First web space syndactyly presents a considerable reconstructive challenge, and because of the rarity and complexity of the condition, there is no consensus on the optimal approach to its reconstruction. This study therefore describes our experience with congenital first web space syndactyly, providing an overview of reconstructive techniques and outcomes. Sixty-nine cases (55 simple and 14 complex/complicated), from 2007 to 2022, were analyzed with descriptive statistics. Dorsal commissural flaps were the initial operative approach in 100% of the complex/complicated cases, whereas Z-plasties were used in 64% of the simple cases. Full-thickness skin grafts were required in 12 (86%) of the complex/complicated cases and in 14 (26%) of the simple cases. Additional procedures such as amputation or osteotomy were performed in five complex/complicated (36%) and five simple (9.1%) cases. Range-of-motion deficits were the most common complication (26%), and 20 (29%) cases required revision surgery. Patients with first web syndactyly often require multiple operations and concurrent procedures on the index finger and thumb to optimize hand function. Reconstruction should be personalized to each patient's unique clinical presentation. Prognosis IIb. The clinical manifestations of CACNA1C-related disorders include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current. Phenotypes can include nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms); nonsyndromic short QT syndrome (QTc <350 ms), with risk of sudden death; Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval; classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three; and CACNA1C-related neurodevelopmental disorder, in which the features tend to favor one or more of the following: developmental delay / intellectual disability, hypotonia, epilepsy, and/or ataxia. The diagnosis of a CACNA1C-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in CACNA1C identified by molecular genetic testing. Treatment of manifestations: Beta-blockers (nadolol preferred) and mexiletine may be used for prolonged QT interval; pacemaker placement / temporary pacing for bradycardia with 2:1 atrioventricular block; quinidine for short QT syndrome and Brugada syndrome; consideration of catheter ablation for symptomatic Brugada syndrome; implantable cardioverter defibrillator (ICD) as soon as body weight allows for those with tachyarrhythmias; feeding therapy with low threshold for clinical feeding evaluation and/or radiographic swallowing study for dysphagia; consideration of gastrostomy tube placement for persistent feeding issues; standard treatment for congenital heart defects, developmental delay / intellectual disability, epilepsy, ataxia, hypoglycemia, recurrent infections, and syndactyly. Prevention of primary manifestations: Arrhythmias must be prevented with the standard therapy, which may include medications, placement of an ICD, and/or ablation. Any surgical intervention must be performed under close cardiac monitoring, as anesthesia is a known trigger for cardiac arrhythmia in individuals with a CACNA1C-related disorder; fever can also be a trigger for arrhythmias in individuals with CACNA1C-related Brugada syndrome and requires aggressive treatment with standard antipyretic drugs. Surveillance: At each visit, measure growth parameters and evaluate nutritional safety of oral intake; assess mobility and self-help skills; monitor developmental progress and educational needs; assess for behavioral issues; assess for new manifestations such as seizures, changes in tone, and movement disorders; monitor for signs/symptoms of hypoglycemia; and monitor for recurrent infections. Every 6-12 months, follow-up evaluations with a cardiologist to include EKG, Holter, & echocardiogram; monitor those with seizures as clinically indicated. Every 12 months, if remote device monitoring is available: evaluate persons with a pacemaker or ICD. Agents/circumstances to avoid: All drugs reported to prolong QT interval (see CredibleMeds®); drugs and dietary practices that could lead to hypoglycemia. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation, institution of measures to prevent cardiac arrhythmias, and awareness of agents/circumstances to avoid. Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward. While predictive genetic testing can be used to identify relatives who are heterozygous for a familial CACNA1C pathogenic variant and at risk for CACNA1C-related cardiac arrhythmias, it cannot be used to predict disease course (i.e., whether CACNA1C-related EKG changes and symptoms will occur and, if so, the age of onset and severity). Pregnancy management: Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans. Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects. Fetuses at risk of being affected with a CACNA1C-related disorder should be monitored for bradycardia and heart rate abnormalities that can be a sign of fetal arrhythmias. CACNA1C-related disorders are inherited in an autosomal dominant manner. Many individuals diagnosed with a CACNA1C-related disorder – particularly those individuals with a syndromic CACNA1C-related disorder (Timothy syndrome or CACNA1C-related neurodevelopmental syndrome) – have the disorder as the result of a de novo pathogenic variant. Some individuals diagnosed with a CACNA1C-related disorder inherited the CACNA1C pathogenic variant from a heterozygous or mosaic parent. If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the proband has a known CACNA1C pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism. Once the CACNA1C pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk for a CACNA1C-related disorder are possible.

Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by gonadal dysfunction attributed to impaired gonadotropin secretion. CHH is associated with approximately 60 genes including FGFR1. Nevertheless, the nucleotide variants of these genes are only related to less than half of the cases. Herein, we report a case of CHH caused by a novel mechanism. A 6-year-old boy presented with hypomasculinized genitalia, hyposmia, and syndactyly. Endocrine examinations showed impaired gonadotropin secretion. Short-read next-generation sequencing (NGS) identified the absence of mutations in the major causative genes for CHH. However, it detected an accumulation of discordant and split reads in a genomic region within the FGFR1 gene. Array-based comparative genomic hybridization did not detect copy-number abnormalities. Targeted long-read NGS and Sanger sequencing identified a de novo 333-bp insertion in exon 9 of the FGFR1 gene. A similarity search revealed that the insertion was an Alu element. This insertion caused a frameshift and resulted in premature termination (p. His409fsTer31). Further, it had several hallmarks of retrotransposition such as target site duplication, an endonuclease cleavage site-like motif, and a poly-A tail. The study results broadened the genetic basis of CHH that considered retrotransposon insertions. Importantly, this case emphasizes the need for additional genomic analyses in patients with CHH who had negative results on short-read NGS and array-based comparative genomic hybridization.

Timothy syndrome (TS) is a rare genetic disorder caused by mutations in the CACNA1C gene, which encodes the L-type calcium channel α1 CaV1.2 subunit. While it is expressed throughout the body, the most serious symptoms are cardiac and neurological. Classical TS type 1 (TS1) and TS type 2 (TS2) mutations cause prolonged action potentials (APs) in cardiomyocytes and in induced neurons derived from pluripotent stem cells taken from TS patients, but the effects of TS mutations on neuronal function in vivo are not fully understood. TS is frequently associated with autistic traits, which in turn have been linked to altered sensory processing. Using the TS2-neo mouse model, we analyzed the effects of TS2 mutation on the visual system. We observed a widening of APs of pyramidal cells in ex vivo patch clamp recordings and an increase in the density of parvalbumin-positive cells in the primary visual cortex. Neurons from TS2-neo mice recorded extracellularly in vivo were less likely to respond to visual stimuli of low spatial frequency, but more likely to respond to visual stimuli of mid-to-high spatial frequency, compared to those from wild-type mice. These results point to a basic processing abnormality in the visual cortex of TS2-neo mice.

Healthcare costs in the United States continue to rise, shifting an increasing financial burden onto patients. Families of children requiring surgery for congenital hand differences (CHDs) are particularly vulnerable, yet there are limited data on the costs associated with these procedures, hindering efforts to address healthcare inequities. Using data from the MarketScan Commercial Claims database from 2016 to 2022, we identified children aged 5 years or younger who underwent surgery for 5 common CHD conditions. Total payments and out-of-pocket payments, including deductibles, copayments, and coinsurance, were collected. Linear regression was used to analyze trends. All costs were inflation-adjusted to 2022 dollars. The study included 3070 cases from 2016 to 2022, with trigger thumb release (70%) and syndactyly repair (16%) being the most common procedures. Median total payment across all procedures was $3763 (interquartile range [IQR] $4030), whereas median out-of-pocket payment was $544 (IQR $1376). Pollicization had the highest median total payment ($11,882 [IQR $16,915]), whereas constriction ring syndrome had the lowest ($2080 [IQR $3720]). High-deductible health plans were associated with higher total and out-of-pocket costs. Regional disparities were significant, with the Northeast having the highest total payments. Procedures performed in ambulatory surgical centers were associated with lower total payments but similar out-of-pocket costs compared with hospital settings. Children undergoing CHD surgery face substantial financial burdens, with significant variability in costs by procedure, region, insurance plan type, and provider specialty. Policymakers should prioritize measures to mitigate out-of-pocket costs and address regional and specialty-driven cost disparities to ensure equitable access to care.

Synpolydactyly (SPD) is a heterogeneous distal-limb malformation syndrome, characterized by webbing and duplication of adjacent digits. SPD1, the most common type, is attributed to disease-causing variants in HOXD13, a transcription factor in the HOXD cluster that is essential for limb development. Here, we present a challenging exome-negative case of familial SPD. The case was resolved using long-read genome sequencing, which revealed a microdeletion in a conserved noncoding regulatory region upstream of the HOXD cluster. Oxford Nanopore WGS-LRS was pursued on two affected sisters, followed by CMA-Cytoscan HT validation. WGS-LRS for two affected siblings revealed a shared microdeletion of ~5.6 kb upstream of EVX2 and HOXD13 [chr2:176073523-176,079,120 (hg38)]. The deletion is predicted to affect the enhancer of several HOXD genes (EH38E2053988) and overlaps with a short stretch of high-sequence homology between human and mouse, called R1. CMA-Cytoscan HT analysis and PCR validation approved segregation of the deletion in the siblings and revealed a paternal inheritance. Our findings expand the genotype-phenotype correlation of the regulatory region upstream of HOXD13 in SPD and highlight the utility of long-read WGS for detecting noncoding variants that are undetectable by exome sequencing.