Epidemiology of congenital polydactyly and syndactyly in Hunan Province, China.

OBJECTIVE: To describe the prevalence and epidemiology of congenital polydactyly and syndactyly in Hunan Province, China, 2016-2020. METHODS: Data were obtained from the Birth Defects Surveillance System in Hunan Province, China, 2016-2020. Prevalence of birth defects (polydactyly or syndactyly) is the number of cases per 1000 births (unit: ‰). Prevalence and 95% confidence intervals (CI) were calculated by the log-binomial method. Chi-square trend tests (χ2trend) were used to determine trends in prevalence by year. Crude odds ratios (ORs) were calculated to examine the association of each demographic characteristic with polydactyly and syndactyly. RESULTS: Our study included 847,755 births, and 14,459 birth defects were identified, including 1,888 polydactyly and 626 syndactyly cases, accounting for 13.06% and 4.33% of birth defects, respectively. The prevalences of total birth defects, polydactyly, and syndactyly were 17.06‰ (95%CI: 16.78-17.33), 2.23‰ (95%CI: 2.13-2.33), and 0.74‰ (95%CI: 0.68-0.80), respectively. Most polydactyly (96.77%) and syndactyly (95.69%) were diagnosed postnatally (within 7 days). From 2016 to 2020, the prevalences of polydactyly were 1.94‰, 2.07‰, 2.20‰, 2.54‰, and 2.48‰, respectively, showing an upward trend (χ2trend = 19.48, P < 0.01); The prevalences of syndactyly were 0.62‰, 0.66‰, 0.77‰, 0.81‰, and 0.89‰, respectively, showing an upward trend (χ2trend = 10.81, P = 0.03). Hand polydactyly (2.26‰ vs. 1.33‰, OR = 1.69, 95%CI: 1.52-1.87) and hand syndactyly (0.43‰ vs. 0.28‰, OR = 1.42, 95%CI: 1.14-1.76) were more common in males than females. Polydactyly (2.67‰ vs. 1.93‰, OR = 1.38, 95%CI: 1.26-1.51) and syndactyly (0.91‰ vs. 0.62‰, OR = 1.47, 95%CI: 1.26-1.72) were more common in urban areas than in rural areas. Compared to maternal age 25-29, hand polydactyly was more common in maternal age < 20 (2.48‰ vs. 1.74‰, OR = 1.43, 95%CI: 1.01-2.02) or ≥ 35 (2.25‰ vs. 1.74‰, OR = 1.30, 95%CI: 1.12-1.50). CONCLUSION: In summary, we have described the prevalence and epidemiology of polydactyly and syndactyly from hospital-based surveillance in Hunan Province, China, 2016-2020. Our findings make some original contributions to the field, which may be valuable for future research.

Revision Surgery Following Primary Reconstruction for Hand Syndactyly.

PURPOSE: Web creep and scar contracture are established complications of syndactyly reconstruction; however, few reports characterize risk factors for revision surgery. The purpose of this investigation was to examine the rate and risk factors of reoperation for congenital hand syndactyly. METHODS: Patients undergoing syndactyly reconstruction from 2007 to 2021 at a single children's hospital were reviewed. Cases with less than 1 year of follow-up were excluded. Demographic, surgical, and outcomes data were recorded by each web space to account for mixed treatments. RESULTS: In total, 514 web spaces in 231 children were reviewed with a mean follow-up of 6.0 years after primary reconstruction; 66 (12.8%) web spaces in 51 (22.1%) children underwent revision. The most common procedures were web space deepening due to web creep (57.9% of cases) and digital scar contracture release (45.6%); these were augmented in a minority (17.5%) of cases by other aesthetic/functional procedures. Revisions occurred at a median of 1.7 years after primary reconstruction. First web spaces (thumb-index finger) were most frequently reoperated (33.3%). On multivariable analysis, first web space involvement, complete syndactyly, and complications after the primary reconstruction significantly increased odds of revision. Age at primary reconstruction was not a significant predictor. Following revision, 10.5% of cases had recurrent web creep, and 14.0% had recurrent scar contracture. Eight (1.6%) web spaces in seven (3.0%) children required multiple revisions. CONCLUSIONS: Approximately 13% of syndactyly reconstructions (22% of patients) require reoperation. Most revisions occur within 4 years of primary reconstruction. Complete syndactyly, complications after the primary reconstruction, and first web space involvement increase the risk of revision; age at primary reconstruction is not a risk factor. Revision outcomes mirror the index procedure, with 10% to 14% of revised web spaces experiencing recurrent web creep or contracture. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Webplasty using an external fixator for complex syndactyly caused by Apert syndrome.

BACKGROUND: Webplasty can be conducted for complex syndactyly caused by Apert syndrome (also referred to as Apert hand) by extending the soft tissue in the lateral direction using an external fixator. This study aimed to verify the usefulness of webplasty without skin grafting. METHODS: Webplasty with lateral extension was conducted at a single institution from 2015 to 2023. The patients were four children with Apert hand aged 1-3 years. A custom-made small external fixator was used for all of the soft tissue extension. RESULTS: Webplasty without skin grafting was completed by the time all five patients were 5-6 years of age. CONCLUSION: Webplasty without skin grafting was possible with lateral extension of the soft tissue using a simple external fixator.

Fraser syndrome with limb reduction defect: a rare and unique anatomic variation.

INTRODUCTION: Fraser syndrome, named after George Fraser, is an autosomal recessive disorder showing a highly variable interfamilial phenotypic variation, with malformations ranging from minor symptoms to lethal anomalies like renal agenesis, incompatible with survival. Limb reduction defects have not been reported to be associated with it. CASE PRESENTATION: A 21-year-old primigravida presented to the antenatal outpatient department with a level two targeted anomaly scan report suggestive of severe oligohydramnios with suspected renal agenesis. The cranial vault bones were compressed, and orbital globes and lenses could not be visualized. Renal agenesis was confirmed due to sleeping adrenals sign, non-visualization of the urinary bladder, and Doppler of renal arteries. A detailed examination of the fetal head in the sagittal section showed the absence of an eye globe and lens, arousing suspicion of Fraser syndrome. After pregnancy termination, a complete fetal autopsy was done to look for any additional findings. CONCLUSION: Patients who have a syndromic mix of acrofacial and urogenital abnormalities with or without cryptophthalmos should be evaluated for Fraser syndrome, which can be diagnosed by clinical examination and perinatal autopsy.

A novel variant in AFF3 underlying isolated syndactyly.

Isolated syndactyly is a common limb malformation with limited known genetic etiology. We used exome sequencing to discover a novel heterozygous missense variant c.2915G > C: p.Arg972Pro in AFF3 on chromosome 2q11.2 in a family with isolated syndactyly in hands and feet. AFF3 belongs to a family of nuclear transcription activating factors and is involved in limb dorsoventral patterning. The variant Arg972Pro is located near the C terminus, a region that is yet to be associated with human disorders. Functional studies did not show a difference in the stability or subcellular localization of the mutant and wild type proteins. Instead, overexpression in zebrafish embryos suggests that Arg972Pro is a loss-of-function allele. These results suggest that variants in the C terminus of AFF3 may cause a phenotype distinct from previously characterized AFF3 variants.

Foot adaptation to climbing in ovenbirds and woodcreepers (Furnariida).

Furnariida (i.e. ovenbirds, woodcreepers and antbirds) cover diverse ecologies and locomotor habits, ranging from strictly terrestrial to climbing birds, with different degrees of acrobatic performances. We know that this variety of locomotor modes is linked to different limb morpho-functional adaptations in other climbing clades of birds, such as woodpeckers and nuthatches. Here, we link the morphological variations to ecological categories, such as different locomotor habits and a gradient of acrobatic performances, in a phylogenetically informed analysis. We used a high-density three-dimensional (3D) geometric morphometric approach on foot bones (tarsometatarsus and all toes) of 55 specimens from 39 species of Furnariida. We found a significant correlation between acrobatic performances and foot bone shapes, partly explained by the phylogenetic relationship between species. Dendrocolaptidae show specific anatomical features, linked to their acrobatic locomotor habits. More specifically, we found that: (1) foot bones are more robust amongst climbing Furnariida, (2) the spread between toes is wider amongst highly acrobatic Furnariida, (3) dermal syndactyly between digits II and III is linked to special osteological features interpreted as functional osteological syndactyly in woodcreepers (tail-assisted climbers) and (4) the hallux claw is straighter than other claws in climbing Furnariida. Our study demonstrates that climbing Furnariida evolved common foot adaptations with subtle phenotypic variations depending on their climbing performances, refining our understanding of how evolution shapes interactions amongst structure, function and ecological traits.

The changing epidemiology of syndactyly in Chinese newborns: a nationwide surveillance-based study.

BACKGROUND: Little is known about the epidemiologic features of syndactyly (SD) in Chinese newborns. METHODS: Using 2007-2019 data from the Chinese Birth Defects Monitoring Network, we conducted a prevalence analysis on overall, isolated and associated syndactyly according to birth year, maternal age, maternal residence, geographic region and infant sex, with special interests in time trends, perinatal outcomes and clinical phenotypes. RESULTS: A total of 13,611 SD cases were identified among 24,157,719 births in the study period, yielding the prevalence of 5.63, 4.66 and 0.97 per 10,000 for overall, isolated, and associated SD, respectively. The prevalence of each type of SD exhibited an upward trend over the period. The prevalence of overall SD varied significantly by maternal residence (urban vs. rural, 6.69/10,000 vs. 4.35/10,000), maternal age (< 20 years, 5.43/10,000; 20-24 years, 5.03/10,000; 25-29 year, 5.65/10,000; 30-34 years, 6.07/10,000; ≥ 35 years, 5.76/10,000), geographic region (central, 5.07/10,000; east, 6.75/10,000; west, 5.12/10,000), and infant sex (male vs. female, 6.28/10,000 vs. 4.86/10,000). Newborns with associated SD were more likely to be born prematurely (29.2% vs. 10.6%) or with low birthweight (30.5% vs.9.8%) than those with isolated SD. The bilaterally, and unilaterally affected cases accounted for 18.4% and 76.7%, respectively. The feet were more frequently involved (64.3%) in those bilaterally affected cases, while right side preference (right vs left: 53.8% vs 46.2%) and upper limbs preference (hand vs foot: 50.8% vs 48.0%) were found in unilateral cases. CONCLUSIONS: The prevalence of syndactyly in China is on the rise and notably higher than that in other Asian and European countries, highlighting the importance of investigating the etiology, epidemiology, and clinical implications of this condition in the Chinese population.

Amniotic band syndrome with CNS involvement: a pediatric neurosurgeon's dilemma-a case series and literature review.

BACKGROUND: Amniotic band syndrome (ABS) is a rare congenital disease characterized by a broad spectrum of congenital anomalies resulting from the strangulated developing organ(s) by the detached fibrous amniotic band. The prevalence of CNS involvement in ABS is rare, but the mortality rate in these cases is high, while morbidity among the surviving patients is inevitable. CASE REPORT: Three-month-old male, 9-month-old female, and newborn female babies were presented with head lump(s), severe facial cleft, syndactyly, and finger amputation. The patient's head imaging confirmed meningoencephalocele as the cause of the head lump in 2 patients; meanwhile, a porencephalic cyst was identified as the origin of head lumps in the other patient. VP shunt placement surgery was performed as the initial management in 2 patients, while one patient directly underwent meningoencephalocele resection surgery. Craniofacial and limb reconstructions were planned as the follow-up management in all cases. Unfortunately, one patient died of complications from suspected aspiration, while another never returned for follow-up treatment. CONCLUSION: Here, we report 3 ABS cases with CNS involvement. Despite the severe disfigurement and disability, the inexistence of fatal malformation might lead to long-term survival. The treatment of malformation(s) that might predispose to another fatal condition and surgery(-ies) to improve functional outcomes and patient's social acceptability should be prioritized in managing the surviving ABS patients.

What are the key risk factors of keloid formation after repair of syndactyly of the toe?

PURPOSE: Keloid formation in toes area is rare. However, occurrence of this phenomenon in toes after the surgery of syndactyly repair has been reported. Risk factors of keloid formation in toes after syndactyly reconstructions are currently unknown. This study aimed to investigate the risk factors of keloid formation after the surgery of syndactyly repair of the toes. METHODS: We retrospectively reviewed our case series including patients who were treated surgically at our institution. We hypothesized some key factors of keloid formation and analyzed each of them statistically. RESULTS: A total of 105 patients were treated surgically at our hospital, and 9 patients were involved keloid formations after operations. Among our hypothesized key factors, the results of multivariate logistic regression analysis revealed the number of affected web spaces (OR 0.031; 95%CI 0.001-0.684; p = 0.028) was significantly different. Digital enlargement was not a significant factor (OR 17.731; 95%CI 0.686-458.174; p = 0.091). CONCLUSION: Involving multiple web space was associated with keloid formation after syndactyly release, on the other hand, toe enlargement did not show a significant difference. However, the digital enlargement showed high Odds ratio, we could not deny its high relativity for keloid formation. Further investigations are needed to clarify the key risk factors of keloid formation after the surgery of syndactyly repair of the toes.

Two-stage surgical treatment for medially angulated great toes in Apert feet by wedged corrective osteotomy with distraction of the inter-metatarsal space: A case report.

BACKGROUND: One of most severe clinical problems related to Apert foot anomalies is medial angulation deformities of the great toe as the foot grows. CASE PRESENTATION: The patient was a 22-month-old Japanese child with Apert syndrome, who had broad bilateral great toe showing medially angulated deformity. We performed two-stage surgical treatment including distraction of the remarkable narrowing the first inter-metatarsal space using an external distractor device, and the corrective wedge-osteotomy of the first metatarsal with a graft of wedged bone in the reverse direction and inter-positioning of the resected local bone between the first and second metatarsal to preserve the space. At 3 years after surgery, the patient did not have any disturbance of gait and could wear normal shoes without weight-bearing pain, and was satisfied with the appearance of the great toes. CONCLUSION: The two-stage surgical method could be an option for surgical treatment of Apert feet.

Hypothesis: Symbrachydactyly.

The term symbrachydactyly has been used for the phenotype of two or three short fingers or toes, hypoplasia of the middle and distal phalanges and variable syndactyly of the affected digits. Some clinicians have extended this diagnosis to include other phenotypes, specifically cleft hand, terminal transverse limb defects, hypoplasia of the thumb and fifth finger with nubbins for fingers 2, 3, and 4 and the hand deformity of the Poland anomaly. A malformations surveillance program can identify enough affected infants to characterize a phenotype. In the Active Malformations Surveillance Program in Boston (1972-2012) among 289,365 births, all infants and fetuses with structural abnormalities were identified from reading the examination findings by the pediatricians and pathologists and the results of diagnostic tests. Liveborn and stillborn infants were included, as well as fetuses from elective terminations because of anomalies identified in prenatal testing. We present the findings in 14 infants, all liveborn, who had symbrachydactyly of one or both hands (n = 12) or feet (n = 2). We suggest restricting the term symbrachydactyly to this single phenotype to improve counseling and to focus future research on identifying the cause(s).

Complications in the 2-Year Postoperative Period Following Pediatric Syndactyly Release.

PURPOSE: Syndactyly surgical release is one of the most common congenital hand surgeries performed by pediatric hand surgeons. The purpose of our study was to evaluate the complications associated with syndactyly release and determine factors that correlate with higher complication rates within the 2-year postoperative period. METHODS: A retrospective chart review was completed for patients who underwent syndactyly release at a single pediatric center between 2005 and 2018. Patients were included if they had a diagnosis of syndactyly and underwent surgical release, and excluded for a diagnosis of cleft hand, incomplete surgical documentation, surgery performed at an outside institution, or follow-up care that did not extend beyond the first postoperative visit. Complications were classified using the Clavien-Dindo (CD) system. RESULTS: Fifty-nine patients met the inclusion criteria, which included 143 webs released in 85 surgeries. A total of 27 complications occurred for the 85 surgeries performed. The severity of complications was CD grade I or II in 23% of surgeries, most commonly unplanned cast changes, and CD grade III in 8% of surgeries. No CD grade IV or V complications occurred. The CD grade III complications included 6 reoperations. The complication rate was higher when performing >1 syndactyly release per surgery. It also was higher for patients undergoing >1 surgical event. Rates of complication per surgery were similar between patients with multiple surgeries compared with those with a single surgery. Concomitant diagnoses and complexity of syndactyly was not associated with a higher complication rate. CONCLUSIONS: Syndactyly release was associated with a complication rate of 31% per surgical event with 44% of these complications related to unplanned cast changes and 8% of complications that required admission or reoperation. Risk factors for complications following syndactyly release include >1web operated on per surgery and undergoing >1 surgical event. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis IV.

Classic Timothy Syndrome Associated With Bilateral Border Digit Syndactyly: A Case Series.

PURPOSE: Timothy syndrome (TS) is characterized by congenital long-QT arrhythmia and limb syndactyly. Patients who undergo syndactyly repair with undiagnosed TS may have their abnormal cardiac electrical activity unmasked during surgery. The purpose of this study was to detail the extremity phenotype seen in patients with TS, which may help hand surgeons in their preoperative assessment. METHODS: This was a retrospective review of all patients with TS seen at our institution from 1998 to 2022. Descriptive statistics regarding their demographics, medical and surgical histories, and syndactyly phenotypes were obtained. RESULTS: Seven patients (5 males and 2 females) with TS were seen at our institution for multidisciplinary evaluation (median age at presentation was 23 months). Six patients had finger syndactyly and 5 had toe syndactyly. One patient did not have any extremity syndactyly and was noted to have a specific TS mutation known to lack musculoskeletal abnormalities. All patients with finger syndactyly had border digit involvement, with 5 out of 6 patients displaying syndactyly of the middle-ring and ring-little finger web spaces. Toe syndactyly was more heterogeneous, with 1 patient lacking any lower extremity syndactyly and others having variable involvement of the second-third, third-fourth, and fourth-little toe web spaces. Complexity ranged from simple to complete. Four patients had intraoperative cardiac events leading to TS diagnoses after surgery. CONCLUSIONS: Bilateral border digit hand syndactyly, with or without bilateral toe syndactyly, should raise concerns for TS and prompt further investigation into potential cardiac disease to avoid perioperative cardiac morbidity and mortality. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Cell death in the developing vertebrate limb: A locally regulated mechanism contributing to musculoskeletal tissue morphogenesis and differentiation.

Our aim is to critically review current knowledge of the function and regulation of cell death in the developing limb. We provide a detailed, but short, overview of the areas of cell death observed in the developing limb, establishing their function in morphogenesis and structural development of limb tissues. We will examine the functions of this process in the formation and growth of the limb primordia, formation of cartilaginous skeleton, formation of synovial joints, and establishment of muscle bellies, tendons, and entheses. We will analyze the plasticity of the cell death program by focusing on the developmental potential of progenitors prior to death. Considering the prolonged plasticity of progenitors to escape from the death process, we will discuss a new biological perspective that explains cell death: this process, rather than secondary to a specific genetic program, is a consequence of the tissue building strategy employed by the embryo based on the formation of scaffolds that disintegrate once their associated neighboring structures differentiate.

Examination of Postoperative Outcomes Using Morphological and X-Ray Classifications and Selection of the Toe to Be Excised in Postaxial Polydactyly of the Foot.

The treatment of postaxial polydactyly requires excision of the medial fifth or lateral sixth toe, and separation of the adjacent fourth/fifth toes if the adjacent toes exhibit skin syndactyly. Morphological changes in the retained toes and reoperation are common problems after such surgery. This study examined the effects of preoperative classifications and selecting the medial fifth or lateral sixth toe for excision on the postoperative outcomes of surgery for postaxial polydactyly. From April 2006 to March 2019, surgery for postaxial polydactyly was performed on 55 feet in 49 patients. The patients' mean age at surgery was 28.8 months. Postoperative esthetic and bone alignment scores, the reoperation rate, and postoperative dysfunction were examined. The postoperative esthetic and bone alignment evaluations were performed by examining postoperative photograph and X-ray images using original scoring systems. The surgical procedure was chosen by the surgeon-in-charge during a preoperative conference after considering the toe growth and bone alignment. In the postoperative esthetic evaluation, excising the lateral sixth toe produced significantly better outcomes than excising the medial fifth toe. The morphological classification also indicated that excising the lateral sixth toe produced better outcomes, as it resulted in the bifurcated toes being clearly independent. Interestingly, the postoperative X-ray-based bone alignment score was not correlated with the esthetic score. The reoperation rate tended to be high after medial fifth toe excision. There were no postoperative functional complications. Lateral sixth toe excision for postaxial polydactyly of the foot produces good postoperative esthetic outcomes.

A Novel Mutation in a Gene Causes Sclerosteosis in a Family of Mediterranean Origin.

Background and Objectives: Sclerostin is an SOST gene product that inhibits osteoblast activity and prevents excessive bone formation by antagonizing the Wnt signaling pathway. Sclerosteosis has been linked to loss of function mutations in the SOST gene. It is a rare autosomal recessive disorder characterized by craniotubular hyperostosis and can lead to fatal cerebellar herniation. Our aim is to describe the clinical and radiological features and the new underlying SOST mutation in a patient with sclerosteosis. Case: A 25-year-old female who was referred to the endocrine clinic for suspected excess growth hormone. The patient complained of headaches, progressive blurred vision, hearing disturbances, increased size of feet, proptosis, and protrusion of the chin. She had normal antenatal history except for syndactyly. Images showed diffuse osseous thickening and high bone mineral density. Biochemical and hormonal tests were normal. Due to progressive compressive optic neuropathy, optic nerve fenestration with decompression hemicraniotomy was performed. Sclerosteosis was suspected due to the predominant craniotubular hyperostosis with syndactyly. Using peripheral leucocyte DNA, genomic sequencing of the SOST gene was performed. This identified a novel deletion homozygous mutation in the SOST gene (c.387delG, p.Asp131ThrfsTer116) which disrupts sclerostin function, causing sclerosteosis. Conclusions: Discovery of the molecular basis of sclerosteosis represents an important advance in the diagnosis and management of this fatal disease.

Surgical treatment in child's congenital toe syndactyly: Risk factor of recurrence, complication and poor clinical outcomes.

INTRODUCTION: Surgical treatment of toe syndactyly remains controversial. The strong demand from parents for a cosmetic release is increasing in our societies. But is it worth it? The objective was to assess medium-long term outcomes and to identify the risk factors of recurrence, complication and poor clinical outcomes. METHODS: Sixty-eight toe syndactylies (38 patients) undergoing surgery between 2008 and 2017 with a follow-up higher than two years were included consecutively and retrospectively. Four children (four syndactylies) were lost to follow-up and excluded. The mean age of the first surgery was 3.9 years old (0.8-16.7) and cohort mean follow-up was 6.9 years (2.8-11.2). In all patients, web release with a commissural dorsal flap was performed and associated a cutaneous resurfacing (spontaneous epithelialization, full-thickness skin graft taken from the popliteal crease, or a hyaluronic acid ester matrix). RESULTS: Eighteen syndactylies (28.1%) in 14 patients recurred and one syndactyly required revision surgery. An age of surgery above two years was the only risk factor for recurrence found in univariate (OD = 0.27[0.08;0.85];p = 0.02) and multivariate studies (IC 95% = 0.05-0.68;p = 0.02). Seven complications (11.7%) in seven syndactylies (6 patients) were reported with six keloids (9.4%) and one scar retraction (1.6%). Each complication underwent an additional procedure. African ethnicity (N = 15) represents a risk factor (N = 4/15; OD = 0.12[0.009;0.97];p = 0.02) for keloids formation. Withey's average score is 4.9 (1-11), mean OxAFQ-C score was 52/60 (30-60), 67% would repeat the surgery and 69% felt satisfied at last follow-up. The simple syndactyly would appear less satisfied than complex or complicated (p = 0.02). CONCLUSIONS: Surgical treatment of child's congenital syndactyly involves a risk of recurrence (28%) and potential complications (11,7%). Performed surgical procedure over two years old increase the risk of recurrence. African ethnicity is a risk factor in scarring complication. Only half of simple syndactylies are satisfied and prone to repeat the surgery.

Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis.

Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.

GLI3 variants causing isolated polysyndactyly are not restricted to the protein's C-terminal third.

Loss of function variants of GLI3 are associated with a variety of forms of polysyndactyly: Pallister-Hall syndrome (PHS), Greig-Cephalopolysyndactyly syndrome (GCPS), and isolated polysyndactyly (IPD). Variants affecting the N-terminal and C-terminal thirds of the GLI3 protein have been associated with GCPS, those within the central third with PHS. Cases of IPD have been attributed to variants affecting the C-terminal third of the GLI3 protein. In this study, we further investigate these genotype-phenotype correlations. Sequencing of GLI3 was performed in patients with clinical findings suggestive of a GLI3-associated syndrome. Additionally, we searched the literature for reported cases of either manifestation with mutations in the GLI3 gene. Here, we report 48 novel cases from 16 families with polysyndactyly in whom we found causative variants in GLI3 and a review on 314 previously reported GLI3 variants. No differences in location of variants causing either GCPS or IPD were found. Review of published data confirmed the association of PHS and variants affecting the GLI3 protein's central third. We conclude that the observed manifestations of GLI3 variants as GCPS or IPD display different phenotypic severities of the same disorder and propose a binary division of GLI3-associated disorders in either PHS or GCPS/polysyndactyly.

The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1.

Fraser syndrome is characterized by cryptophthalmos, syndactyly and other autopod defects, and abnormalities of the respiratory and urogenital tracts. Biallelic variants in GRIP1 can cause Fraser syndrome 3 (FRASRS3), and five unrelated FRASRS3 cases have been reported to date. Four cases are fetuses with homozygous truncating variants. The remaining case is an almost 9-year-old Turkish girl compound heterozygous for a truncation variant and a possibly frame-shift intragenic deletion. We present a 15.5-year old Pakistani boy with homozygous truncating variant c.1774C>T (p.Gln592Ter). Of the hallmarks of the disease, the boy has cryptophthalmia, midface retrusion, very low anterior hairline, hair growth on temples extending to the supraorbital line and also on alae nasi, agenesis of right kidney, and cutaneous syndactyly of fingers and toes but no symptoms in any other organs, including lungs, anorectal system, genitalia, and umbilical system. This case is the oldest known individual with FRASRS3, and our findings show that a homozygous GRIP1 truncating variant can manifest with a non-lethal phenotype than in the reported cases with such variants, expanding the phenotypic and mutational spectrum of GRIP1.