Developmental outcome of children with Robin sequence treated with the current Paris protocol.

AIM: We aimed to investigate the developmental outcome of children with Robin sequence (RS) for whom continuous positive airway pressure was the main strategy to release upper airway obstruction. METHODS: We included children with isolated RS or RS associated with Stickler syndrome who were aged 15 months to 6 years. We used the French version of the Child Development Inventory and calculated the developmental quotient (DQ) for eight different domains and the global DQ (DQ-global). We searched for determinants of risk of delay. RESULTS: Of the 87 children, for 71%, the developmental evolution was within the norm (DQ-global ≥86 or ≥-1 SD), 29% were at high risk of delay (DQ-global <86 or <-1 SD), and only 3% were at very high risk of delay (DQ-global <70 or <-2 SD). The DQs for expressive language and language comprehension were lower in our study population than the general population, but an improvement was noticed with the children's growth. CONCLUSION: Risk of a developmental delay was not greater for children with the most severe respiratory phenotype than the others. Children whose mothers had low education levels were more at risk than the others.

Study protocol for a multicenter, multinational, observational registry of epidemiology, treatment and outcome of patients with Robin sequence.

BACKGROUND: Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis and upper airway obstruction. Diagnosis and treatment are characterized by heterogeneity, resulting in a lack of uniformly collected data. METHODS: We have set up a prospective, observational, multicenter, multinational registry aimed at obtaining routine clinical data from RS patients receiving different treatment approaches and enabling an assessment of outcomes obtained through different therapeutic approaches. Patient enrolment has started in January 2022. Disease characteristics, adverse events and complications depending on the different diagnostic and treatment approaches and their effects on neurocognition, growth, speech development and hearing outcome are evaluated using routine clinical data. In addition to characterizing the patient population and comparing outcomes achieved with different treatment approaches, the registry will evolve to focus on endpoints such as quality of life and long-term developmental status. DISCUSSION: This registry will provide data on different treatment approaches collected during routine care with diverse framework conditions and will allow assessing diagnostic and therapeutic outcomes of children with RS. These data, urgently demanded by the scientific community, may contribute to refining and personalizing existing therapeutic approaches and increase knowledge about the long-term outcome of children born with this rare condition. TRIAL REGISTRATION: DRKS00025365.

Peri- and neonatal factors influencing mortality and morbidity 2 years after esophageal atresia primary repair: a single center retrospective study.

Long-term digestive, respiratory, and neurological morbidity is significant in children who have undergone surgery for esophageal atresia (EA), especially after staged repair for long-gap EA. Risk factors for morbidity after primary repair (non-long-gap populations) have been less documented. We investigated peri- and neonatal factors associated with unfavorable outcomes in children 2 years after primary esophageal anastomosis. This was a single-center retrospective study, based on neonatal, surgical, and pediatric records of children born between December 1, 2002, and December 31, 2018, and followed up to age 2 years. The primary endpoint was unfavorable outcome at 2 years of age, defined by death or survival with severe respiratory, digestive, or neurologic morbidity. Univariate analyses followed by logistic regression analyses were performed to identify the peri- and neonatal risk factors of unfavorable outcomes among survivors at discharge. A total of 150 neonates were included (mean birth weight 2520 ± 718 g, associated malformations 61%); at age 2, 45 (30%) had one or more severe morbidities and 11 had died during the neonatal stay and 2 after discharge (8.7% deaths). In multivariate analyses of the 139 survivors at discharge, duration of ventilatory support (invasive and non-invasive) for more than 8 days (OR 3.74; CI95% [1.68-8.60]; p = 0.001) and achievement of full oral feeding before hospital discharge (OR 0.20; CI95% [0.06-0.56]; p = 0.003) were independently associated with adverse outcome after adjustment for sex, preterm birth, associated heart defect, any surgical complication, and the occurrence of more than one nosocomial infections during the neonatal stay. CONCLUSIONS: Post-operative ventilation and feeding management strategies may represent an opportunity for quality-of-care improvement to positively impact long-term outcomes after primary esophageal atresia repair. WHAT IS KNOWN: • Children operated on for esophageal atresia experience long-term digestive, respiratory, and neurologic morbidity, especially after multiple-stage esophageal repair. • Exclusive oral feeding at discharge is associated with a decreased risk of medical complications in the first years of life, in studies including all types of esophageal atresia repair. Outcomes of children after primary repair (non-long gap populations) have been less documented. WHAT IS NEW: • In our retrospective cohort of children with one-stage esophageal atresia repair, ventilatory support for more than 8 days and inability to achieve full oral feeding before hospital discharge in the neonatal period were independently associated with adverse digestive, respiratory, and neurologic outcomes at 2 years in survivors. • Both these factors are potentially modifiable, representing an opportunity for quality-of-care improvement to positively impact long-term outcomes. These results might also help identify children at risk of unfavorable evolution, to customize a multi-disciplinary follow-up program.

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.

Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1.

DNA polymerase δ is one of the three main enzymes responsible for DNA replication. POLD1 heterozygous missense variants in the exonuclease domain result in a cancer predisposition phenotype. In contrast, heterozygous variants in POLD1 polymerase domain have more recently been shown to be the underlying basis of the distinct autosomal dominant multisystem lipodystrophy disorder, MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome OMIM # 615381), most commonly a recurrent in-frame deletion of serine at position 604, accounting for 18 of the 21 reported cases of this condition. One patient with an unusually severe phenotype has been reported, caused by a de novo c. 3209 T > A, (p.(Ile1070Asn)) variant in the highly conserved CysB motif in the C-terminal of the POLD1 protein. This region has recently been shown to bind an iron-sulphur cluster of the 4Fe-4S type. This report concerns a novel de novo missense variant in the CysB region, c.3219 G > C, (p.(Ser1073Arg)) in a male child with a milder phenotype. Using in silico analysis in the context of the recently published structure of human Polymerase δ holoenzyme, we compared these and other variants which lie in close proximity but result in differing degrees of severity and varying features. We hypothesise that the c.3219 G > C, (p.(Ser1073Arg)) substitution likely causes reduced binding of the iron-sulphur cluster without significant disruption of protein structure, while the previously reported c.3209 T > A (p.(Ile1070Asn)) variant likely has a more profound impact on structure and folding in the region. Our analysis supports a central role for the CysB region in regulating POLD1 activity in health and disease.

Weaning children from prolonged enteral nutrition: A position paper.

Enteral nutrition (EN) allows adequate nutritional intake in children for whom oral intake is impossible, insufficient or unsafe. With maturation and health improvements, most children ameliorate oral skills and become able to eat orally, therefore weaning from EN becomes a therapeutic goal. No recommendations currently exist on tube weaning, and practices vary widely between centres. With this report, the French Network of Rare Digestive Diseases (FIMATHO) and the French-Speaking Group of Paediatric Hepatology, Gastroenterology and Nutrition (GFHGNP) aim to develop uniform clinical practice recommendations for weaning children from EN. A multidisciplinary working group (WG) encompassing paediatricians, paediatric gastroenterologists, speech-language therapists, psychologists, dietitians and occupational therapists, was formed in June 2018. A systematic literature search was performed on those published from January 1, 1998, to April 30, 2020, using MEDLINE. After several rounds of e-discussions, relevant items for paediatric tube weaning were identified, and recommendations were developed, discussed and finalized. The WG members voted on each recommendation using a nominal voting technique. Expert opinion was applied to support the recommendations where no high-quality studies were available.

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review.

Objectives: Cyproheptadine is a first-generation H1-antihistamine drug first that was distributed in the 1960s. While its orexigenic effect was observed early, cyproheptadine is not yet authorized for this indication in all countries today. There is an increasing medical interest and demand for the orexigenic effect of cyproheptadine, especially in children with poor appetite. As cyproheptadine might be evaluated in future clinical trials, we wanted to assess its safety profile. Methods: Using the French national pharmacovigilance database, we retrospectively analyzed all pediatric and adult reports of adverse effects of cyproheptadine recorded since its first distribution in France. Next, we performed a systematic review of the literature of cyproheptadine adverse effects. Results: Since 1985, 93 adverse effects were reported in the French pharmacovigilance database (adults 81.7%, children 18.3%); these were mainly neurological symptoms (n = 38, adults 71%, children 28.9%), and hepatic complications (n = 15, adults 86.7%, children 13.3%). In the literature, the most frequent adverse effect reported was drowsiness in adults or children, and five case reports noted liver complications in adults. We estimated the frequency of hepatic adverse effects at 0.27 to 1.4/1000, regardless of age. Conclusion: Cyproheptadine can be considered a safe drug. Mild neurological effects appear to be frequent, and hepatotoxicity is uncommon to rare. Randomized controlled trials are needed to evaluate the safety and efficacy of cyproheptadine before authorization for appetite stimulation, especially in young children as studies at this age are lacking. Possible hepatic complications should be monitored, as very rare cases of liver failure have been reported.

Quality of life and phonatory and morphological outcomes in cognitively unimpaired adolescents with Pierre Robin sequence: a cross-sectional study of 72 patients.

BACKGROUND: Pierre Robin sequence (PRS) is a heterogeneous condition involving retro(micro)gnathia, glossoptosis and upper airway obstruction, very often with posterior cleft palate. Patients with PRS, either isolated or associated with Stickler syndrome have good intellectual prognosis. Nevertheless, the quality of life in adolescence and the phonatory and morphological outcomes are rarely analysed. We assessed the phonatory and morphological outcomes of 72 cognitively unimpaired adolescents with PRS, studied their oral (COHIP-SF19), vocal (VHI-9i) and generic quality of life (QoL; KIDSCREEN-52), and searched for determinants of these outcomes. RESULTS: Two-thirds of our adolescents retained low or moderate phonation difficulties, but risk factors were not identified. For 14%, morphological results were considered disharmonious, with no link to neonatal retrognathia severity. Only one vs two-stage surgery seemed to affect final aesthetic results. The oral QoL of these adolescents was comparable to that of control patients and was significantly better than that of children with other craniofacial malformations (COHIP-SF19 = 17.5, 15.4 and 25.7, respectively). The oral QoL of the adolescents with non-isolated PRS was significantly worse (COHIP-SF19 = 24.2) than that of control patients and close to that of children with other craniofacial malformations. The vocal QoL of the adolescents (mean [SD] VHI-9i = 7.5 [5.4]) was better than that of patients with other voice pathologies and better when phonation was good. The generic QoL of the adolescents was satisfactory but slightly lower than that of controls, especially in dimensions concerning physical well-being, relationships and autonomy. QoL results were lower for adolescents with non-isolated than isolated PRS. Only non-isolated PRS and low oral QoL affected generic QoL. CONCLUSION: Morphological or phonatory impairments remain non-rare in adolescents with PRS but do not seem to be directly responsible for altered QoL. These adolescents, especially those with non-isolated PRS, show self-confidence and social-relation fragility. We must focus on long-term functional and psychological results for PRS patients and improve therapy protocols and follow-up, notably those affecting the oral aspects of the disease.

Managing infants with craniofacial malformations - Where to go next?

Treatment of infants with craniofacial malformations, e.g. Robin sequence, is characterized by considerable heterogeneity and a lack of randomized trials to identify an optimal approach. We propose to establish an international register using a common minimal dataset that will better allow for a comparison between key determinants and outcomes in these patients. In infants, this should include an assessment of mandibular micrognathia, glossoptosis, upper airway obstruction, weight gain and mode of feeding. Later on, neurocognition, speech development, hearing and quality of life should also be included. Together, these data will help better to advice parents on which treatment to choose for their baby with a craniofacial malformation.

Objective measurements for upper airway obstruction in infants with Robin sequence: what are we measuring? A systematic review.

STUDY OBJECTIVES: Identifying optimal treatment for infants with Robin sequence (RS) is challenging due to substantial variability in the presentation of upper airway obstruction (UAO) in this population. Objective assessments of UAO and treatments are not standardized. A systematic review of objective measures of UAO was conducted as a step toward evidence-based clinical decision-making for RS. METHODS: A literature search was performed in the PubMed and Embase databases (1990-2020) following PRISMA guidelines. Articles reporting on RS and UAO treatment were included if the following objective measures were studied: oximetry, polysomnography, and blood gas. Quality was appraised by the methodological index for nonrandomized studies (range: 0-24). RESULTS: A total of 91 articles met the inclusion criteria. The mean methodological index for nonrandomized studies score was 7.1 (range: 3-14). Polysomnography was most frequently used (76%) followed by oximetry (20%) and blood gas (11%). Sleep position of the infant was reported in 35% of studies, with supine position most frequently, and monitoring time in 42%, including overnight recordings, in more than half. Of 71 studies that evaluated UAO interventions, the majority used polysomnography (90%), of which 61% did not specify the polysomnography technique. Reported polysomnography metrics included oxygen saturation (61%), apnea-hypopnea index (52%), carbon dioxide levels (31%), obstructive apnea-hypopnea index (27%), and oxygen desaturation index (16%). Only 42 studies reported indications for UAO intervention, with oximetry and polysomnography thresholds used equally (both 40%). In total, 34 distinct indications for treatment were identified. CONCLUSIONS: This systematic review demonstrates a lack of standardization, interpretation, and reporting of assessment and treatment indications for UAO in RS. An international, multidisciplinary consensus protocol is needed to guide clinicians on optimal UAO assessment in RS. CITATION: Logjes RJH, MacLean JE, de Cort NW, et al. Objective measurements for upper airway obstruction in infants with Robin sequence: what are we measuring? A systematic review. J Clin Sleep Med. 2021;17(8):1717-1729.

Should autism spectrum disorder be considered part of CHARGE syndrome? A cross-sectional study of 46 patients.

BACKGROUND: Behavioral problems are an important issue for people with CHARGE syndrome. The similarity of their behavioral traits with those of people with autism raises questions. In a large national cross-sectional study, we used specific standardized tools for diagnosing autism (Autism Diagnostic Interview-Revised and Diagnostic and Statistical Manual of Mental Disorders, 5th edition, DSM-5) and evaluating behavioral disorders (Developmental Behavior Checklist-Parents, DBC-P) to investigate a series of individuals with CHARGE syndrome, defined by Verloes's criteria. We evaluated their adaptive functioning level and sensory particularities and extracted several data items from medical files to assess as potential risk factors for autism and/or behavioral disorders. RESULTS: We investigated 64 individuals with CHARGE syndrome (35 females; mean age 10.7 years, SD 7.1 years). Among 46 participants with complete results for the Autism Diagnostic Interview-Revised (ADI-R), 13 (28%) had a diagnosis of autism according to the ADI-R, and 25 (54%) had a diagnosis of autism spectrum disorder (ASD) according to the DSM-5 criteria. The frequency of autistic traits in the entire group was a continuum. We did not identify any risk factor for ASD but found a negative correlation between the ADI-R score and adaptive functioning level. Among 48 participants with data for the DBC-P, 26 (55%) had behavioral disorders, which were more frequent in patients with radiological brain anomalies, impaired adaptive functioning, later independent walking, and more sensory particularities. CONCLUSIONS: ASD should be considered to be an independent risk requiring early screening and management in children born with CHARGE syndrome.

[Creation of a tool to help assess eating disorders in young children]. / Création d'un outil d'aide à l'évaluation des troubles de l'oralité alimentaire du jeune enfant.

In order to optimize the care of young hospitalized children with eating disorders, the Orality group at the Necker-Enfants malades University Hospital in Paris has created a therapeutic education tool: the Fleur des sens. This flower which is to be colored at the end of the meal with the child has nine petals representing nine foods that make up the meal, which were initially difficult or even impossible for the young patient to eat. This tool participates in the educational diagnosis and then in the formative evaluation of the child. It is also useful for the parents' understanding of the disease, making the link between sensoriality and food orality.

Functional Vision Analysis in Patients With CHARGE Syndrome.

PURPOSE: To evaluate functional vision in patients with CHARGE syndrome (coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital and urinary anomalies, and ear anomalies) by using a new questionnaire entitled VISIOCHARGE. METHODS: Ophthalmological data including fundus description and visual acuity, when available, were extracted from the charts of 83 patients with CHARGE syndrome, and the VISIOCHARGE questionnaire was prospectively mailed to 55 of those patients. The answers from the 36 responders (18 males) allowed for the calculation of three scores that assessed distance vision, near vision, and overall ability scores. RESULTS: Visual acuity measurements were extracted from the charts of 20 of the 36 patients. The mean visual acuity was 20/50. The mean distance vision score of 0.62 ± 0.30 and near vision score of 0.78 ± 0.23 were correlated with visual acuity in the 20 patients (ρ = 0.64, P = .002 and ρ = 0.61, P = .005, respectively) and were associated with the severity of colobomatous malformation (P = .049 and P = .008, respectively). Severity of the ocular malformation was not associated with the overall ability score (P = .64). CONCLUSIONS: The VISIOCHARGE questionnaire is feasible for patients with CHARGE syndrome and may help in the assessment of visual function. The mean visual acuity and answers to the VISIOCHARGE questionnaire showed relatively good visual skills in patients with CHARGE syndrome in everyday life, even in those with bilateral colobomas, which contrasts with the pessimistic conclusions usually resulting from the initial fundus examination. [J Pediatr Ophthalmol Strabismus. 2020;57(2):120-128.].

Scurvy: A New Old Cause of Skeletal Pain in Young Children.

We report 3 cases of scurvy in children that occurred during a short period (2018) in a general pediatrics unit of a tertiary hospital for children in Paris. All children were around 3 years of age and were admitted for skeletal pain and altered general state, which mimicked infectious or malignant diseases. Their selective diet was not the prominent issue. The diagnosis of scurvy was delayed, after too many unnecessary examinations and medications. Bone imaging findings (X-ray and MRI) were a posteriori considered typical, but lesions were not easily identified as scurvy lesions because scurvy is not well-known by pediatricians and radiologists who should be mindful of this historical diagnosis.

Severity of Retrognathia and Glossoptosis Does Not Predict Respiratory and Feeding Disorders in Pierre Robin Sequence.

Pierre Robin sequence (PRS) may lead to life-threatening respiratory and feeding disorders. With the aim to analyse the association of the severities of retrognathia and glossoptosis with those of respiratory and feeding disorders, we retrospectively studied a series of 50 infants with retrognathia, glossoptosis, cleft palate, and airway obstruction. The patients were managed from birth to at least 6 years of age by a single pediatric team at the Armand Trousseau Hospital in Paris within a 12 years period (2000-2012). Retrognathia and glossoptosis were graded in the neonatal period according to a specific clinical examination. Ventilation assistance was required for 32/50 (64%) patients, and enteral feeding for 41/50 (82%). The grades of retrognathia and glossoptosis and the severity of respiratory disorders did not differ between patients with isolated PRS and syndromic PRS. Severe respiratory disorders were more common and long-lasting feeding (>12 months) was more frequently required in patients with syndromic PRS compared with isolated PRS (42 vs. 13%, p = 0.04 and 42 vs. 4%, p < 0.01 respectively). Using univariate analysis, neurological impairments and laryngomalacia were associated with severe respiratory disorders [Odds ratio (OR) 5.0, 95% CI 1.3-19.6; and OR 14.6, 95% CI 1.3-161.4; p < 0.05] as well as with long-lasting feeding (>12 months) disorders (OR 18.6, 95% CI 3.9-89.2 and OR 20.4, 95% CI 3,4-122.8; p < 10-2). Syndromic SPR status was also associated with severe respiratory disorders (OR 4.9, 95% CI 1-32.5; p < 0.05). Using multivariate analysis, only syndromic PRS status was predictive for severe respiratory disorders (adjusted OR 8, 95% CI 1.47-44.57; p < 0.05); and only neurological impairments remained a significant risk for long lasting feeding disorders (>12 months) (adjusted OR 21.72, 95% CI 3.4-138.63; p < 10-2). The grades of retrognathia and glossoptosis were not predictive factors for the severity of respiratory and feeding disorders. Conclusion: In children with PRS, the severity of clinical conditions may not correlate with anatomic variables but rather with laryngeal abnormalities, neurological impairement and syndromic PRS status.

A Program for Weaning Children from Enteral Feeding in a General Pediatric Unit: How, for Whom, and with What Results?

OBJECTIVE: To describe a series of children who were hospitalized for a tube-weaning program in the general pediatric ward of a pediatric tertiary university hospital: describe our method, to determine the success rate of our inpatient pediatric tube weaning program, and search for relevant factors linked to its success or failure. METHOD: We analyzed the medical files of consecutive children who were hospitalized for gastric-tube weaning over an 8-year period. We analyzed outcomes in terms of feeding and growth with at least 2 years of data. Success (weaning within 3 months) and failure were compared by characteristics of children. RESULTS: We included 37 children (29 females) with mean (SD) age 31.4 (21) months. Most had a severe medical history (30% prematurity; 50% intrauterine growth restriction, 50% neurological and genetic anomalies). The weaning program was successful for half of the children. Factors linked to success of the program were female sex (p = 0.0188), normal neurodevelopment (p = 0.0016), nasogastric tube (p = 0.0098), and with <24 months on EF before the stay (p = 0.0309). DISCUSSION: Comparing the efficiency of various methods and results among teams was difficult, which indicates the need to establish consensus about the outcome criteria. We confirm the need for these types of stays and programs.

Hair analysis does not allow to discriminate between acute and chronic administrations of a drug in young children.

There are many differences between the hair from children and that of adult subjects, the hair being thinner, more porous with a different growth rate from the usual 1 cm/month observed in adults. In order to determine whether hair analysis could discriminate between chronic use and acute administration of a drug in children like in adults, we analyzed hair from 18 children aged between 1 day and 15 years in whom the administration of different drugs was known (single therapeutic administration or acute intoxication). A strand of hair was sampled within 1 to 45 days after treatment or intoxication. Analysis was conducted using LC/MS/MS. In the 10 youngest children, aged between 1 day and 29 months, the compounds administered in hospital or responsible for intoxication (lidocaine, ropivacaine, diazepam, midazolam, levetiracetam, morphine, ketamine, methadone, buprenorphine, THC, MDMA) were found in all segments of the hair independently of the time of sampling (1-45 days after ingestion). The concentrations detected were similar along the hair shaft, showing a radial diffusion and incorporation of the analytes in the hair of young children from the sebum. Concentrations could be very high when sampled shortly after administration (72 ng/mg for methadone, 75 ng/mg for MDMA after 3 days) and lower when sampling later (1.2 ng/mg for MDMA after 45 days). In these cases, hair analysis allowed to highlight the compounds responsible for intoxication even when they had disappeared from the blood or urine but should not be used to discriminate long-term exposure to a drug. In the eight remaining children aged from 34 months to 15 years, the drugs used in hospital (lidocaine, diazepam, morphine) or responsible for intoxication (THC, codeine, buprenorphine) were not found in any analyzed segments sampled 1 to 5 days after administration of the drugs, in agreement with the non-incorporation of the drugs from the sebum into the hair. For those children aged over 34 months, hair analysis allows to determine the chronic administration of a drug, like in adults.

MED13L loss-of-function variants in two patients with syndromic Pierre Robin sequence.

We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the cause of an intellectual disability syndrome with associated facial dysmorphism. Our findings suggest that MED13L-related disorders are a possible differential diagnosis for syndromic PRS.

CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays.

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.

Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome.

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.