Syndromic Patients Research Articles

Utility of Papilledema for Detection of Elevated Intracranial Pressure in Craniosynostosis

Papilledema is swelling of the optic disk due to fluid accumulation around the optic nerve and is commonly used to detect increased intracranial (ICP) in craniosynostosis. This study aimed to assess the prevalence and utility of papilledema detection in patients with single-suture, multi-suture, and syndromic craniosynostosis and the differences before and after surgical intervention. A retrospective review of ophthalmology examinations of patients diagnosed with craniosynostosis treated between 2008 and 2023 was performed. Demographics, diagnosis, and operative data were collected. A total of 1509 ophthalmology exams of 519 patients were reviewed. The overall rate of papilledema in patients with craniosynostosis was 2.12%. The single-suture and multi-suture involvement rates were 1.15% and 5.81%, respectively. Non-syndromic patients with preoperative and postoperative examinations had an overall rate of 3.13%. Most had single suture involvement, and the average age of papilledema examination was 72 months. Syndromic patients with preoperative and postoperative examinations had an overall rate of 17.65%. The majority had multiple suture involvement, and the average age of papilledema examination was 26 months. The overall papilledema detection rate was low in patients with craniosynostosis. Multi-suture involvement and syndromic diagnosis had increased rates of papilledema. The average age of diagnosis was in older children. Syndromic patients had papilledema examination at a younger age. The authors' findings support the concept that fundoscopic ophthalmologic examination will benefit patients with multi-suture involvement, an associated syndrome, and older age.

Influence of Bone Defects After Endoscope-Assisted Suturectomy on Monobloc Advancement in Syndromic Bilateral Coronal Craniosynostosis Patients.

Surgery is performed for craniosynostosis to enlarge intracranial volume and improve cranial morphology. Endoscope-assisted suturectomy is one of the effective treatments. Compared with other techniques, it is reported to be low invasive and enables improvement of cranial volume and morphology at an early age. At the National Center for Child Health and Development (Tokyo, Japan), endoscope-assisted suturectomy is performed for all patients with craniosynostosis under the age of 3 months. Bone defects are sometimes observed several years after endoscope-assisted suturectomy. In syndromic bilateral coronal craniosynostosis patients in whom fused coronal sutures are removed, bone defects often remain in the temporal region. These may cause difficulty in setting the osteotomy line and placing distraction device for later monobloc advancement. In the present study, syndromic bilateral coronal craniosynostosis patients who underwent endoscope-assisted suturectomy between 2017 and 2022 at our hospital were retrospectively reviewed to investigate residual bone defects after the operation. As monobloc advancement, tongue-in-groove technique and placing internal distractors were assumed, and cranial bone defects between the ages of 3 and 5 years were evaluated in 3D by using image processing software. Five patients were included, and in 2 patients, the bone defects in the temporal regions were deemed large enough to interfere with making the bandeau or restrict the use of internal distractors for monobloc advancement. When performing suturectomy for syndromic craniosynostosis patients with midfacial concavity, careful surgical strategies that take into account future monobloc advancement should be considered.

CSIG-05. IS THERE ANY BRAIN TUMOR PREDISPOSITION IN RELATED PALLISTER-HALL SYNDROMES AT THE NEW GENOMICS ERA

Abstract Pallister-Hall Syndrome (PHS) and its related syndromes are a spectrum of congenital malformations. They are associated to GLI3 mutations and specific brain tumors. Considered as lethal, it is now well established that this disease may be miss-diagnosed with the report of adult cases. Here, we discuss the management of the genetic counselling and the risk of neurologic tumor predisposition in GLI3-related PHS. We comprehensively reviewed the scientific literature using various databases to explore the risk of neurologic tumors and evolving practice of neuro-cancer genetic counseling in GLI3-related PHS. The review of literature showed that GLI3 is involved in tissue development as well as in cancer. GLI3 was identified as either a pro or anti-cancerous protein. In fact, GLI3 is described as upregulated in multiple cancers and is found to positively regulate malignant behavior. In neuro-oncology GLI gene was first identified as a highly expressed gene in human glioma and then as having an anti-cancerous role in medulloblastoma where GLI3 seems act as a tumor suppressor. In mutational studies, GLI3-germinal mutations are characterized by a high recurrence of hypothalamic hamartoma in syndromic patients. GLI3-somatic alterations have been also demonstrated in cell samples of patients with non-syndromic hypothalamic hamartoma. In addition, while inactivation of GLI3 is suggested to be associated with medulloblastoma, mutations are not common in sporadic medulloblastoma. The association of germinal GLI3 variants in syndromic patients with medulloblastoma has been identified in only one patient harboring GLI3 H302X variant. Our review permitted us to conclude that germline GLI3 mutations may predispose to a specific non-severe form of delayed hypothalamic hamartoma, which can be revealed in pauci or asymptomatic and unrecognized mutated individuals. The likelihood of having a neuro-cancer predisposition in GLI3 mutated families seems to be insignificant.

Increased lengthening frequency does not adversely affect the EOSQ scores in magnetically controlled growing rod surgeries in 133 subjects followed to final fusion.

Magnetically Controlled Growing Rod (MCGR) allows frequent outpatient rod lengthening when treating Early Onset Scoliosis (EOS) patients. But there is lack of expert consensus on the optimal MCGR lengthening interval. EOS 24-Item Questionnaire (EOSQ) is validated for assessing health-related quality of life (HrQOL), family burden, and satisfaction. This is the first study assessing how MCGR lengthening intervals affects patient-perceived outcomes. This is a multicentred cohort study with subjects recruited from 2012 to 2018 and followed till fusion. EOS subjects who underwent MCGR surgeries were grouped into high, mediumor low lengthening interval subgroups based on 16 and 20week cut-offs. Repeated measure analysis was performed on EOSQ's specified 12 domains. EOSQ results were taken: before index surgery, after index surgery, and prior to definitive treatment. Demographic, clinical and radiographic data were included in model adjustment. 133 subjects with mean follow-up of 3.5 (± 1.3)years were included, with 60 males and 73 females; 45 idiopathic, 23 congenital, 38 neuromuscular, and 27 syndromic patients. Mean Cobb angle at surgery was 67° (± 22°) with mean age of 8.3 (± 2.5)years. Between groups, clinical and radiographic parameters were comparable. Higher EOSQ scores in mediumlengthening interval subgroup was present in fatigue (p = 0.019), emotion (p = 0.001), and parental impact (p = 0.049) domains, and overall score (p = 0.046). Trendline contrast between subgroups were present in general health (p = 0.006) and physical function (p = 0.025) domains. Patient-perceived outcome improvements appear similar between lengthening interval subgroups. All MCGR lengthening intervals were tolerated by patients and family, with no negative impact observed. Prognostic Level III.

The natural course of newborns with transient congenital hypothyroidism.

The incidence of congenital hypothyroidism (CH) has increased worldwide over the last decades, mainly due to the lowering of screening thresholds, resulting in the increased identification of newborns with transient CH. Several studies have reported the prevalence and the predictive parameters of transient CH, but reports on the long-term outcome are rare. This study aimed to assess the long-term course of neonates with transient CH. Neonates diagnosed with transient and permanent CH between the years 1998 and 2018 at the Pediatric Endocrine Institute of Ha'Emek Medical Center were enrolled in the study. Data were retrieved retrospectively from medical files. A total of 76 newborns (45M, 59%) with transient CH and 53 (25M, 47%) with permanent CH were included in the study. The major causes of transient CH were prematurity (29%) and subclinical hypothyroidism (30%). During retrospective follow-ups of up to 23 years, reinitiation of levothyroxine therapy was not required, apart from four patients with underlying syndromic etiologies. Neurodevelopmental impairment occurred in 16% of children with transient CH compared with 29.4% in the permanent CH group. Transient CH is frequent among preterm infants but is generally limited to infancy. Subclinical hypothyroidism frequently presents as overt hypothyroidism at birth, but in most cases, the requirement for levothyroxine supplemental therapy is limited to the first years of life, suggesting that long-term follow-up of thyroid function tests may be unnecessary for non-syndromic children. The high rate of neurodevelopmental impairment in newborns with transient CH emphasizes the need for neurodevelopmental monitoring in these patients. A high rate of transient CH has been identified over the past decades following the lowering of TSH screening thresholds. The long-term outcome of transient CH has been evaluated in a few studies with inconclusive results. In the current study, we assessed the long-term outcomes of transient CH for up to 23 years. We found that 29% of cases were attributed to prematurity and 30% to subclinical hypothyroidism. No morphological anomalies were identified. Only syndromic patients (three with Down syndrome and one with Coffin-Lowry syndrome) required levothyroxine supplemental therapy at the time of the study, indicating that long-term thyroid function monitoring may be unnecessary. The high prevalence of neurodevelopmental impairment suggests the need for close neurodevelopmental monitoring in this population.

Perioperative Management and Outcomes of Pediatric Craniosynostosis Patients Undergoing Cranioplasty: A Retrospective Analysis

Cranioplasty is a major surgical procedure typically performed in children under 1 year of age, often associated with significant complications. The scientific literature on perioperative management for children with craniosynostosis undergoing cranioplasty is limited. The authors' objective was to retrospectively evaluate the management, complication rates, and outcomes among children undergoing cranioplasty at our institution. The authors conducted a single-center retrospective analysis of craniosynostosis children who underwent cranioplasty at Fondazione IRCCS San Gerardo dei Tintori between 2009 and 2023. 102 children were studied. Median admission age was 307 days, 30.4% of patients had syndromic disease; 28.4% underwent multi-suture cranioplasty. Median blood loss was 225 ml, and 85% of patients required red blood cell transfusion. There was a significant difference neither in indexed blood loss between the single and the multi-suture groups nor in perioperative transfusion requirement. 93.2% of patients in the single-suture group were extubated upon completion of the procedure against 65.5% of multi-suture group. No deaths were recorded. All patients were admitted to the intensive care unit after surgery. 8.8% patients suffered at least one complication. Airway management was the most common (7.8% of patients), intraoperative blood loss >90% of estimated blood volume occurred in 4 (3.9%) patients, whereas 3 children (2.9%) developed intracranial hypertension. Syndromic patients exhibited a significantly higher incidence of perioperative complications. Managing children’s cranioplasty perioperative care is challenging, especially in multi-suture and syndromic cases. These findings stress the importance of multidisciplinary collaboration, precise intraoperative management, and comprehensive postoperative monitoring.

Molecular diagnosis of patients with syndromic short stature identified by trio whole-exome sequencing.

Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature. Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature. Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results. Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients.

Distraction osteogenesis in craniosynosotosis: technical note

Introduction: Craniosynostosis is a group of diseases whose main characteristic is the premature fusion of one or more cranial sutures. They can be subdivided into non-syndromic and syndromic. The posterior vault distraction osteogenesis (PVDO) has become the standard procedure for managing the intracranial hypertension of these patients. The objective of this paper is to report the experience of the Sobrapar Hospital (Campinas, Brazil) in treating and following up on syndromic craniosynostosis patients subjected to PVDO and highlight the lessons learned throughout this process. Methods: The medical records of the patients treated at the Sobrapar Hospital between 2013 and 2023 were reviewed. Results: The total of patients initially candidates to PVDO was 79, and 75 of them proceeded to the surgery. The mean age of surgery was 8,16 months old (ranging from 4 months to 12 years old). The length of stay ranged from 2 to 14 days, with a mean of 3,29 days. The distraction achieved ranged from 13 mm to 30 mm, with a mean distance of 23 mm. The postoperative complications were mostly cutaneous. CSF leak occurred in 3 patients. Conclusion: PVDO provides a progressive formation of a vascularized bone, its intracranial volume expansion is greater than the FOA, increasing the posterior fossa’s size (even when the craniotomy is supratorcular) and it improves Chiari’s symptoms, even when the radiologic abnormalities are not necessarily solved. A specialized and multidisciplinary team is essential to improving the success rates of the surgery.

Cochlear implantation in syndromic patients: difficulties and lessons learnt.

Identify the prevalence of syndromes in a cohort of patients who underwent cochlear implantation, to report on the presence of inner and middle ear malformations and highlight the surgical difficulties encountered. Observational, retrospective study. Tertiary referral children's hospital pediatric cochlear implant program. An IRB-approved retrospective chart review of children undergoing cochlear implantation at a tertiary academic medical center, from 2018 to 2023. Preoperative imaging data of syndromic patients in that cohort with special attention to the presence of inner ear or middle ear malformations were collected. Abnormal intraoperative findings and difficulties reported by the surgeons were also noted. 1024 children were unilaterally implanted for bilateral profound hearing loss. There were 45 cases diagnosed with associated syndromes (4.3%). The commonest syndromes were Jervell and Lange Nielsen (JLN) syndrome followed by Waardenberg syndrome (WS), in a prevalence of 34% and 32% respectively. These syndromes had no associated inner ear malformations (IEM). Less common syndromes included Branchio-oto-renal (BOR) syndrome, CHARGE association and Treacher Collins syndrome, 3 cases each, and keratosis icthyosis deafness syndrome (KID), Usher syndrome and Albino, 2 cases each and an H syndrome case. There were 9 cases (20%) with IEM, with 6 cases of perilymph gusher. Two cases had middle ear anomalies and one case had a facial nerve course abnormality. The outcome of these cases was similar to non-syndromic cases. Children with syndromic HL should be dealt with on a case by case scenario to diagnose inner and middle ear malformations. Additional disabilities can affect the rehabilitation procedures. All children with congenital hearing loss should undergo pediatric, cardiologic, ophthalmologic and nephrologic examination in order to exclude the syndromic etiology of hearing loss.

Latent disentanglement in mesh variational autoencoders improves the diagnosis of craniofacial syndromes and aids surgical planning

Background and objective:The use of deep learning to undertake shape analysis of the complexities of the human head holds great promise. However, there have traditionally been a number of barriers to accurate modelling, especially when operating on both a global and local level. Methods:In this work, we will discuss the application of the Swap Disentangled Variational Autoencoder (SD-VAE) with relevance to Crouzon, Apert and Muenke syndromes. The model is trained on a dataset of 3D meshes of healthy and syndromic patients which was increased in size with a novel data augmentation technique based on spectral interpolation. Thanks to its semantically meaningful and disentangled latent representation, SD-VAE is used to analyse and generate head shapes while considering the influence of different anatomical sub-units. Results:Although syndrome classification is performed on the entire mesh, it is also possible, for the first time, to analyse the influence of each region of the head on the syndromic phenotype. By manipulating specific parameters of the generative model, and producing procedure-specific new shapes, it is also possible to approximate the outcome of a range of craniofacial surgical procedures. Conclusion:This work opens new avenues to advance diagnosis, aids surgical planning and allows for the objective evaluation of surgical outcomes. Our code is available at github.com/simofoti/CraniofacialSD-VAE.

Using A Disentangled Neural Network to Objectively Assess the Outcomes of Midfacial Surgery in Syndromic Craniosynostosis.

Advancements in artificial intelligence and the development of shape models that quantify normal head shape and facial morphology provide frameworks by which the outcomes of craniofacial surgery can be compared. In this work, we will demonstrate the use of the Swap Disentangled Variational Autoencoder (SD-VAE) to objectively assess changes following midfacial surgery. Our model is trained on a dataset of 1405 3D meshes of healthy and syndromic patients which was augmented using a technique based on spectral interpolation. Patients with a diagnosis of Apert and Crouzon syndrome who had undergone sub- or trans-cranial midfacial procedures utilising rigid external distraction were then interpreted using this model as the point of comparison. A total of 56 patients met our inclusion criteria, 20 with Apert and 36 with Crouzon syndrome. By using linear discriminant analysis to project the high-dimensional vectors derived by SD-VAE onto a 2D space, the shape properties of Apert and Crouzon syndrome can be visualised in relation to the healthy population. In this way, we are able to show how surgery elicits global shape changes in each patient. To assess the regional movements achieved during surgery, we use a novel metric derived from the Malahanobis distance to quantify movements through the latent space. Objective outcome evaluation, which encourages in-depth analysis and enhances decision making, is essential for the progression of surgical practice. We have demonstrated how artificial intelligence has the ability to improve our understanding of surgery and its effect on craniofacial morphology.

BONE FORMATION IN UNILATERAL CLEFT LIP AND PALATE PATIENTS AFTER EARLY SECONDARY GINGIVOALVEOLOPLASTY AND BONE GRAFT: LONG-TERM STUDY.

The aim of this study was to conduct a comparative analysis, utilizing CT scans, of ossification patterns in unilateral cleft lip and palate (UCLP) patients who underwent early secondary gingivoalveoloplasty (esGAP) versus those who underwent traditional alveolar bone grafting harvested from the iliac crest (IC). 22 CT scans of patients consecutively treated with esGAP were compared with those of 21 patients treated with bone grafting from iliac crest (IC). Inclusion criteria were non syndromic UCLP patients in permanent dentition. Two parameters were considered: the alveolar thickness, measured at three levels, and the nasoalveolar height. All measurements were normalized and ratios of the affected versus non affected sides were provided as well as the statistical comparison between the two groups' ossification outcomes. In the esGAP sample nasoalveolar height was categorized as ideal and good in 86.36% and in 13.64% of the cases and no mediocre or insufficient ossification was detected, while in the bone grafting sample 38.10% had ideal and good ossification, 14.29% mediocre and 9.52% insufficient. As regard the alveolar thickness, when we consider the average of three levels, for the esGAP sample was ideal and good in 57.57% and in 30.30% of the cases and for the IC sample in 41.27% and in 25.40% of the cases, respectively. The analysis detected a statistically significant difference in the ossification outcomes in the two samples. EsGAP yields superior ossification grades in comparison to IC bone grafting.

Biobank for craniosynostosis and faciocraniosynostosis, rare pediatric congenital craniofacial disorders: a study protocol.

Craniosynostosis (CRS) is a rare congenital cranial malformation in which 1 or more cranial or facial sutures are fused in utero or rapidly fused in early infancy. The cranial sutures separate the skull bone plates and enable rapid growth of the skull in the first 2years of life, in which growth is largely dictated by growth of the brain. CRS is a rare disease that occurs in 1 in 2100 to 1 in 2500 births and may be either nonsyndromic (also referred to as isolated) or syndromic. In syndromic CRS, other birth defects are present next to the CRS. The distinction between nonsyndromic and syndromic manifestations is made on the basis of dysmorphologic evaluation and genetic evaluation. Owing to advances in genetic diagnostics, nonsyndromic patients are increasingly recognized as syndromic patients. CRS treatment is almost entirely surgical and is sometimes paired with postoperative helmet therapy for maintenance. Corrective procedures are complex, long, and associated with the risk of numerous complications, including heavy blood loss and its sequelae. Although surgery may restore a normal appearance, even in nonsyndromic patients, patients may experience persistent deficits in intellectual ability and cognitive function. The European Commission (EC) has prioritized rare diseases in recent horizon European research programs; indeed, collections or even individual samples may be extremely valuable for research. Here, we present a study protocol in which the combined expertise of clinicians and researchers will be exploited to generate a biobank dedicated to CRS. The generation of the CRS biobank presented in this study will include the collection of different types of biological materials as well as advanced radiological images available to the scientific community. The activation of a CRS biobank will provide an opportunity to improve translational research on CRS and to share its benefits with the scientific community and patients and their families.

Treatment of Orthognathic Surgical Class III Patient with Coffin–Siris Syndrome: A Case Report

We present a case report of a 26-year-old female suffering from Coffin–Siris Syndrome, who underwent orthodontic treatment and surgery to solve her malocclusion and to improve her aesthetics and functional occlusion. Methods: The presurgical phase involved multibracket self-ligating attachments, namely a Damon prescription. The patient underwent maxillofacial surgery to correct the severe skeletal malocclusion and to relocate the bone bases to the right position. Post-surgical orthodontic treatment was performed to complete the alignment. Results: The patient’s aesthetics and functional abilities improved. Conclusions: Syndromic patients can undergo orthodontic treatment if comorbidities and collaboration allow it. The support and collaboration of families and psychotherapists must be considered, but clinical cases of syndromic patients can be faced and solved. Obviously, each syndromic patient is considered unique, and the risk–benefit ratio must be correctly assessed for each one.

Anaesthetic Challenge in a Child with Hurler’s Syndrome: Encouraging Experience with Neuraxial Blockade

Mucopolysaccharidoses are uncommon genetic diseases with multisystem involvement. The potential for airway difficulties and varying success rate of neuraxial blockade demands considerable expertise in the anesthetic management in these patients. Airway management has evolved significantly in such syndromic patients with the increasing use of video laryngoscopes and Supraglottic airway devices. However, airway catastrophes are not uncommon. This calls for better utilization of neuraxial and peripheral nerve blocks along with the use of newer agents for sedation having a favorable pharmacological profile. Here, we present a case of child having Hurler disease with an inguinal hernia successfully operated under subarachnoid blockade.

Frequency of fistula in patients operated for primary cleft palate repair in a tertiary care center.

Objective: To determine the frequency of fistula in patients undergoing primary cleft palate repair. Study Design: Descriptive Case Series study. Setting: Burns and Plastic Surgery Center, HMC, Peshawar. Period: February 2023 to December 2023. Methods: Patient of both genders males and females undergoing primary cleft palate repair were included in the study with age ranging from 9 to 18 months age excluding patients with comorbids and syndromic patients. Non-probability consecutive sampling was adopted. The data was acquired from patients and hospital record and analyzed with statistical package for social sciences (SPSS). Results: Our study shows that among 169 patients, mean age was 10 months with SD ± 5.11. 100(59%) patients were male and 69(41%) patients were female. More over 3(2%) patients had fistula while 166(98%) patients didn’t had fistula. Conclusion: In this study we observed an internationally acceptable frequency of post-palatal repair fistula for primary cleft palate in our study population.

A Potential Pathogenic SRD5A2 Mutation and rs632148, rs523349 and rs522638 Polymorphisms in Increasing the Risk of Syndromic Hypospadias in Indonesian Population

BACKGROUND: Hypospadias, a congenital birth defect in male, is the opening of the urethra located on the ventral side of the penis. Several mutations in SRD5A2 encoding steroid 5 alpha-reductase type 2 protein have been identified in hypospadias and polymorphisms in this gene have been known to be associated with an increased risk of hypospadias. In this study, several crucial molecular analyses of the SRD5A2 gene and the association of the identified variants to the risk of syndromic hypospadias in Indonesian population were conducted.METHODS: Thirty-two isolated and 29 syndromic hypospadias patients were enrolled in this study. DNA was isolated from whole blood for the amplification of all exons and exon-intron boundaries of SRD5A2 by polymerase chain reaction (PCR), followed by Sanger sequencing. In silico analysis was performed using PolyPhen-2, Sorting Intolerant from Tolerant (SIFT) and Align GVGD. Statistical analysis was performed using Chi-squared test.RESULTS: A novel missense mutation c.32T>C/p.Leu11Pro was identified in one isolated hypospadias patient and the in silico analysis predicted the mutation to be pathogenic. Three polymorphisms were identified, two in the non-coding region (c.-62G>C/rs632148 and c.281+15T>C/rs522638) and one in exon-1 (c.265C>G/p.Val89Leu/rs523349). Mutant alleles of these polymorphisms were significantly associated with syndromic hypospadias with odds ratios (OR) of 3.4, 3.13 and 2.54 respectively.CONCLUSION: This study suggests that SRD5A2 mutation is one of the causes of hypospadias in Indonesian population and rs632148, rs523349 and rs522638 polymorphisms are significantly associated with an increased risk of syndromic hypospadias.KEYWORDS: mutation, polymorphism, SRD5A2, syndromic hypospadias

The diagnostic yield of genetic and metabolic investigations in syndromic and nonsyndromic patients with autism spectrum disorder, global developmental delay, or intellectual disability from a dedicated neurodevelopmental disorders genetics clinic.

First-tier genetic investigations for patients with neurodevelopmental disorders (NDDs) may include chromosomal microarray, Fragile X testing, and screening for inherited metabolic diseases, but most remain undiagnosed upon completion of testing. Here, we report the diagnostic yields of genetic testing for 537 patients with at least one of autism spectrum disorder, global developmental delay, and/or intellectual disability. Patients were assessed in a single neurodevelopmental genetics clinic, and each underwent a standardized history and physical examination. Each patient was characterized as syndromic or nonsyndromic based on clinical features. Our results demonstrate that multigene sequencing (with an NDD gene panel or exome) had a higher diagnostic yield (8%; 95% confidence interval [CI]: 5%, 13%) than chromosomal microarray and Fragile X testing combined (4%; 95% CI: 3%, 7%). Biochemical screening for inherited metabolic diseases had a diagnostic yield of zero. The diagnostic yield of genetic testing was significantly higher for syndromic patients than for nonsyndromic patients (odds ratio [OR] 3.09; 95% CI: 1.46, 6.83) and higher for female patients than for male (OR 3.21; 95% CI: 1.52, 6.82). These results add to the growing evidence supporting a comprehensive genetic evaluation that includes both copy number analysis and sequencing of known NDD genes for patients with NDDs.

Minimally Invasive Method for Treatment of Syndromic Congenital Vertical Talus Deformity in Children.

Congenital Vertical Talus (CVT) is a rare form of rigid flatfoot commonly seen in patients with underlying neurologic syndromes. This study aims to evaluate the long-term effectiveness of the minimally invasive method for correcting CVT deformity in a large cohort of syndromic patients. A single author recorded preoperative, 2-week postoperative, 1-year postoperative, and most recent radiographic measurements and complications for 25 patients treated with the minimally invasive method from 2006 to 2021. Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires were administered for 12 patients after January 1, 2015, when the institution began collecting PROMIS in all orthopaedic patients. Average follow-up was 55 months (13-111); 18 patients had minimum 24-month follow-up. Forty feet in 25 patients were analyzed. The average preoperative lateral talar axis-first metatarsal base angle (TAMBA) was 68.7 ± 21.3 vs 12.1 ± 8.9 after initial surgical intervention (P < .0001). There was a statistically significant increase in the lateral TAMBA between the initial postoperative and final follow-up visits (13.0 vs 21.6, P = .02). Radiographic recurrence of talonavicular deformity was noted in 12 feet (30.9%); 7 (15.55%) required corrective surgery. Larger preoperative lateral TAMBA was predictive of recurrence. Notably, patients with arthrogryposis experienced higher radiographic recurrence than other syndromic patients (45.0% vs 14.3%, P = .0384). PROMIS scores were within population norms. The study suggests that less than one-third of syndromic CVT patients experienced a radiographic recurrence of talonavicular deformity, with 15% requiring further surgical intervention at an average of 55 months following the initial procedure. A higher incidence of radiographic recurrence occurred in patients with distal arthrogryposis. These findings, along with the satisfactory patient-reported outcomes, suggest that the minimally invasive technique is an effective treatment method for syndromic CVT, underscoring the necessity for clinicians to provide detailed prognoses and consider more intensive follow-up for those at higher risk.

Management of Midface Deficiency in Syndromic Craniosynostosis with Lefort III Distraction Osteogenesis, Outcomes, and Pitfalls.

Syndromic craniosynostosis is characterized by premature fusion of cranial sutures resulting in midface deficiency. Lefort III Distraction Osteogenesis (DO) has emerged as an effective surgical intervention for addressing this complex condition. This case series outlines the outcomes, encountered difficulties, and insights gained through the utilization of Lefort III Distraction Osteogenesis (DO). Six patients (age range: 8-18years) diagnosed with syndromic craniosynostosis underwent Lefort III DO for midface deficiency correction. Comprehensive preoperative orthodontic preparation and meticulous surgical planning were executed. The present paper highlighted the promising outcomes with Lefort III DO, such as significant advancements in midface projection, enhanced posterior pharyngeal space, improved ocular position, and the establishment of functional occlusion. However, some complications such as CSF blepharocele, pin-tract infection, cranial pin perforation, and loosening of the halo frame were encountered. These challenges were addressed with prompt intervention and close postoperative monitoring. Lefort III DO emerges as a valuable approach in effectively addressing midface deficiency in syndromic craniosynostosis patients. While yielding favorable outcomes in terms of facial aesthetics and function, it requires meticulous surgical technique and vigilant postoperative care to address potential complications. This paper contributes insights into the effective management and potential challenges associated with Lefort III DO in treating midface deficiency in syndromic craniosynostosis patients.