Limb Anomalies Research Articles

Prenatal Diagnosis and Management of Thrombocytopenia-Absent Radius Syndrome.

Prenatal Diagnosis and Management of Thrombocytopenia-Absent Radius Syndrome.

Generation of a mouse model of the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies syndrome.

Heterozygous variants in bromodomain and plant homeodomain containing transcription factor (BPTF) cause the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) syndrome (MIM#617755) characterized by intellectual disability, speech delay and postnatal microcephaly. BPTF functions within nucleosome and remodeling factor (NURF), a complex comprising sucrose non-fermenting like (SNF2L), an Imitation SWItching (ISWI) chromatin remodeling protein encoded by the SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1) gene. Surprisingly, ablation of Smarca1 resulted in mice with enlarged brains, a direct contrast to the phenotype of NEDDFL patients. To model the NEDDFL syndrome, we generated forebrain-specific Bptf knockout (Bptf conditional Knockout (cKO)) mice. The Bptf cKO mice were born in normal Mendelian ratios, survived to adulthood but were smaller in size with severe cortical hypoplasia. Prolonged progenitor cell cycle length and a high incidence of cell death reduced the neuronal output. Cortical lamination was also disrupted with reduced proportions of deep layer neurons, and neuronal maturation defects that impaired the acquisition of distinct cell fates (e.g. COUP-TF-interacting protein 2 (Ctip2)+ neurons). RNAseq and pathway analysis identified altered expression of fate-determining transcription factors and the biological pathways involved in neural development, apoptotic signaling and amino acid biosynthesis. Dysregulated genes were enriched for MYC Proto-Oncogene, BHLH Transcription Factor (Myc)-binding sites, a known BPTF transcriptional cofactor. We propose the Bptf cKO mouse as a valuable model for further study of the NEDDFL syndrome.

Acro-callous syndrome: A case report.

A malformative syndrome of unknown prevalence, the diagnosis is based on morphological ultrasound and magnetic resonance imaging of the fetus. The transmission is genetic and autosomal recessive. Courtnes has established 4 diagnostic criteria to affirm the acrocal syndrome and to eliminate the amalgam with other polymalformative syndrome.

Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (MCAP): A Rare Dynamic Genetic Disorder

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is an uncommon malformation syndrome, characterized by primary megalencephaly, capillary malformations of the midline face and body, or distal limb anomalies such as syndactyly and polymicrogyria. Herein, we report a young male child, who presented with complaints of increasing head size, delay in speech, and one episode of focal seizure with distinctive morphological and neuroradiological manifestations which led to the diagnosis of MCAP. We have also reviewed recently published literature and the various diagnostic criteria proposed by authors to achieve the early clinical diagnosis of these patients in the outpatient department.

Prenatal diagnosis of acrania/exencephaly/anencephaly sequence (AEAS): additional structural and genetic anomalies.

To analyse additional structural and genetic anomalies in fetuses with acrania/exencephaly/anencephaly sequence (AEAS). A retrospective analysis of 139 fetuses with AEAS diagnosed between 2006 and 2020 in a single tertiary referral ultrasound department. The median gestational age at diagnosis decreased from 15weeks in 2006 to 13weeks in 2020 (- 0.21 per each year; p = 0.009). In 103 fetuses, the defects were limited to the neural tube (NTD) (74.1%), in 36 fetuses (25.9%), there were additional structural non-NTD anomalies. The most common were ventral body wall defects present in 17.8% (23/139), followed by anomalies of the limbs (7.2%; 10/139), face (6.5%; 9/139) and heart (6.5%; 9/139). Genetic anomalies were diagnosed in 7 of the 74 conclusive results (9.5%; 7/74; trisomy 18, n = 5; triploidy, n = 1; duplication of Xq, n = 1). In univariate logistic regression models, male sex, limb anomalies and ventral body wall defects significantly increased the risk of genetic anomalies (OR 12.3; p = 0.024; OR 16.5; p = 0.002 and OR 10.4; p = 0.009, respectively). A significant number of fetuses with AEAS have additional structural non-NTD anomalies, which are mostly consistent with limb body wall complex. Genetic abnormalities are diagnosed in almost 10% of affected fetuses and trisomy 18 is the most common aberration. Factors that significantly increased the odds of genetic anomalies in fetuses with AEAS comprise male sex, limb anomalies and ventral body wall defects.

An unusual association: duodenal atresia and situs inversus incompletes-a case report and discussion

Coming across a number of duodenal atresia in daily practice any paediatric surgeon may conclude that it’s one of the most technically challenging small gut atresia with variations of pathology that has an incidence of 1 in 4000 or 5000 live births. It has marked association with a number of conditions like downs syndrome (trisomy 21) being on crest, accounting for 20-40% of cases. Other prominent associations include VACTERL (vertebral, anotectal malformation, cardiac, tracheo esophageal, renal, limb) anomalies, concurrent other small gut atresias, preduodenal portal vein. A relatively rare association we have come across recently has been situs transverus co existing with duodenal atresia that prompted us to rummage through literature for similar cases embarking us to publish our own finding as very little has been said so far in this regard.

Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem disorder caused by compound heterozygous or homozygous variants in the gene OTUD6B. Herein, we describe novel pathogenic compound heterozygous variants in OTUD6B identified via whole-exome sequencing in an index case exhibited the severe IDDFSDA phenotype. The potential pathogenicity of the novel frameshift and missense variants in the index case was investigated using in silico tools. The truncating frameshift variant in one allele was predicted to undergo degradation via nonsense-mediated decay of the mRNA molecule. To predict the severity of the damage to the protein caused by the missense variant in the other allele and its effects on phenotypic severity was further investigated together with a previously reported first homozygous missense variant in the same domain in another patient with a less severe IDDFSDA phenotype using structural modeling and molecular dynamics (MD) simulations for the first time. Based on these analyzes, it is anticipated that Tyr216Cys in the earlier reported case with less severe IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the presented index case with the severe IDDFSDA phenotype will lead to significant distortion in the overall fold of OTUD6B. Our findings suggest that compound LOF and ultrarare missense variants may be contribute to the underlying variability expressivity associated with this disorder. In conclusion, our findings support that the clinical severity could be related with the predicted functional severity of the variations in OTUD6B. However, additional functional studies are required.

The incidence and spectrum of congenital hand differences in patients with Fanconi anaemia: analysis of 48 patients.

We analysed the spectrum of congenital hand differences in a cohort of patients with Fanconi anaemia (FA). Data of 48 FA patients at the National Cancer Institute were reviewed focusing on age at diagnosis, type and severity of limb difference and any potential association with other known clinical anomalies that are part of the FA phenotype, specifically VACTERL-H and PHENOS. Twenty-eight patients had an upper limb difference, which always included thumb hypoplasia. Twenty-three patients had bilateral upper limb differences, including varying combinations and severities of thumb hypoplasia, radial dysplasia and thumb duplication. Patients with a limb difference were diagnosed at a younger age (<2years: 15/28 with limb anomaly versus 4/20 without a limb anomaly). However, 7/28 with limb anomalies, usually thumb hypoplasia, were not diagnosed until after 6years of age. This study demonstrates the broad spectrum of radial ray anomalies within the FA phenotype along with the possibility of either unilateral or bilateral upper limb differences and adds further merit to consideration of screening for FA in all cases of radial ray anomaly.Level of evidence: II.

SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome.

Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies. In this report, we summarized the current evidence to determine a possible genotype-phenotype association among NS individuals. Twenty-four articles comprising of 84 NS (including 9 patients with a severe form of NS [Rodriguez syndrome]) patients were examined, of which 76% were caused by variants in SF3B4 (OMIM *605593, Splicing Factor 3B, Subunit 4). Within the SF3B4 gene, variants located in exon 3 commonly occurred (20%) from a total identified variant, while hotspot location was identified in exon 1 (12%), and primarily occurred as frameshift variants (64%). Thirty-five distinct pathogenic variants within SF3B4 gene were identified with two common sites, c.1A > G and c.1060dupC in exons 1 and 5, respectively. Although no significant genotype-phenotype association was found, it is notable that patients with frameshift SF3B4 variants and predicted to lead to nonsense-mediated RNA decay (NMD) of the transcripts tended to have a more severe clinical manifestation. Additionally, patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations. Taken together, this article summarizes the pathogenic variants observed in SF3B4 and provides a possible genotype-phenotype relationship in this disease.

Neuroimaging appearance of hypothalamic hamartomas in monozygotic twins with Pallister-Hall syndrome: case report and review of the literature

BackgroundPallister-Hall syndrome (OMIM #146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include: characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects.Case presentationWe report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins.Discussion and conclusionsWe review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas’ sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome.Graphical

Congenital hand differences: Prevalence among school going children in Mangalore city

IntroductionCongenital upper extremity anomalies are present in 1 in every 626 live births. They are mostly isolated phenomena but can also be associated with other congenital deformities and may be the only external feature of a syndromic entity. A study on it in India, especially the southern part, is limited. As the quality of life gets compromised, there is a need to identify and diagnose the anomalies at the earliest. Current study is aimed to identify congenital hand deformities among the school-going population in the coastal city of Mangalore.A cross sectional study was done in the schools in Mangalore city. By simple random sampling, 35 out of 70 schools were selected, and 10,000 children in age group of 5–15years were included by non-probability sampling after taking their consent from school authorities and parents. Data was analyzed by FISHER's exact test. Result41 cases of congenital hand anomalies were identified with 23 boys and 18 girls. Twelve children had bilateral involvement. 28 cases where of polydactyly followed by four cases of acrosyndactyly with constriction band, three cases each of syndactyly and camptodactyly,one case of lobster hand and one case each of transverse deficiency of hand and forearm. Associated lower limb anomalies were seen in 9 cases. Familial associations were seen in 6 cases, and 1 polydactyly child had a downs syndrome association. All cases[4cases] of acrosyndactyly with constriction band syndrome were operated at childhood, and most other deformities were unoperated. Polydactyly[duplication] tops the list and needs further studies to look into genetic, environmental, and regional variations. ConclusionThe prevalence of congenital hand difference in Mangalore is 41 per 10000 school-going children examined. A future national registry in India should be the way forward to assess the true prevalence and risk factors.

Genetic and Phenotypic Spectrum of KBG Syndrome: A Report of 13 New Chinese Cases and a Review of the Literature.

KBG syndrome (KBGS) is a rare autosomal dominant inherited disease that involves multiple systems and is associated with variations in the ankyrin repeat domain 11 (ANKRD11) gene. We report the clinical and genetic data for 13 Chinese KBGS patients diagnosed by genetic testing and retrospectively analyse the genotypes and phenotypes of previously reported KBGS patients. The 13 patients in this study had heterozygous variations in the ANKRD11 gene, including seven frameshift variations, three nonsense variations, and three missense variations. They carried 11 variation sites, of which eight were previously unreported. The clinical phenotype analysis of these 13 patients and 240 previously reported patients showed that the occurrence rates of craniofacial anomalies, dental anomalies, global developmental delays, intellectual disability/learning difficulties, limb anomalies, and behavioural anomalies were >70%. The occurrence rates of short stature, delayed bone age, and spinal vertebral body anomalies were >50%. The frequency of global developmental delays and intellectual disability/learning difficulties in patients with truncated ANKRD11 gene variation was higher than that in patients with missense variation in the ANKRD11 gene (p < 0.05). Collectively, this study reported the genotypic and phenotypic characteristics of the largest sample of KBGS patients from China and discovered eight new ANKRD11 gene variations, which enriched the variation spectrum of the ANKRD11 gene. Variation in the ANKRD11 gene mainly caused craniofacial anomalies, growth and developmental anomalies, skeletal system anomalies, and nervous system anomalies. Truncated variation in the ANKRD11 gene is more likely to lead to global growth retardation and intellectual disability/learning difficulties than missense variation in ANKRD11.

Further Characterization of SMC1A Loss of Function Epilepsy Distinct From Cornelia de Lange Syndrome.

Cornelia de Lange syndrome is a rare developmental malformation syndrome characterized by small stature, limb anomalies, distinctive facial features, developmental delays, and behavioral issues. The diagnosis of Cornelia de Lange syndrome is made clinically or on the basis of an identified variant in one of the genes associated with Cornelia de Lange syndrome. SMC1A variants are the cause of 5% of the cases of Cornelia de Lange syndrome. SMC1A is located on the X-chromosome and is thought to escape X-inactivation in some females. Patients with SMC1A variants are being increasingly identified through panel testing or exome sequencing without prior clinical suspicion of Cornelia de Lange syndrome. In general, intractable epilepsy is not considered a prominent feature of Cornelia de Lange syndrome, yet this is found in these patients with SMC1A variants. Here we report on a series of patients with SMC1A variants and intractable epilepsy. In contrast to patients with typical SMC1A-associated Cornelia de Lange syndrome, all of the identified patients were female, and when available, X-inactivation studies were highly skewed with truncating variants. We describe the medical involvement and physical appearance of the participants, compared to the diagnostic criteria used for classical Cornelia de Lange syndrome. We also report on the clinical characteristics of the epilepsy, including age of onset, types of seizures, electroencephalographic (EEG) findings, and response to various antiepileptic medications. These findings allow us to draw conclusions about how this population of patients with SMC1A variants fit into the spectrum of Cornelia de Lange syndrome and the broader spectrum of cohesinopathies and allow generalizations that may impact clinical care and, in particular, epilepsy management.

Congenital Disorders of the Pediatric Thumb.

Surgical timing for pediatric trigger thumb treatment is controversial for numerous reasons including the potential for spontaneous resolution, the possibility of bilateral involvement, and anesthesia concerns regarding the developing brain. Hence, a reasonable approach is to delay the surgical procedure until the patient is ≥3 years of age. Preaxial polydactyly is usually unilateral and sporadic, with the most common reconstruction method consisting of excision of the diminutive thumb with preservation and soft-tissue reconstruction of the dominant thumb. The surgical procedure is typically performed around the patient age of 1 year to decrease the risks of anesthesia but allow reconstruction prior to the development of a tip-to-tip pinch. Triphalangeal thumb and thumb hypoplasia are often found in the setting of systemic anomalies such as Holt-Oram syndrome, thrombocytopenia absent radius syndrome, Fanconi anemia, VACTERL (vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophageal fistula, renal defects, and limb anomalies), and/or Blackfan-Diamond anemia. As such, patients should receive adequate workup for these entities. A surgical procedure should be performed only once patients have been medically cleared. The status of the carpometacarpal joint in thumb hypoplasia determines whether reconstruction with first web space deepening, collateral ligament stabilization, and opponensplasty compared with index pollicization is performed.

EP268: DVL2 – A newly identified genetic cause of Robinow syndrome?

Robinow syndrome is a clinically recognizable syndrome characterized by skeletal, genitourinary, and craniofacial findings and, less frequently, cardiac anomalies. The clinical picture is distinctive with short-limbed short stature, distal limb anomalies with broadening of the thumbs and great toes, and craniofacial features including frontal bossing, wide spaced and prominent eyes, and a depressed nasal root with short nose. It is a heterogeneous condition with six established Robinow-associated genes to date - ROR2, NXN, WNT5A, FZD2, DVL1, and DVL3 - all of which are involved in the well-described WNT/planar cell polarity signaling pathway.

Anesthetic implications in Poland syndrome

: Poland Syndrome (PS) is a rare birth defect described as unilateral absence of pectoralis major, pectoralis minor, serratus anterior and external oblique muscles and upper limb anomalies. It is also associated with variable thoracic muscle, chest wall and lower limb deformities. Dextrocardia, diaphragmatic hernia, liver and GIT anomalies, renal agenesis have also been reported in literature. In addition, there is association of PS with patient’s susceptibility to malignant hyperthermia (MH). For patients requiring general anesthesia, special preparation and execution are recommended.We share our anesthesia management in a child with PS posted for ear reconstruction and described that patients with PS requires special preparation and attention in intraoperative and post-operative period. In patients of PS requiring general anesthesia adequate preparation must be made keeping in mind not only the anatomical changes but also the much higher possibility of MH in such patients.

Hybrid Renal Cortical Imaging with Single Photon Emission Computerized Tomography/Computed Tomography in a Pediatric Patient with Severe Caudal Regression Syndrome

Caudal regression syndrome (CRS) or sacral agenesis is a rarely seen malformation with a varying degree of structural abnormalities, including multiorgan system dysfunctions, reported with higher incidence among children of mothers with diabetes, as in this case. Spinal anomalies can range from coccyx hemiagenesis to the total absence of lower lumbar vertebrae and sacrum in most severe cases. Herein, we have presented a 9-year-old patient with CRS who had renal failure. Technetium-99m dimercaptosuccinic acid renal scintigraphy revealed bilaterally non-functioning kidneys with no renal cortical uptake. Renal anomalies in CRS with vertebral, anorectal, cardiac, trachea-esophageal, renal, and limb anomalies association include one-sided renal agenesis, multicystic dysplastic kidneys, and ureter duplications.

Morphological Variations of Sacrum in Adult Indian Population

Introduction: The sacrum is considered as a highly variable bone. Several morphological variations have been documented which exhibit differences in the frequency of occurrence and morphological characteristics in various study populations. Variant anatomy of the sacrum may be associated with backache, enuresis, neurological anomalies of the lower limb and functional disorders of lower urinary tract. Purpose: The purpose of this study was to identify and describe morphological variations of sacrum in Indian population and enable comparison with different populations. Materials and Methods: The study was conducted on 108 dry adult human sacra and morphological characteristics and variations were noted. Results: Sacral skewness was observed in 7.4% sacra with right sided skewness being predominant. The presence of accessory auricular surface (AAS) was noted in 13% sacra which was at the level of S3 vertebra in most sacra. Spina bifida (SB) was observed in 11.1% sacra and it was most commonly located at S1 vertebral level. Furthermore, the lumbo-sacral transitional vertebra (TV) was documented in 10.2% sacra. Conclusions: Sacrum displays numerous variations in Indian population such as skewness, AAS, SB and TV. Thorough knowledge of morphological characteristics and variations of sacrum is vital and should be contemplated during diagnosis and treatment of sacrum-related diseases. KEY WORDS: Accessory auricular surface, Spina bifida, Transitional vertebra, Sacral skewness, Variations.

Meckel-Gruber Syndrome with Multiple Congenital Anomalies- A Rare Lethal Case

Meckel-Gruber Syndrome (MGS), a rare autosomal recessive malformation syndrome with incidence of one per 13,250-140,000 live birth. It is a classical triad of occipital encephalocele, infantile polycystic kidneys and postaxial polydactyly with associated multiple congenital anomalies. It leads to the death of foetus in utero or shortly after birth. Most important diagnostic tools for MGS are antenatal ultrasonography and chromosomal study. A 3.14 kg dead female foetus was delivered from 19-year-old primigravida on the first visit to hospital with full term pregnancy. Sonography revealed no cardiac activity of the foetus in utero. Termination of pregnancy was done by the decision of obstetrician and consent of patient. Gross multiple anomalies along with microanatomical changes were noticed in foetus. Typical triad of polycystic kidney resulted to oligohydramnios, protrusion of meninges with brain tissue resulted to occipital encephalocele and limb anomalies might be hereditary or due to mutational changes. Histological changes were supportive of gross anatomical changes and ultrasound scan findings. Major changes as multiple cystic lesions in kidney, non functional alveoli in lungs and fibrous tissues with deranged hepatocytes in foetal liver were noticed. Concluding through all investigations and family history might confirm the diagnosis and help in further treatment or termination of pregnancy timely and directs for further genetic and chromosomal counselling.

Acrorenal Syndrome: Unusual Association of Limb and Renal Anomaly.

Acrorenal Syndrome: Unusual Association of Limb and Renal Anomaly.