Bilateral Postaxial Polydactyly Research Articles

Exploring Genetic Variants in Ellis-Van Creveld Syndrome: Insights from a Consanguineous Family

Background: Ellis-Van Creveld Syndrome (EVC) is a rare genetic disorder characterized by skeletal abnormalities and developmental anomalies, presenting significant challenges in diagnosis and understanding its genetic underpinnings. Objective: This study aimed to comprehensively investigate the clinical and molecular aspects of EVC within a consanguineous family from Pakistan, identifying the genetic variants involved. Methods: A detailed clinical assessment was conducted on all family members, documenting phenotypic features such as polydactyly, syndactyly, dental abnormalities, and short stature. Pedigrees were constructed following established guidelines to depict familial relationships and inheritance patterns. Venous blood samples were collected for genomic DNA extraction using the Phenol-Chloroform Method. Microsatellite marker analysis was performed for linkage mapping, guided by the UCSC Genome Browser and Rutgers Combined Linkage-Physical Map. Mutation screening of the EVC and EVC2 genes was conducted using Sanger sequencing, with primers designed targeting exon-intron boundaries and coding exons. PCR amplification and sequencing were performed according to standard protocols. Data analysis was carried out using SPSS version 25. Results: Clinical assessment revealed classical EVC phenotypes, including bilateral postaxial polydactyly in 80% of affected individuals and dental abnormalities in 70%. Microsatellite marker analysis identified linkage to the EVC/EVC2 locus on chromosome 4p16.2. However, Sanger sequencing of the 21 coding exons of EVC and the 22 exons of EVC2 did not detect any pathogenic mutations. Haplotype analysis confirmed the segregation of specific markers with affected individuals, suggesting the involvement of additional genetic factors. Conclusion: The study's findings challenge the traditional understanding of EVC, highlighting the necessity for advanced genomic techniques such as whole-genome sequencing to fully elucidate its genetic contributors. These insights underscore the heterogeneous nature of EVC and emphasize the importance of comprehensive genetic screening for accurate diagnosis and personalized management of this rare genetic disorder.

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

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. 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. 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. 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. 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. 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. 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.

RF02 | PMON323 Pituitary stalk interruption syndrome, polydactyly, polymicrogyria and a ZRSR2 variant

Abstract Background Pituitary stalk interruption syndrome (PSIS) may associate with brain midline defects and also with polydactyly (GLI2 mutations) but rarely with brain cortex anomalies. Clinical Case We report a boy referred at age 19 months because of growth failure. Bilateral postaxial polydactyly, syndactyly of the toes, and a nodule on the tongue were noted at term birth. The neonatal course was complicated by marked but transient hypoglycemia. During infancy, the acquisition of gross motor skills was slightly delayed. Upon referral, body length was 4.1 SD below the level of mid-parental height. Extremely low concentrations of circulating IGF-I (8 mcg/L) and IGFBP-3 (861 mcg/L) were suggestive of growth hormone (GH) deficiency which was corroborated by glucagon test (peak GH 3.3 mcg/L, peak cortisol 14.6 mcg/dL) in an euthyroid and normoprolactinemic state, and in the absence of polydipsia or polyuria. Brain MRI disclosed not only a PSIS triad (with a virtual absence of the pituitary stalk and the anterior pituitary, and with an ectopic position of the posterior pituitary) but also abnormal sulcation and polymicrogyria (pointing to abnormal lamination in the cortex) on both sides in the posterior cingulum. Familial history is positive for holoprosencephaly and polydactyly in two male relatives, who died neonatally. Whole exome sequencing showed a rare maternally inherited variant in ZRSR2 on the X chromosome (c. 1207_1208delAG (p.Arg403Glyfs*24)) (OMIM 300028). ZRSR2 isdepleted from loss-of-function variants in the reference population, and has not been associated with congenital anomalies or with pituitary dysfunction. This ZRSR2 variant escapes nonsense mediated decay and segregates in this family according to an X-linked recessive pattern. X-inactivation studies and gene expression studies are ongoing to correlate the ZRSR2 variant to the patient's phenotype. Conclusion This case describes a toddler with polydactyly and short stature, based on GH deficiency due to PSIS, in combination with polymicrogyria. Studies are ongoing to link the patient's phenotype to a rare variant in ZRSR2. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Ellis-Van Creveld syndrome: a case report

Ellis-Van Creveled (EVC) syndrome, also called chondroectodermal dysplasia, is a rare genetic disorder with autosomal recessive type of inheritance with 25% risk of transmission to subsequent pregnancies. The syndrome is due to mutation of EVC1 and EVC2 genes on chromosome 4p16, characterized by acromesomalic dwarfism, bilateral postaxial polydactyly, ectodermal dysplasia affecting nails, teeth and congenital heart malformation. One third of the patients die at an early age or during infancy from cardio respiratory problems. The birth prevalence of EVC syndrome is 1/5000 live births in Amish population and 7/1,000,000 live birth in non-Amish population. There are a very few case reports in the literature. We reported a case of 14-year male presenting with typical features of this syndrome.

De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome.

Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.

An intrafamilial phenotypic variability in Ellis-Van Creveld syndrome due to a novel 27 bps deletion mutation.

Ellis-van Creveld (EvC) syndrome is an autosomal recessive disease, characterized by ectodermal, skeletal, and cardiac anomalies. We report intrafamilial phenotypic variability in three new EvC syndrome cases. Affected males in this study showed only ectodermal abnormalities, whereas an affected female showed the classical presentation of EvC Syndrome, including bilateral postaxial polydactyly of hands and feet, and congenital heart defects. Whole exome sequencing was performed to identify the causative variant, followed by validation and segregation analysis using Sanger sequencing. A homozygous deletion variant (c.731_757del) was identified in exon 6 of the EVC gene (NM_153717.2). The identified variant is considered to be the most likely candidate variant for the EvC syndrome in the family based on previous reports validating the role of EVC variants in the EvC syndrome. The disease correctly segregated in the family members, as all affected members were homozygous, and obligate carriers were heterozygous. Our family is remarkable in highlighting the variable expressivity of the EvC phenotype within the same family, due to a homozygous deletion mutation in the EVC gene. The variable expressivity might be due to the hypomorphic nature of mutation, or the presence of additional variants in modifier genes or in the regulatory regions of the EVC/EVC2 genes.

Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A

Polydactyly or hexadactyly is characterized by an extra digit/toe with or without a bone. Currently, variants in ten genes have been implicated in the non-syndromic form of polydactyly.DNA from a single affected individual having bilateral postaxial polydactyly was subjected to whole exome sequencing (WES), followed by Sanger sequencing. Homology modeling was performed for the identified variant and advance microscopy imaging approaches were used to reveal the localization of the DACH1 protein at the base of primary cilia.A disease-causing biallelic missense variant (c.563G > A; p.Cys188Tyr; NM_080760.5) was identified in the DACH1 gene segregating perfectly within the family. Structural analysis using homology modeling of the DACH1 protein revealed secondary structure change that might result in loss of function or influence downstream interactions. Moreover, siRNA-mediated depletion of DACH1 showed a key role of DACH1 in ciliogenesis and cilia function.This study provides the first evidence of involvement of the DACH1 gene in digits development in humans and its role in primary cilia. This signifies the importance and yet unexplored role of DACH1.

Bilateral postaxial polydactyly with hallux valgus in both feet: report of an adult case.

Bilateral postaxial polydactyly with hallux valgus in both feet: report of an adult case.

Ellis–van creveld syndrome: A rare autosomal recessive genetic disorder

Ellis–van Creveld syndrome is a rare genetic disorder with autosomal recessive inheritance, mainly affecting the Amish population living in Pennsylvania, USA, with an incidence of 1:244,000 for the general population. This syndrome consists of characteristic features such as bilateral postaxial polydactyly, chondroectodermal dysplasia, congenital heart defects, and hypoplastic nails and teeth. There have been few case reports of this syndrome published mainly in dental literature. We report a case of a 40-year-old male presenting with typical features of this syndrome.

Ellis Van Creveld Syndrome - A Diagnosis to be Considered in Every Case of Polydactyly

Ellis van creveld Syndrome (EVS) is a rare genetic disorder involving predominantly bones and heart. We report a case of 1 year 2 months old female child with EVS with positive similar family history in elder sibling. Our patient had classical bilateral postaxial polydactyly of hands and feet associated with congenital heart disease.

A perfect diagnosis of Ellis-van Creveld syndrome by oral manifestations: a case report

Ellis-van Creveld syndrome is an extremely rare congenital genetic disorder having autosomal recessive inheritance. The characteristic features of this syndrome are bilateral postaxial polydactyly, acromesomelic dwarfism, ectodermal dysplasia affecting nails, congenital cardiac malformation, edentulous maxillary and mandibular incisors, non-appearance of mucobuccal fold, congenitally missing teeth, slight serrations of the alveolar ridge and multiple small alveolar notches. The present case describes the oral manifestations of the patient which leads to a perfect diagnosis of this syndrome. Ellis-van Creveld syndrome requires a multidisciplinary management and, hence the dental surgeons play an important role in these cases.

A rare case report of Ellis Van Creveld syndrome in an Indian patient and literature review

Ellis Van Creveld syndrome (EVC) is a rare genetic disorder having autosomal recessive inheritance affecting the Amish population of Pennsylvania in USA with incidence of 1:244,000 for the general population. This syndrome consists of characteristic features such as bilateral postaxial polydactyly, chondroectodermal dysplasia, congenital heart defects and hypoplastic nails and teeth. There are few case reports of this syndrome reported in dental literature. We report a case of a 17 year old female presenting typical features of this syndrome and the oral findings of this patient which are the key diagnostic features.

Foot polydactyly and bipartite medial cuneiform: A case of co-occurrence in a Celtic skeleton from Verona (Italy)

We report a case of bilateral foot polydactyly and bipartite medial cuneiform in a male individual buried in a Celtic/Roman necropolis (3rd to 1st century BCE) in the city of Verona (Italy). During the construction of an underground garage in the main courtyard of the Bishop's Seminary at Verona between 2005 and 2010, archaeologists uncovered the remains of 174 individuals (108 non-adults and 66 adults). It is thought that these graves could belong to some of the first inhabitants of the urban area of Verona. The individual presented here (US 2807) is a middle-aged male (40–50 years) in a good state of preservation. His estimated stature is 1756mm (±32.1mm). This male presents congenital anomalies in the feet and dental agenesis. We believe this to be the only known archaeological case of bilateral postaxial polydactyly with forked (Y) shape, in which both fifth metatarsals are associated with complete bipartition of the left medial cuneiform and partial bipartition of the right one. Polydactyly is fairly common in modern clinical cases but bipartite medial cuneiform is relatively rare; neither of these congenital conditions is well documented archaeologically.

Congenital talipes equinovarus: frequency of associated malformations not identified by prenatal ultrasound.

To establish the frequency of prenatally undetected associated malformations (identified at birth) in infants with apparent "isolated" club foot deformity. A cohort study of all infants with unilateral or bilateral club foot deformity identified at birth among 311 480 infants surveyed between 1972 and 2012 at Brigham and Women's Hospital in Boston. Those with talipes equinovarus were divided into "isolated" and "complex", based on the findings in examination and by chromosome analysis. One hundred and forty-two infants had "isolated" talipes equinovarus (TEV), and 66 had the "complex" type. Six (4.2%) of the 142 infants with "isolated" TEV were found at birth to have associated malformations that had not been identified by imaging during pregnancy. These abnormalities included hip dislocation (n = 2), bilateral post-axial polydactyly of the feet (n = 1), penile chordee (n = 1), and hypospadias (n = 2). In this consecutive series of infants with isolated talipes equinovarus, 95.8% had no additional malformations identified by examination at birth. None of the additional findings were severe enough to affect the medical prognosis of the affected infant. © 2014 John Wiley & Sons, Ltd.

Fetal Autopsy of Meckel Gruber Syndrome –A Case Report

Meckel Gruber syndrome is a rare autosomal recessive lethal malformation characterized by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post-axial polydactyly. One such rare case at 28 weeks of gestation was terminated and its case report with the phenotypic features, fetal autopsy and histo-pathological examination are discussed.

555 Perinatal Neuroblastoma with a Germline Interstitial 2P Duplication Involving the Mycn Gene: a Case Report

Background/AimsMYCN proto-oncogene is located on chromosome 2p24. MYCN amplification is a poor prognostic factor in neuroblastoma. However, the role of germline MYCN copy number gain is unclear. It is unknown...

Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

This report describes a case of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in a 1-year-old boy, born to healthy nonconsanguineous parents. Megalencephaly and bilateral postaxial polydactyly of upper and lower limbs were noted at birth. He had profound developmental delay and moderate hypotonia. Magnetic resonance imaging (MRI) of the brain revealed hydrocephalus, polymicrogyria in both frontal lobes and perisylvian regions, and thin corpus callosum. Array-comparative genomic hybridization was normal. The patient's clinical and radiologic findings fit the classic description of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. The possible overlap between megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome and other similar conditions is discussed.

Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice site mutation in intron 4 in the NEK1 gene

ObjectiveTo demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff). Case ReportA 34-year-old woman with no past history of fetal SRPS was referred to the hospital at 21 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed a narrow thorax, short ribs, short limbs with marginal spurs, and postaxial hexadactyly in both the hands and feet. A diagnosis of SRPS III (Verma-Naumoff) was made. Amniocentesis was performed. The karyotype was 46,XY. Molecular genetic analysis of the amniotic fluid cells identified a homozygous splice site mutation in intron 4 (c.331-1 A > G) or IVS4-1 A > G in the NEK1 gene. The parents were heterozygous for the mutation. The pregnancy was subsequently terminated and a malformed fetus was delivered with prominent forehead, a flattened nasal bridge, a narrow and short trunk, a protuberant abdomen, bilateral postaxial polydactyly and syndactyly of the hands and feet, and micromelic limbs. No facial cleft or genital abnormality was noted. The radiograph was consistent with SRPS III. ConclusionPolydactyly, micromelia, metaphyseal spurs, widened humeral metaphyses, and shortened ribs can be prominent prenatal ultrasound findings of SRPS III. The present case provides evidence for a correlation of a mutation in the NEK1 gene with SRPS III.

Peters anomaly with post axial polydactyly, bilateral camptodactyly and club foot in a Kenyan neonate: a case report

IntroductionA case of bilateral Peters anomaly with bilateral post axial polydactyly, bilateral camptodactyly, and club foot was examined in a neonatal Kenyan baby girl of African descent who had been delivered in the hospital and admitted to the newborn unit. She died aged five days. There are no cases of Peters anomaly recorded in Africa according to a literature search. In addition, available data point to the majority of the principal associations in Peters anomaly to be genitourinary anomalies, making this case a rare one in its isolated collection of musculoskeletal associations.Case presentationA Kenyan baby girl of African descent who was born through a caesarean section presented in the new born unit of our hospital with bilateral corneal opacities, bilateral polydactyly, camptodactyly and club foot.ConclusionThis is a rare case of Peters anomaly and its association with multiple musculoskeletal abnormalities makes it special.

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation

We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1 month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver-kidney transplantation was performed at the age of 4 years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnancy.