Search Results (25)

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID. Full article

Introduction: Fraser syndrome (FS) is a rare autosomal recessive disorder. However, the clinical presentation remains variable. Diagnosis is based on a series of major and minor clinical criteria that can be supported by genetic tests. Prenatal diagnosis remains challenging. Methods: Herein, we reported a case of Fraser syndrome that was missed by ultrasound and diagnosed late at birth. The newborn presented with cryptophthalmos–syndactyly syndrome and absence of the right kidney. Based on a literature review of articles from the past 20 years, the authors found 40 cases, including indexed cases on PUBMED, Scopus, Web of Science, and Scholar using keywords related to “Fraser syndrome”. Through this report, we discuss the polymalformative syndrome, the clinical and paraclinical aspects of this syndrome, its clinical management, and highlight the importance of prenatal diagnosis in the light of research. Results: Our study found that consanguine parents (41.0%) were increasing risk factors for FS and poor socio-economic status delayed the early detection of FS. Among the 40 cases, 27 cases were detected postnatally. More than half of the cases resulted in poor perinatal outcomes. The common findings were cryptophthalmos (87.5%), syndactyly (87.5%), renal abnormalities (55.5%), and genital abnormalities (42.5%). Conclusions: A prenatal diagnosis of Fraser syndrome is still difficult. Thus, a counseled ultrasound scan at a specialized center should be recommended in suspected cases with indirect signs and risk factors of consanguinity. Full article

Background: Syndactyly, the congenital fusion of digits, compromises hand function and esthetics. Although surgical separation is the standard treatment, the optimal timing of the intervention remains controversial. Methods: We prospectively analyzed 20 pediatric patients (86 operated fingers) undergoing syndactyly repair, comparing early (≤24 months) versus delayed (>24 months) surgery. Outcome measures included range of motion (ROM) at the metacarpophalangeal (MP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints; complications (synostosis, nail deformities, finger length disparity, webbing); and patient-reported outcomes assessed by the Disabilities of the Arm, Shoulder, and Hand (DASH) and overall esthetic satisfaction scores. Results: The median age at surgery was 31 months (IQR25/75: 24.75–36.5), with a median follow-up of 72 months (IQR25/75: 42.0–86.25). Notably, digits III (28.24%) and IV (29.41%) were predominantly affected. Delayed surgery resulted in significantly improved MP ROM (90.98° ± 8.44° vs. 73.13° ± 22.37°, p = 0.004) and DIP ROM (76.28° ± 22.24° vs. 67.19° ± 22.78°, p = 0.028), with a non-significant trend toward better PIP ROM (93.00° ± 25.18° vs. 77.37° ± 30.29°, p = 0.075). Furthermore, the incidence of synostosis was markedly reduced in the delayed surgery group (6.0% vs. 38.9%, p = 0.001). Despite superior joint function associated with delayed intervention, early surgery patients reported higher satisfaction with cosmetic results (3.00 vs. 2.80, p = 0.028), while the DASH scores remained comparably low between groups (0.00 vs. 0.24, p = 0.141). Finger length disparities and webbing were minimal. Conclusions: Our study challenges the conventional advocacy for early syndactyly repair, by demonstrating that delaying surgery beyond 24 months significantly enhances joint mobility and reduces the synostosis rate. However, the higher satisfaction observed as a result of early intervention suggests that surgical timing should be individualized for affected fingers, joints, and severities to balance the functional and cosmetic outcomes. Further studies are needed to define the optimal surgical timing and techniques for pediatric syndactyly. Full article

Ellis-van Creveld syndrome (EvC) is a rare genetic disorder (7:10,000,000) caused by biallelic pathogenic variants in EVC and EVC2, which are located in close proximity on chromosome 4p16.2 in a divergent orientation. These genes encode ciliary complex proteins essential for Hedgehog signaling. EvC is characterized by congenital heart disease (CHD), postaxial polydactyly, and rhizomelic shortening. We present a case of a female newborn from southeast Mexico carrying a novel missense variant in EVC, which is aligned with a systematic review aimed at exploring genotype–phenotype correlations in EVC-related EvC. A PRISMA-based systematic review was conducted in PubMed, Web of Science, and OVID/Medline (until December 2024). Studies reporting EVC variants in EvC were included. Data extraction and quality assessment were performed independently by four reviewers, and genotype–phenotype correlation analysis was conducted. Fifteen studies (n = 66 patients) met the inclusion criteria. The most prevalent features were postaxial polydactyly (95.5%), nail hypoplasia (68.2%), and CHD (66.7%) with atrioventricular canal as the most frequent subtype. Fifty-five distinct EVC variants across 132 alleles were identified, predominantly affecting the N-terminal region (first 699 amino acids). They were syndactyly correlated with pathogenic variants in exons 6, 12, and 13, which were proximal to the second and third coiled-coil domains. This review confirms the key clinical features of EVC-related EvC and highlights genetic heterogeneity. The correlation between syndactyly and specific exonic variants suggests potential genotype–phenotype associations, warranting further functional studies. Full article

Objectives: Monitoring pregnancies is essential for community well-being. However, not all pregnancies progress normally, and some require termination. The objective was to emphasize the importance of trust in the doctor–patient relationship during this challenging time for expectant parents. Case report: During fetal morphology examination, parents were warned of a poor fetal prognosis, prompting a request for pregnancy termination. They consulted another specialist, who reassured them that the fetus appeared normal, though slightly hypotrophic. The child was born at 35 weeks gestational age and admitted to the neonatal ICU level III in an impaired general condition and polymalformative syndrome (triangular facies, epicanthic eyes, hypertelorism, retrognathia, low base of the nose, triangular mouth, lips angled downward, and small, dysplastic, and low-set earlobes). The child had syndactyly of fingers and toes. Cytogenetic analysis revealed a karyotype of 69, XX, +mar. The indirect DNA analysis revealed that the third gonosome is a Y chromosome. Death occurred 30 days post delivery, following severe dyspnea and bronchial obstruction, with desaturation and bradycardia. Conclusions: Triploid pregnancies are usually lost in the first trimester; however, very rarely, live births can occur. Hope for a positive outcome encouraged parents to continue the pregnancy, leading to a profoundly sorrowful experience and added strain on the healthcare system. Complex decisions put pressure on the patient–doctor relationship, as misplaced hope can impact both parties. Expectant parents facing difficult diagnoses require attentive support during this challenging time, grounded on a foundation of trust between doctor and patient. Full article

Objectives: This systematic review provides an in-depth analysis of the surgical treatment of foot syndactyly, offering insights into the various options and their applications. The objective is to improve treatment standardization and optimize patient care in cases of foot syndactyly. Methods: By synthesizing the existing evidence, the authors propose a treatment algorithm to guide clinicians in decision-making, considering the type and severity of syndactyly. Results: Sixteen articles were included in the systematic review, comprising a total of 395 patients. The mean age at surgery was 6 years (range: 0.66–23 years). Clinical outcomes were assessed after a mean follow-up of 33.2 months (range: 4–82.8 months). Several surgical procedures were described in the included articles. Conclusions: Continued research efforts and collaborative initiatives are crucial to further refine our understanding of complications and enhance surgical practices in foot syndactyly procedures. Full article

Background/Objectives: Arterial Tortuosity Syndrome (ATS) is a rare, autosomal recessive connective tissue disorder characterized by arterial twists, abnormal bulges, constriction, and tears. Patients have distinctive features and disease manifestations. The syndrome’s full clinical spectrum and course remain incompletely understood. Methods: We sought to review the medical records of Qatari patients who had ATS. The cohort study included 21 patients who were genetically confirmed by mutations in the SLC2A10 gene. Results: The study revealed that the NM_030777.4(SLC2A10):c.243C>G (p.Ser81Arg) mutation in SLC2A10 leads to mild outcomes of no mortality and less morbidity. Novel features such as a flat philtrum, bulbous noses, bilateral nasolacrimal duct obstruction, allergic conjunctivitis, latent nystagmus, café au lait spots, eczema, dermatitis, allergic reactions, bilateral temporomandibular joint cysts, bilateral syndactyly (toes), parapelvic cysts, kidney malrotation, vesicoureteral reflux, and nephrolithiasis were identified in our cohort. Furthermore, rare features previously documented in a limited number of patients, including leg length discrepancy, epilepsy, and migraine headaches, were also observed in our cohort. Conclusions: Our data contributes new insights into the life course of ATS in Qatari patients. These findings underscore the importance of effective education strategies through repeated counseling aimed at preventing cousin marriage and the syndrome within the cohort. Full article

Genetic disorders are caused by a hereditary change in the structure of DNA that may hurt the health and life of animals. Several recessive haplotypes and a few causative mutations are known in Holstein Friesian cattle: CDH (Holstein cholesterol deficiency), haplotypes with a homozygous deficiency in Holstein (HH1, HH3, HH4, HH5, HH6, HH7), BLAD (bovine leukocyte adhesion deficiency), DUMPS (deficiency of uridine monophosphate synthase), FXI (factor XI deficiency), HHM (mule foot, syndactyly), and BC (citrullinaemia). From a breeding point of view, these genetic diseases have highly negative effects and are a significant problem for breeders, exposing them to economic losses and hurting animal welfare. This study aimed to characterize the Polish population of Holstein Friesian dairy cattle, considering the carrier status of twelve selected genetic defects. This study was based on genotype data collected from 78,884 cows and 691 bulls of the Holstein Friesian variety. The studies were performed using Illumina Infinium microarrays. Among both bulls and cows, the highest numbers of carriers were detected for HH5 (appropriately 6.7% and 5.4%). The lowest numbers of carriers were detected for DUMPS, factor XI, and HHM. The study revealed one calf suffering from cholesterol deficiency. Full article

Conventional radiography is widely used for postmortem foetal imaging, but its role in diagnosing congenital anomalies is debated. This study aimed to assess the effectiveness of X-rays in detecting skeletal abnormalities and guiding genetic analysis and counselling. This is a retrospective analysis of all post-abortion diagnostic imaging studies conducted at a centre serving a population of over 300,000 inhabitants from 2008 to 2023. The data were analysed using descriptive statistics. X-rays of 81 aborted foetuses (total of 308 projections; mean: 3.8 projections/examination; SD: 1.79) were included. We detected 137 skeletal anomalies. In seven cases (12.7%), skeletal anomalies identified through radiology were missed by prenatal sonography. The autopsy confirmed radiological data in all cases except for two radiological false positives. Additionally, radiology failed to identify a case of syndactyly, which was revealed by anatomopathology. X-ray is crucial for accurately classifying skeletal abnormalities, determining the causes of spontaneous abortion, and guiding the request for genetic counselling. Formal training for both technicians and radiologists, as well as multidisciplinary teamwork, is necessary to perform X-ray examinations on aborted foetuses and interpret the results effectively. Full article

Apert syndrome is an inherited condition with autosomal dominant transmission. It is also known as acrocephalosyndactyly type I, being characterized by a syndrome of craniosynostosis with abnormal head shape, facial anomalies (median hypoplasia), and limb deformities (syndactyly, rhizomelic shortening). The association can suspect the prenatal diagnosis of these types of anomalies. The methodology consisted of revising the literature, by searching the PubMed/Medline database in which 27 articles were selected and analyzed, comprising 32 cases regarding the prenatal diagnosis of Apert syndrome. A series of ultrasound parameters, the anatomopathological abnormalities found, the obstetric results, and the genetic tests were followed. The distribution of imaging results (US, MRI) identified in the analyzed cases was as follows: skull-shaped abnormalities were evident in 96.8% of cases, facial abnormalities (hypertelorism 43.7%, midface hypoplasia 25%, proptosis 21.8%), syndactyly in 87.5%, and cardiovascular abnormalities in 9.3%. The anomalies detected by the ultrasound examination of the fetus were confirmed postnatally by clinical or gross evaluation or imaging. The management of these cases requires an early diagnosis, an evaluation of the severity of the cases, and appropriate parental counseling. Full article

Background: The diagnostic process for children and adults manifesting a constellation of ectodermal abnormalities requires a conscientious and highly structured process. Material and Methods: Six girls (aged 6-month–8 years) and two older girls (aged 13 and 16 years) were born with variable skin lesions of varying intensities associated with noticeable cranial and skeletal malformation complexes. Cleft palate, abnormal dentition, and multiple papillomas were evident around the mouth, mostly bilateral but asymmetrical in the upper and lower limbs. Exaggerated frontal bossing (macrocephaly) and in some patients’ microcephaly with variable skeletal defects of the craniocervical junction and diverse forms of lower limb deformities of syndactyly, polydactyly, and split-hand/foot (ectrodactyly). Results: All patients manifested the constellation of abnormalities with variable intensities ranging between alopecia, papillomas, striated skin pigmentations split-hand/foot (ectrodactyly), and major bone defects. A 3D reconstruction CT scan was directed mainly to further scrutinize children with pseudo cleft lip, submucus cleft, and cleft palate. Interstingly, they manifested massive demineralization of the cranium associated with severely defective dentition. A spine 3D reconstruction CT scan in two girls showed marked cystic cavitation of the upper jaw associated with excessive cavitation of the mastoid, causing tremendous frailty of the mastoid bone. A 3D sagittal CT scan showed odontoid hypoplasia and C1-2 instability associated with the rudimentary atlas and the persistence of extensive synchondrosis of the cervico-thoracic spine. The overall clinical and radiological phenotypic characterizations were consistent with the diagnosis of focal dermal hypoplasia (Goltz syndrome). Two children manifested heterozygous mutations in the PORCN gene, chromosome Xp11. Conclusions: In this study, we believe it’s a good opportunity to share our novel scientific findings, which are intriguing and can be inspiring to readers, and to further aid the current scientific literature with exceptionally new unveiling results. This is the first comprehensive study of the cranio-skeletal malformation complex in children with GS. Full article

Syndactyly is the most common congenital malformation of the hand, leading to the fusion of the digits and frequently affecting the ring and middle fingers. The incidence is 1 out of 2500 children, predominantly occurring in boys and Caucasians. Clinically, the malformation may present as a soft tissue or bony fusion, resulting in the union of the fingers characterised as complete or incomplete. This fusion may involve the phalanges but may also extend to the carpal/tarsal bones, even to the metacarpal or metatarsal level, rarely to the distal end of the forearm and lower leg. The malformation is mostly isolated but may occur together with other disorders or malformations such as synostosis, acro-syndactyly, cleft hand, clinodactyly, or polydactyly. Syndromic syndactyly can be observed in cases of Apert syndrome, Poland’s syndrome, Pfeiffer syndrome, and many others. A girl born in June of 2019 was diagnosed with congenital malformation of the right hand at birth—affecting the right middle, ring, and little fingers, respectively. After X-ray imaging, the fusion of the third and fourth proximal phalanges to a common metacarpal was identified, forming a unique diagnosis of clino-syndactyly with metacarpal aplasia. Surgical intervention was advocated for, including a wedge osteotomy to correct the synchondrosis at the phalangeal base and a dorsal flap to close the interdigital space created during the correction of the III and IV. fingers. A trapezoid flap for the release of the syndactyly of the IV and V. fingers was applied. The paper aims to present this surgical correction and its results regarding an atypical case of syndactyly with clinodactyly and metacarpal aplasia. Full article

Maternal smoking during pregnancy has been associated with adverse effects on foetal development, including congenital limb anomalies. This systematic review aimed to provide an updated assessment of the association between maternal smoking during pregnancy and the risk of congenital limb anomalies. A systematic search was conducted to identify relevant studies published up to February 2023. Studies reporting on the relationship between maternal smoking during pregnancy and congenital digital anomalies or congenital limb reduction defects were included. Two independent reviewers screened the studies, extracted data, and assessed the quality of the included studies. Meta-analyses were performed to estimate the pooled odds ratios with 95% confidence intervals using fixed and random-effects models. In total, 37 publications comprising 11 cohort and 26 case-control studies were included in the systematic review. The meta-analysis demonstrated a significant increased risk of congenital limb reduction defects (pooled OR: 1.27, 95% CI: 1.18–1.38) in infants born to mothers who smoked during pregnancy. Similarly, a significant relationship was observed for the development of polydactyly/syndactyly/adactyly when considered as a single group (pooled OR: 1.32, 95% CI: 1.25–1.40). Yet, in contrast, no significant association was observed when polydactyly (pooled OR: 1.06, 95% CI: 0.88–1.27) or syndactyly (pooled OR: 0.91, 95% CI: 0.77–1.08) were considered individually. This systematic review provides updated evidence of a significant relationship between maternal smoking during pregnancy and increased risk of congenital limb anomalies. These findings highlight the potential detrimental effects of smoking on foetal limb development and underscore the importance of smoking cessation interventions for pregnant women to mitigate these risks. Full article

AMACO (VWA2 protein), secreted by epithelial cells, is strongly expressed at basement membranes when budding or invagination occurs in embryos. In skin, AMACO associates with proteins of the Fraser complex, which form anchoring cords. These, during development, temporally stabilize the dermal–epidermal junction, pending the formation of collagen VII-containing anchoring fibrils. Fraser syndrome in humans results if any of the core members of the Fraser complex (Fras1, Frem1, Frem2) are mutated. Fraser syndrome is characterized by subepidermal blistering, cryptophthalmos, and syndactyly. In an attempt to determine AMACO function, we generated and characterized AMACO-deficient mice. In contrast to Fraser complex mutant mice, AMACO-deficient animals lack an obvious phenotype. The mutually interdependent basement membrane deposition of the Fraser complex proteins, and the formation of anchoring cords, are not affected. Furthermore, hair follicle development in newborn AMACO-deficient mice showed no gross aberration. Surprisingly, it appears that, while AMACO is a component of the anchoring cords, it is not essential for their formation or function. Full article

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means. Full article