Congenital hypoplasia of first digital ray of hands as an isolated presentation in four subjects.
ABSTRACT: Congenital hypoplasia of thumb is rare malformation which is less likely to appear as an isolated entity. Four independent subjects exhibiting various grades of underdeveloped first digital ray were recruited. The affected autopods had narrow palms, medial or valgus inclinations of index fingers and thenar weakness, while the postaxial digits were least affected. According to the classification of hypoplastic thumb by Blauth and Schneider-Sickert (1981), the phenotypes were concordant with types 3 and 4. In one of the subjects there was contralateral preaxial polydactyly. All cases were sporadic and nonsyndromic and parental consanguinity was witnessed in two individuals. Recurrent appearance of similar phenotypes may suggest genetic etiologies which should be elucidated with the help of high-throughput genetic methods.
Project description:BACKGROUND:Polydactyly is a common genetic limb deformity characterized by the presence of extra fingers or toes. This anomaly may occur in isolation (nonsyndromic) or as part of a syndrome. The disease is broadly divided into preaxial polydactyly (PPD; duplication of thumb), mesoaxial polydactyly (complex polydactyly), and postaxial polydactyly (PAP: duplication of the fifth finger). The extra digits may be present in one or both the limbs. Heterozygous variants in the GLI3, ZRS/SHH, and PITX1 have been associated with autosomal dominant polydactyly, while homozygous variants in the ZNF141, IQCE, GLI1, and FAM92A have been associated with autosomal recessive polydactyly. Pathogenic mutations in the GLI3 gene (glioma-associated oncogene family zinc finger 3) have been associated with both nonsyndromic and syndromic polydactyly. METHODS:Here, we report an extended five generation kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Whole-exome sequencing followed by variant prioritization, bioinformatic studies, Sanger validation, and segregation analysis was performed. RESULTS:Using exome sequencing in the three affected individuals, we identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of the GLI3 encoding gene. CONCLUSION:To the best of our knowledge, the present study reports on the first familial case of nonsyndromic postaxial polydactyly due to the GLI3 variant in Pakistani population. Our study also demonstrated the important role of GLI3 in causing nonsyndromic postaxial polydactyly.
Project description:Ulnar hypoplasia is a rare longitudinal limb deficiency in which the ulna shows various degrees of deficiency. The condition is normally associated with radial defects, and in severe cases there is a reduction of postaxial/ulnar digits. Ulnar deficiency is an integral part of several syndromic malformations like Weyer's oligodactyly syndrome, limb/pelvis hypoplasia/aplasia syndrome, and ulnar-mammary syndrome. Here, we report an isolated unilateral ulnar deficiency in a boy who was a product of a consanguineous marriage. The subject demonstrated mesomelic shortening of the left arm with reduced zeugopod and autopod, and preaxial absence of two fingers. Additional findings in the affected limb were severe flexion contracture at the elbow joint, reduced and narrow palm, hypoplastic digits, and clinodactyly. Roentgenographic study revealed rudimentary ulna, dysplastic and posteriorly dislocated radius, crowding of carpals, and complete absence of digit rays of the thumb and index finger. Despite this anomaly, the subject could manage his daily life activities well. We present detailed clinical features and differential diagnosis of this rare limb malformation.
Project description:Asymmetric crying face (ACF) is a minor congenital anomaly that is often associated with a high rate of major malformations and may be considered an indication of a syndromic clinical presentation. Here, we report a 21-month-old male presenting with left- sided ACF, thenar hypoplasia, and esophageal atresia. Ultrasonographic images of the volar surface of the left hand evidenced the absence of muscle tissue around the thenar prominence at the level of the first metacarpal bone. No pathogenic copy number variation was detected on array-comparative genomic hybridization analysis (CGH). The association of esophageal atresia, thenar hypoplasia, and ACF has not been reported before. We discuss the possibility of a distinct association or of a sequence of anomalies associated with ACF.
Project description:BACKGROUND:Carpal tunnel syndrome (CTS), the most common neuropathy, is caused by a compression of the median nerve in the carpal tunnel and is related to aging. The initial symptom is numbness and pain of the median nerve distributed in the hand area, while thenar muscle atrophy occurs in advanced stages. This atrophy causes failure of thumb motion and results in clumsiness; even after surgery, thenar atrophy does not recover for an extended period. Medical examination and electrophysiological testing are useful to diagnose CTS; however, visits to the doctor tend to be delayed because patients neglect the symptom of numbness in the hand. To avoid thenar atrophy-related clumsiness, early detection of CTS is important. OBJECTIVE:To establish a CTS screening system without medical examination, we have developed a tablet-based CTS detection system, focusing on movement of the thumb in CTS patients; we examined the accuracy of this screening system. METHODS:A total of 22 female CTS patients, involving 29 hands, and 11 female non-CTS participants were recruited. The diagnosis of CTS was made by hand surgeons based on electrophysiological testing. We developed an iPad-based app that recorded the speed and timing of thumb movements while playing a short game. A support vector machine (SVM) learning algorithm was then used by comparing the thumb movements in each direction among CTS and non-CTS groups with leave-one-out cross-validation; with this, we conducted screening for CTS in real time. RESULTS:The maximum speed of thumb movements between CTS and non-CTS groups in each direction did not show any statistically significant difference. The CTS group showed significantly slower average thumb movement speed in the 3 and 6 o'clock directions (P=.03 and P=.005, respectively). The CTS group also took a significantly longer time to reach the points in the 2, 3, 4, 5, 6, 8, 9, and 11 o'clock directions (P<.05). Cross-validation revealed that 27 of 29 CTS hands (93%) were classified as having CTS, while 2 of 29 CTS hands (7%) did not have CTS. CTS and non-CTS were classified with 93% sensitivity and 73% specificity. CONCLUSIONS:Our newly developed app could classify disturbance of thumb opposition movement and could be useful as a screening test for CTS patients. Outside of the clinic, this app might be able to detect middle-to-severe-stage CTS and prompt these patients to visit a hand surgery specialist; this may also lead to medical cost-savings.
Project description:PURPOSE:Greig cephalopolysyndactyly (GCPS) (OMIM 175700), a rare autosomal dominant disorder, is characterized by a distinct combination of craniofacial, hand and foot malformations. The hand and foot malformations often require orthopedic assessment and treatment. The disorder is caused by point mutations or deletions in the GLI3 gene, located on chromosome 7p14.3. Herewith, we review the hand and foot malformations in a cohort of 13 patients referred for genetic testing. METHODS:We reviewed the medical files of 13 patients with GCPS seen at the Center for Human Genetics in Leuven between 2003 and 2005. Clinical, molecular and radiological findings, when available, were recorded. RESULTS:We identified six different point mutations in the GLI3 gene, two microdeletions and three larger chromosomal deletions. In the hands, preaxial polydactyly was never observed, but the malformations included postaxial polydactyly, broad thumbs, clinodactyly of the thumbs and various degrees of syndactyly. In the feet the spectrum of malformations included preaxial polydactyly, postaxial polydactyly, different degrees of syndactyly and broad halluces. Syndactyly of the toes and hallux abnormalities were present in all patients. Most frequently, syndactyly was present between toes 1-2-3. The broadening of the hallux was either due to a complete or partial duplication of the first toe or to broadening of the distal phalanx. Mental retardation was found in three cases and was associated with a large chromosomal deletion of the GLI3 region. CONCLUSION:We found the classic hand and foot malformations associated with GCPS in our cohort of patients. Patients with a large chromosomal deletion had mental retardation, but no structural brain anomalies were found.
Project description:Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.
Project description:An asymptomatic absence of flexor pollicis longus without association with any other anomaly or hypoplasia of the thenar muscles in a 28-year-old patient is reported due to its rarity. The inability to flex the interphalangeal joint of the thumb and the absent flexor crease of the thumb led us to identify the absent tendon, and the tendon could not be palpated in the flexor crease of the thumb. Routine X-rays, ultrasound scans, and a computed tomography with soft tissue enhancement was used to confirm and document the condition. The patient was not referred for a magnetic resonance imaging, facilities for which are not available in the center where the author is working, as he was not keen in surgical interference.
Project description:Associated with anomalies such as VACTERL and Fanconi anemia, congenital hypoplasia of the thumb has a strong association with radial hypoplasia. The majority of patients have bilateral thumb underdevelopment, and those that have a unilateral deformity tend to have the right hand more commonly affected. In order to gain an opposable thumb, patients with a deficient carpometacarpal (CMC) joint, a floating thumb, or complete absence of the thumb can benefit with a thumb amputation and a translocation of the index finger (pollicization) to the thumb position. This video demonstrates the technical steps involved in performing a pollicization procedure in a patient with radial hypoplasia. The video is available electronically.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all individual participants included in the video. The authors declare that they have no conflict of interest.Pollicization allows for improved functional results in patients with radial hypoplasia.This video has reviewed the essential steps in performing a pollicization procedure in patients with radial hypoplasia.
Project description:BACKGROUND:Greig cephalopolysyndactyly syndrome is a rare multiple congenital anomaly syndrome characterized by the triad of polysyndactyly (preaxial or mixed preaxial and postaxial), macrocephaly, and ocular hypertelorism. Little is known about the neuropsychological phenotype and the developmental features of this syndrome. CASE PRESENTATION:We describe the clinical features of a 7-year-old Italian white boy affected by Greig cephalopolysyndactyly syndrome in comorbidity with autism spectrum disorder and the case of his 45-year-old white father, carrying the same point deletion (c.3677del) in the GLI3 gene and showing subclinical autistic symptoms. We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills of the child. Concurrently, the father underwent his first psychiatric evaluation of cognitive skills and autistic symptoms. CONCLUSIONS:We report the first clinical description of an association between autistic symptoms and Greig cephalopolysyndactyly syndrome in two members of the same family with the same genetic point deletion. Further research is required in order to draw an accurate conclusion regarding the association between Greig cephalopolysyndactyly syndrome and autism.
Project description:OBJECTIVES:To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype. METHODS:The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan, and underwent detailed clinical and phenotypic examination. RESULTS:The affected arms of patients had complete absence of first digital rays, medial inclinations of second and fifth fingers, narrowing of palms, missing carpals, and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies, and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects. CONCLUSION:Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia, compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations.