotype correlations in individuals with cardiovascular defects being related to the acceptor substrate-binding subdomain of B3GAT3.

Clinical and Genetic Findings in a Series of Eight Families with Arthrogryposis

The term “arthrogryposis” is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys–Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.

A Novel 4q32.3 Deletion in a Child: Additional Signs and the Role of MARCH1.

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics.

L1 syndrome is a rare developmental disorder characterized by hydrocephalus of varying severity, intellectual deficits, spasticity of the legs, and adducted thumbs. Therapy is limited to symptomatic relief. Numerous gene mutations in the L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in L1 syndrome patients, and those affecting the extracellular domain of this transmembrane type 1 glycoprotein show the most severe phenotypes. Previously analyzed rodent models of the L1 syndrome focused on L1-deficient animals or mouse mutants with abrogated cell surface expression of L1, making it difficult to test L1 function-triggering mimetic compounds with potential therapeutic value. To overcome this impasse, we generated a novel L1 syndrome mouse with a mutation of aspartic acid at position 201 in the extracellular part of L1 (p.D201N, hereafter termed L1-201) that displays a cell surface-exposed L1 accessible to the L1 mimetics. Behavioral assessment revealed an increased neurological deficit score and increased locomotor activity in male L1-201 mice carrying the mutation on the X-chromosome. Histological analyses of L1-201 mice showed features of the L1 syndrome, including enlarged ventricles and reduced size of the corpus callosum. Expression levels of L1-201 protein as well as extent of cell surface biotinylation and immunofluorescence labelling of cultured cerebellar neurons were normal. Importantly, treatment of these cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine rescued impaired cell migration and survival as well as neuritogenesis. Altogether, the novel L1 syndrome mouse model provides a first experimental proof-of-principle for the potential therapeutic value of L1 mimetic compounds.

A truncation mutation in the <i>L1CAM</i> gene in a child with hydrocephalus

<abstract> <p>Hydrocephalus is a neurodevelopmental, X-linked recessive disorder caused by mutations in the <italic>L1CAM</italic> gene. The <italic>L1CAM</italic> gene encodes for L1CAM protein which is essential for the nervous system development including adhesion between neurons, Myelination, Synaptogenesis etc. Herein, the present study has reported mutations in L1 syndrome patient with Hydrocephalus and Adducted thumb. Genomic DNA was extracted from patients whole blood (n = 18). The 11 exons of the <italic>L1CAM</italic> gene were amplified using specific PCR primers. The sequenced data was analysed and the pathogenicity of the mutation was predicted using the various bioinformatics programs: PROVEAN, PolyPhen2, and MUpro. The results revealed that the proband described here had nonsense mutation G1120→T at position 1120 in exon 9 which is in extracellular immunoglobulin domain (Ig4) of the <italic>L1CAM</italic> gene. This nonsense mutation is found to be truncated with a deleterious effect on developing brain of the child, and this is the first report of this novel mutation in patient with X-linked Hydrocephalus in India.</p> </abstract>

Trabecular variation in the first metacarpal and manipulation in hominids.

The dexterity of fossil hominins is often inferred by assessing the comparative manual anatomy and behaviors of extant hominids, with a focus on the thumb. The aim of this study is to test whether trabecular structure is consistent with what is currently known about habitually loaded thumb postures across extant hominids. We analyze first metacarpal (Mc1) subarticular trabecular architecture in humans (Homo sapiens, n = 10), bonobos (Pan paniscus, n = 10), chimpanzees (Pan troglodytes, n = 11), as well as for the first time, gorillas (Gorilla gorilla gorilla, n = 10) and orangutans (Pongo sp., n = 1, Pongo abelii, n = 3 and Pongo pygmaeus, n = 5). Using a combination of subarticular and whole-epiphysis approaches, we test for significant differences in relative trabecular bone volume (RBV/TV) and degree of anisotropy (DA) between species. Humans have significantly greater RBV/TV on the radiopalmar aspects of both the proximal and distal Mc1 subarticular surfaces and greater DA throughout the Mc1 head than other hominids. Nonhuman great apes have greatest RBV/TV on the ulnar aspect of the Mc1 head and the palmar aspect of the Mc1 base. Gorillas possessed significantly lower DA in the Mc1 head than any other taxon in our sample. These results are consistent with abduction of the thumb during forceful "pad-to-pad" precision grips in humans and, in nonhuman great apes, a habitually adducted thumb that is typically used in precision and power grips. This comparative context will help infer habitual manipulative and locomotor grips in fossil hominins.

Adducted thumb as an isolated morphologic finding: an early sonographic sign of impaired neurodevelopment: A STROBE compliant study.

Fetal adducted thumbs have been described in association with hydrocephalus and other abnormalities, but in cases without other structural malformations the determination of prognosis and recurrence risk is challenging. The aim of our study is to analyze the characteristics, natural history, and postnatal outcome of such cases.A retrospective study was conducted over a period of 4 years in a tertiary referral center. All fetuses diagnosed as adducted thumbs without other structural malformations comprised the study group. Prenatal sonographic features and neonatal outcome are documented.There were 4 cases of fetal adducted thumbs diagnosed during the study period. No cases demonstrated other structural malformations throughout the gestation. A smaller head was noted in 2 cases during the follow-up, and all cases presented with polyhydramnios on the first or ensuing scans. Three cases died after birth due to swallowing or breathing difficulty, and the surviving 1 showed convulsion and mental retardation.Fetal adducted thumb might be an early and specific sonographic marker of impaired neurodevelopment. Close follow-up and genetic investigation should be performed in these cases. Ultrasound examination plays an important role in the prenatal diagnosis and counseling of cases without detailed prenatal genetic analysis.

Prenatal diagnosis of fetal adducted thumbs

Purpose: One of the greatest challenges with the finding of adducted thumbs in the prenatal setting is the determination of whether this finding is associated with an underlying genetic syndrome. The aim of the present study is to describe the characteristics and outcome of prenatal sonographic diagnosis of adducted thumbs.Methods: A retrospective study was conducted over a period of 17 years in a tertiary referral center. All fetuses diagnosed prenatally with adducted thumbs comprised the study group. Prenatal sonographic assessment and neonatal outcome are presented.Results: Six fetuses were evaluated for adducted thumbs over the 17-year period. In three cases, the parents elected termination of pregnancy for severe associated anomalies. In one case partial resolution was observed during the third trimester. Of the remaining two fetuses, one had a single umbilical artery and in the second the adducted thumbs were an isolated finding. Post-natal evaluation in both cases revealed bilateral adducted thumbs. Apart from orthopedic follow up no further interventions were needed.Conclusions: Prenatal diagnosis of adducted thumbs should be followed by a meticulous fetal ultrasound examination combined with genetic counseling. According to our cohort, if associated anomalies are excluded, isolated cases seem to have a favorable diagnosis.

Identification of novel mutations in L1CAM gene by a DHPLC-based assay

X-linked hydrocephalus, MASA syndrome, X-linked complicated Spastic Paraplegia Type I, and X-linked partial agenesis of the corpus callosum are rare diseases mainly affecting male population and broadly referred as L1 syndrome, caused by mutations in the L1CAM gene. In the present study 36 boys and a male fetus whose clinical features were consistent with L1 syndrome were analyzed by dHPLC assay and direct sequencing of L1CAM gene. Sequence analysis of the 14 different aberrant dHPLC elution profiles demonstrated that six of them were associated with already reported polymorphisms, four with previously described causative variants while the remaining four represented novel L1CAM mutations. The dHPLC method proposed identified eight (21 %) causative L1CAM mutations in our patients while direct sequencing failed to detect any variation in patients negative to dHPLC analysis. We conclude that the dHPLC assay represents a fast and efficient method for the screening of L1CAM mutations and that L1 syndrome should be considered in the differential diagnosis of intellectual disability in children, especially when other signs such as hydrocephalus or adducted thumbs are present.

A New Splicing Mutation in the L1CAM Gene Responsible for X-Linked Hydrocephalus (HSAS).

X-linked hydrocephalus (XLH) is a genetic disorder leading to a syndrome characterized by mental retardation, bilateral adducted thumbs, and spasticity of upper and lower limbs. In most cases, X-linked mutation leads to a defective activity of the neuronal cell adhesion molecule L1CAM(L1 cell adhesion molecule, OMIM 308840). Depending on mutations of L1CAM, four X-linked neurological syndromes have been described. These syndromes are very different albeit each one possesses marked variability. In the present study, we describe a novel L1CAM mutation in a 33-year-old woman reporting two voluntary terminations of pregnancy due to fetal hydrocephalus. The genetic analysis identified the potential splicing variant c.1267+5delG. When analyzed in vitro, this mutation produces the skipping of exon 10. The same mutation was confirmed in analyzing DNA from amniocytes from the second pregnancy, and ultrasound scan and autopsy confirmed the occurrence of a severe L1 syndrome. These data describe a novel L1 mutation which improves our understanding on genotype-phenotype correlation while confirming the importance of prenatal screening for L1CAM mutations.