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.

Imaging Factors Affecting Prenatal Counseling in Orofacial Clefts.

INTRODUCTION: We aim to correlate pre- and postnatal data regarding the cleft type and surgical prognostic factors associated to orofacial clefts. METHODS: Retrospective study concerning all cases of orofacial cleft evaluated prenatally (US+/-MRI) between 2015 and 2020 with available postnatal outcomes. We compared prenatal imaging (cleft type and surgical prognostic factors) with postnatal findings. RESULTS: 48 fetuses were included. Median gestational age at first US/MRI examination: 29+2 WG and 31+6 WG, respectively. The prenatal diagnosis was in accordance with postnatal findings with regard to the cleft type in 88% of the cases (n = 42/48) for US and/or MRI, 84% (n = 38/45) for US only, and 90% (n = 37/41) for MRI only. The nasal septum deviation and nostril collapse were underestimated by prenatal US in 48% (n = 12/25) and 44% (n = 11/25) of cases, respectively (Cohen's kappa of 0.22 and 0.32, respectively). Pre- and postnatal examinations were in accordance with 75% of cases (n = 8) regarding evaluation of anteroposterior maxillary shift in case of unilateral alveolar cleft and in 90% and 80% of cases (n = 10) regarding the degree of protrusion/deviation of the premaxillary protrusion in case of bilateral cleft, respectively. CONCLUSION: Prenatal imaging can accurately assess the type of orofacial cleft and evaluate maxillary shift and deviation of the premaxilla. It underestimates the nose deformity.

Evaluation of prenatal breastfeeding workshop to inform and support mother with antenatal diagnosis of cleft lip/palate.

INTRODUCTION: To support mother with antenatal diagnosis of cleft lip/palate (CL/P), we implement an antenatal breastfeeding workshop to promote breastfeeding and its continuation. The aim of this study was to evaluate patient satisfaction after this workshop and efficiency of this workshop on breastfeeding rates and duration. MATERIALS AND METHODS: We conducted a prospective study from February 2018 to April 2022. Patients received two surveys after the workshop and after birth, to evaluate their satisfaction. A prospective breastfeeding follow-up were pursued by email, at 1-3-6 and 12 months to determine if the breastfeeding had been continued or stopped. RESULTS: We included 124 pregnant women who participated to the workshop. After the workshop, most participants (114/124) answered to the first survey. Amongst the 114 participants who answered to the first survey, 45 participated to a face-to-face workshop; and 69 to a teleworkshop. Participants were globally satisfied or very satisfied from the workshop; and felt more capable to breastfeed their child. 95/124 participants answered to the second survey. Most of the participants considered that the workshop had help them carry on a maternal milk feeding to their child Breastfeeding was pursued 1 month at 90%, 3 months at 62.5%, 6 months at 41.9%, after 6 months at 18.4%. Duration of breastfeeding were not statistically different, depending on the cleft type(p = 0.022). CONCLUSION: The prenatal information helped the future mothers and met their requests and needs. The satisfaction rate reflected the importance of informing and supporting mothers in their feeding choices for their infants. The rate of breastfeeding at birth of a cleft-infant, whatever its type, for mothers who participated in the breastfeeding workshop, was over 90%.

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients.

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flares, esthetic deformities, and, in severe forms, life-threatening conditions. There is no approved medical therapy for patients with lymphatic malformations. In this proof-of-concept study, we developed a genetic mouse model of PIK3CA-related lymphatic malformations that recapitulates human disease. Using this model, we demonstrated the efficacy of alpelisib, an approved pharmacological inhibitor of PIK3CA in oncology, in preventing lymphatic malformation occurrence, improving lymphatic anomalies, and extending survival. On the basis of these results, we treated six patients with alpelisib, including three children, displaying severe PIK3CA-related lymphatic malformations. Patients were already unsuccessfully treated with rapamycin, percutaneous sclerotherapies, and debulking surgical procedures. We assessed the volume of lymphatic malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib administration was associated with improvements in the six patients. Previously intractable vascular malformations shrank, and pain and inflammatory flares were attenuated. MRI showed a decrease of 48% in the median volume of lymphatic malformations over 6 months on alpelisib. During the study, two patients developed adverse events potentially related to alpelisib, including grade 1 mucositis and diarrhea. In conclusion, this study supports PIK3CA inhibition as a promising therapeutic strategy in patients with PIK3CA-related lymphatic anomalies.

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.

Contribution of computed tomography and magnetic resonance imaging in the analysis of fetal craniofacial malformations.

A wide range of craniofacial malformations can be diagnosed in utero using ultrasonography. However, even with highly experienced sonographers and diagnostic physicians and optimal conditions of examination, some anatomical structures cannot be properly analyzed by this technique. The aim of this pictorial essay is to show the additional value of fetal magnetic resonance imaging and computed tomography in this setting and to illustrate the role of these modalities in facial clefts; craniosynostosis; ear, eye and nose abnormalities; otomandibular dysplasias; and facial cephaloceles.

The histopathology of congenital haemangioma and its clinical correlations: a long-term follow-up study of 55 cases.

AIMS: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes. METHODS AND RESULTS: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank. CONCLUSION: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma.

Soft tissue angiomatosis: another PIK3CA-related disorder.

AIM: Angiomatosis of soft tissue (AST) is a rare, high-flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non-syndromic AST arises as a consequence of a somatic mutation. METHODS AND RESULTS: Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients' personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio -0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups. CONCLUSIONS: AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.

Efficacy and Tolerance of Sirolimus (Rapamycin) for Extracranial Arteriovenous Malformations in Children and Adults.

Managing extracranial arteriovenous malformations is challenging. Sirolimus (rapamycin) is increasingly being used when surgery and embolization are not advised. Because of its anti-angiogenic properties here we report all extracranial arteriovenous malformation cases treated with sirolimus in 2 French tertiary centers for vascular anomalies. The outcomes were efficacy (complete, partial, no response) based on arteriovenous malformation volume and necrosis/hemorrhage and side effects. We retrospectively included 10 patients (7 children). The sirolimus dose ranged from 0.6 to 3.5 mg/m2. Median (interquartile range [IQR]) treatment time was 24.5 (4.5; 35) months. Five patients showed no response and 5 showed partial response at a median (IQR) of 3 (1; 5) months followed in 2 cases by therapeutic resistance (i.e., progressive disease after 9 and 24 months of treatment). The most frequent side effect was mouth ulcers. This study shows poor efficacy of sirolimus for treating extracranial arteriovenous malformations.

Author Correction: Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

The 'Competing interests' statement of this Article has been updated; see accompanying Amendment for further details.

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.

Verrucous hemangioma (also known as verrucous venous malformation): A vascular anomaly frequently misdiagnosed as a lymphatic malformation.

Verrucous hemangioma or verrucous venous malformation is a superficial venous malformation frequently misdiagnosed as a lymphatic malformation because of its classical hyperkeratotic appearance. Clinical characteristics of VVM were studied in patients with a histologically confirmed VVM, and validated in a prospective study of 18 patients. VVM was made of separated vascular elements with irregular shape, in a linear disposition, with variable thickness and keratosis. Its specific vascular pattern consisting of an erythematous patch with scattered small red to violet dots was easily identified using dermoscopy. In many cases, the typical clinical presentation of verrucous hemangioma is sufficient to establish the diagnosis and a biopsy may not be required.

Congenital fibroblastic connective tissue nevi: Unusual and misleading presentations in three infantile cases.

BACKGROUND: Fibroblastic connective tissue nevi (FCTN) are benign skin conditions characterized by bland spindle cells infiltrating the reticular dermis and the upper subcutis with preservation of adnexal structures. A subset of FCTN expresses CD34, which may cause difficulties in the differential diagnosis, in particular with dermatofibrosarcoma (DFSP). We aim to study clinical and histological main features of congenital FCTN to better understand their heterogeneity. METHODS: We present 3 cases of congenital FCTN with misleading pseudo-tumoral presentations and compare them with published cases in literature. We provide a diagnostic algorithm for congenital neonatal connective tissue tumors. RESULTS: Clinically, FCTN mostly present as well-limited and nontender plaques or nodules mainly located in the neck and face areas or in the trunk. Histologically, FCTN are composed of irregularly distributed fascicles of bland spindled cells and are defined by a list of fundamental features: (i) no atypia, pleomorphism, or mitotic activity; (ii) skin appendages entrapped but unaffected; (iii) no evidence for malignancy. In most cases CD34 is positive, but in some cases, cells can express SMA or are even CD34- and SMA-. CONCLUSION: The initial presentation and natural history of FCTN fit better with a neoplasm than with a hamartoma. Thus, we suggest replacing the term "nevus" with tumor and considering fibroblastic connective tissue tumor (FCTT) as the right denomination of this clinico-pathological entity. FCTTs are difficult to diagnose due to their clinical heterogeneity. Clinical and histological malignant and benign differential diagnoses are discussed.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Predictors of speech outcomes in children with Pierre Robin sequence.

BACKGOUND: Pierre Robin sequence (PRS) has worse speech outcomes than isolated cleft palate. We aimed to search for possible associations of phonological outcomes with PRS status (isolated vs syndromic), clinical severity, soft palate muscles deficiency, or surgical procedure. METHODS: We designed a retrospective study of 130 children (male/female ratio: 0.4) with isolated (96) or syndromic (34) PRS with cleft palate. Grading systems were used to classify retrognathia, glossoptosis, and respiratory and feeding disorders. Electromyography was used to investigate levator veli palatini muscles. Hard cleft palate was measured using maxillary casts. Intravelar veloplasty was performed using the Sommerlad's technique. Phonological outcomes were assessed using the Borel-Maisonny classification. RESULTS: Cleft palate was repaired in one stage (65.5%) or hard palate closure was postponed (34.5%). Velopharyngeal insufficiency was more frequent in syndromic PRS (53%) vs. isolated PRS (30.5%) (p = 0.01), but was not statistically associated with clinical grade, hard cleft palate width, soft palate electromyography, and surgical procedure. CONCLUSIONS: In children with PRS, anatomic variables, initial clinical severity, and soft palate muscle deficiency are not predictors of speech prognosis.

Efficiency of prenatal diagnosis in Pierre Robin sequence.

OBJECTIVES: To analyze the efficiency of prenatal diagnosis of Pierre Robin sequence (PRS) regarding the final specific diagnosis and to determine whether infants have more severe respiratory disorders with than without prenatally suspected PRS. METHODS: Review of the outcome of all prenatal cases of suspected PRS managed in our prenatal diagnosis center during the last 15 years; analysis of the consistency between prenatal and postnatal diagnoses in 2 groups of women with and without a family history of PRS; comparison of the grades of disease severity for infants with and without prenatally suspected PRS. RESULTS: Fifty-nine files were studied. Prenatal and postnatal consistencies of a specific diagnosis of PRS were 100% for women with a family history of PRS and with prenatally suspected nonisolated PRS. It was 78.6% for those with prenatally suspected isolated PRS. We describe 13 terminations of pregnancy. The 41 children living beyond 18 months seem to have more functionally severe phenotypes than the 227 children without prenatally suspected PRS. CONCLUSION: Prenatal diagnosis of isolated PRS is a challenge as other features can be missed. Use of prenatal chromosomal microarray can improve the accuracy of diagnosis. In all cases, adequate neonatal care should be offered.

Head and neck teratoma: from diagnosis to treatment.

INTRODUCTION: Head and neck teratoma is a rare entity. Its prognosis mostly depends on the risk of neonatal respiratory distress, its extension and potential malignancy. Surgical management must be as complete as possible to avoid recurrences and malignant transformation. The authors present a retrospective analysis of 6 cervicofacial teratomas and a review of the literature. The aim of the study was to analyse prenatal, neonatal and postnatal management of teratoma. MATERIALS AND METHODS: Charts of children presenting with a head and neck teratoma, managed by our maxillofacial and plastic surgery unit, were analysed and antenatal, clinical, biological, radiological and pathological characteristics were collected. Surgical treatment, recurrences and surgical outcomes were analysed. RESULTS: Six patients were included: 2 with a cervical teratoma, 2 with a facial teratoma and 2 with intraoral teratomas. In 2 cases, the lesions were diagnosed antenatally and both patients required neonatal resuscitation. All the patients underwent early surgery, and 3 with complete excisions. All patients with an initial incomplete excision eventually presented a recurrence and therefore second look surgery. No malignant transformation was noted. CONCLUSION: Early prenatal diagnosis is crucial to neonatal care. Early surgery and meticulous follow-up are critical in the long-term favourable outcome.

Prenatal assessment of a fast-growing giant epignathus.

Epignathus is a very rare fetal tumor. We report a case of fast-growing giant epignathus with severe distortion of the right part of the face and orbit. A thorough prenatal work-up was performed by the association of Magnetic Resonance Imaging and Ultrasonography. A multidisciplinary approach was crucial to assess the operability and provide careful counseling to help parents understand and reach decision.

Relational development in children with cleft lip and palate: influence of the waiting period prior to the first surgical intervention and parental psychological perceptions of the abnormality.

BACKGROUND: The birth of a child with a cleft lip, whether or not in association with a cleft palate, is a traumatic event for parents. This prospective, multidisciplinary and multi-centre study aims to explore the perceptions and feelings of parents in the year following the birth of their child, and to analyse parent-child relationships. Four inclusion centres have been selected, differing as to the date of the first surgical intervention, between birth and six months. The aim is to compare results, also distinguishing the subgroups of parents who were given the diagnosis in utero and those who were not. METHODS/DESIGN: The main hypothesis is that the longer the time-lapse before the first surgical intervention, the more likely are the psychological perceptions of the parents to affect the harmonious development of their child. Parents and children are seen twice, when the child is 4 months (T0) and when the child is one year old (T1). At these two times, the psychological state of the child and his/her relational abilities are assessed by a specially trained professional, and self-administered questionnaires measuring factors liable to affect child-parent relationships are issued to the parents. The Alarme Détresse BéBé score for the child and the Parenting Stress Index score for the parents, measured when the child reaches one year, will be used as the main criteria to compare children with early surgery to children with late surgery, and those where the diagnosis was obtained prior to birth with those receiving it at birth. DISCUSSION: The mental and psychological dimensions relating to the abnormality and its correction will be analysed for the parents (the importance of prenatal diagnosis, relational development with the child, self-image, quality of life) and also, for the first time, for the child (distress, withdrawal). In an ethical perspective, the different time lapses until surgery in the different protocols and their effects will be analysed, so as to serve as a reference for improving the quality of information during the waiting period, and the quality of support provided for parents and children by the healthcare team before the first surgical intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00993993.

Craniofacial phenotype in the branchio-oculo-facial syndrome: four case reports.

Branchio-oculo-facial syndrome represents a craniofacial disorder in which affected patients may develop a wide range of distinctive features that include cleft lip and/or palate, cervical aplastic skin defect, malformed pinna, and ocular anomalies. This study reports four new cases confirmed by the identification of mutations in the TFAP2A gene and describes in detail the findings in the craniofacial region. The four cases included two familial and two sporadic, and three have been followed since the birth. Two out of the four cases showed atypical features. One patient presented brainstem immaturity with dysregulation of sympathetic and parasympathetic systems, which have so far not been described in the literature and were associated with anxiety, panic attacks, and tiredness. Another patient had as an additional feature a hypoplastic thumb with distal implantation.