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Genes Aug 2023Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group... (Review)
Review
Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in , which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in . Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.
Topics: Humans; DNA Helicases; Histones; Hypertelorism; Intellectual Disability; Language Development Disorders; Megalencephaly; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Developmental Disabilities
PubMed: 37761804
DOI: 10.3390/genes14091664 -
International Journal of Gynaecology... Dec 2023Treacher Collins syndrome (TCS) should be suspected if the triad of micrognathia, glossoptosis, and posterior cleft palate, and deformed external ears are observed... (Review)
Review
Treacher Collins syndrome (TCS) should be suspected if the triad of micrognathia, glossoptosis, and posterior cleft palate, and deformed external ears are observed during prenatal ultrasonography, excepting Pierre Robin sequence. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures are conducive to differentiation. Molecular genetics testing can establish a definite diagnosis. A 28-year-old pregnant Chinese woman was referred for systematic ultrasound examination at 24 weeks. Two-dimensional and three-dimensional ultrasound showed polyhydramnios, micrognathia, absence of nasal bone, microtia, secondary cleft palate, mandibular hypoplasia, glossoptosis, and normal limbs and vertebrae. Pierre Robin sequence was misdiagnosed with the triad of micrognathia, glossoptosis, and posterior cleft palate. Final diagnosis of TCS was confirmed by whole-exome sequencing. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures can facilitate a differential diagnosis between Pierre Robin sequence and TCS, with the triad of micrognathia, glossoptosis, and posterior cleft palate.
Topics: Pregnancy; Female; Humans; Adult; Mandibulofacial Dysostosis; Pierre Robin Syndrome; Micrognathism; Glossoptosis; Cleft Palate; Prenatal Diagnosis
PubMed: 37231986
DOI: 10.1002/ijgo.14881 -
American Journal of Medical Genetics.... Feb 2024Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and...
Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal-onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Proto-Oncogene Proteins p21(ras); Craniosynostoses; Heart Defects, Congenital; Noonan Syndrome; Ultrasonography, Prenatal
PubMed: 37774117
DOI: 10.1002/ajmg.a.63397 -
Journal of Neurosurgery. Pediatrics Oct 2023Ridging along the metopic suture line can be a common cause of concern for parents and has been theorized to represent a mild form of trigonocephaly, a cranial deformity...
OBJECTIVE
Ridging along the metopic suture line can be a common cause of concern for parents and has been theorized to represent a mild form of trigonocephaly, a cranial deformity associated with risks of negative cosmetic outcomes, if not surgically corrected. Yet the literature contains sparse reports of long-term cosmetic results or expectations for infants with isolated metopic ridging compared with those with severe trigonocephaly, or even what objective metrics discriminate isolated metopic ridging from severe trigonocephaly. Therefore, the authors' goals for this study were to 1) quantify the degree of frontal deformity among patients with metopic ridge, metopic craniosynostosis, and normocephalic head shapes; and 2) document the natural history of frontal deformities in isolated metopic ridge patients in the 1st year of life.
METHODS
This was a retrospective cohort study of patients with normocephalic head shapes, metopic ridges, and metopic craniosynostoses who presented at < 1 year of age to the Connecticut Children's neurosurgery clinic from January 2019 to December 2021. Data were collected regarding demographics and photograph-based craniometrics.
RESULTS
A total of 212 normocephalic, 34 metopic ridge, and 29 metopic craniosynostosis patients were included. Both the normocephalic and metopic ridge groups had a significantly higher anterior arc angle (AAA) value compared with the metopic craniosynostosis group (p < 0.0001). The AAA did not differ significantly among normocephalic patients and those with ridging. Over the course of 1 year of follow-up, patients with metopic ridging demonstrated a slight decrease in AAA values, but overall remained within the same range as normocephalic patients.
CONCLUSIONS
Photograph-based craniometrics suggest that metopic ridge patients with frontal bone angulations > 2.2 radians have a mild degree of frontal constriction that does not significantly worsen over the 1st year of life.
Topics: Infant; Child; Humans; Retrospective Studies; Craniosynostoses; Cranial Sutures; Cephalometry
PubMed: 37548529
DOI: 10.3171/2023.6.PEDS23201 -
Brain Structure & Function Dec 2023The shape of the cranium is one of the most notable physical changes induced in domestic dogs through selective breeding and is measured using the cephalic index (CI)....
The shape of the cranium is one of the most notable physical changes induced in domestic dogs through selective breeding and is measured using the cephalic index (CI). High CI (a ratio of skull width to skull length > 60) is characterized by a short muzzle and flat face and is referred to as brachycephaly. Brachycephalic dogs display some potentially harmful changes in neuroanatomy, and there are implications for differences in behavior, as well. The path from anatomy to cognition, however, has not been charted in its entirety. Here, we report that sleep-physiological markers of white-matter loss (high delta power, low frontal spindle frequency, i.e., spindle waves/s), along with a spectral profile for REM (low beta, high delta) associated with low intelligence in humans, are each linked to higher CI values in the dog. Additionally, brachycephalic subjects spent more time sleeping, suggesting that the sleep apnea these breeds usually suffer from increases daytime sleepiness. Within sleep, more time was spent in the REM sleep stage than in non-REM, while REM duration was correlated positively with the number of REM episodes across dogs. It is currently not clear if the patterns of sleep and sleep-stage duration are mainly caused by sleep-impairing troubles in breathing and thermoregulation, present a juvenile-like sleeping profile, or are caused by neuro-psychological conditions secondary to the effects of brachycephaly, e.g., frequent REM episodes are known to appear in human patients with depression. While future studies should more directly address the interplay of anatomy, physiology, and behavior within a single experiment, this represents the first description of how the dynamics of the canine brain covary with CI, as measured in resting companion dogs using a non-invasive sleep EEG methodology. The observations suggest that the neuroanatomical changes accompanying brachycephaly alter neural systems in a way that can be captured in the sleep EEG, thus supporting the utility of the latter in the study of canine brain health and function.
Topics: Dogs; Humans; Animals; Sleep; Sleep, REM; Electroencephalography; Brain; Craniosynostoses
PubMed: 37742302
DOI: 10.1007/s00429-023-02706-y -
Genes Dec 2023Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb... (Review)
Review
Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient's lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient's benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.
Topics: Child; Humans; Young Adult; Adult; Mandibulofacial Dysostosis; Cleft Palate; Micrognathism; Syndrome; RNA Splicing Factors
PubMed: 38254920
DOI: 10.3390/genes15010029 -
Child's Nervous System : ChNS :... Oct 2023Very few clinical entities have undergone so many different treatment approaches over such a short period of time as craniosynostosis. Surgical treatments for this... (Review)
Review
Very few clinical entities have undergone so many different treatment approaches over such a short period of time as craniosynostosis. Surgical treatments for this condition have ranged from simple linear craniectomies, accounting for the specific role of cranial sutures in assuring the normal growth of the skull, to more complex cranial vault reconstructions, based on the perceived role of the skull base in affecting the growth of the skull. While a great deal of evolution has occurred, there remains controversy regarding the ideal treatment including the best surgical technique, the optimal age for surgery, and the long-term morphological and neurodevelopmental outcomes. The evolution of the surgical management of craniosynostosis in the last 50 years has been affected by several factors. This includes the awareness of needing to operate on affected children during infancy to achieve the best results, the use of multistage operations, the availability of more sophisticated surgical tools, and improved perioperative care. In some forms of craniosynostosis, the operations can be carried out at a very young age with low morbidity, and with the postoperative use of a molding helmet, springs, or distractors, these operations prove to be as effective as traditional larger cranial reconstructions performed in older children. As a consequence, complex surgical operations have become progressively less utilized. A second relevant advance was the more recent advent of a molecular diagnosis, which allowed us to understand the pathogenesis of some associated malformations and neurodevelopmental issues that were observed in some children despite appropriate surgical treatment. Future research should focus on improving the analysis of longer-term outcomes and understanding the natural history of craniofacial conditions, including what issues persist despite optimal surgical correction. Progress in molecular investigations concerning the normal and pathological development of cranial sutures could be a further significant step in the management of craniosynostosis, possibly favoring a "medical" treatment in the near future. Artificial intelligence will likely have a role in establishing the diagnosis with less reliance on radiographic studies and in assisting with surgical planning. Overall, much progress has been made, but there remains much to do.
Topics: Humans; Child; Infant; Neurosurgery; Artificial Intelligence; Craniosynostoses; Skull; Cranial Sutures; Skull Base
PubMed: 37584742
DOI: 10.1007/s00381-023-06113-w -
American Journal of Medical Genetics.... Oct 2023The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and... (Review)
Review
The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and oculoauriculovertebral spectrum (OAVS). Main clinical findings include widely spaced eyes, epibulbar dermoid, broad nose, mandibular hypoplasia, and preauricular tags. Here, we describe a case series of 32 Brazilian individuals with OAFNS and review the literature ascertaining individuals presenting phenotypes compatible with the diagnosis of OAFNS, aiming to refine the phenotype. This series emphasizes the phenotypic variability of the OAFNS and highlights the occurrence of rare craniofacial clefts as a part of the phenotype. The ectopic nasal bone, a hallmark of OAFNS, was frequent in our series, reinforcing the clinical diagnosis. The absence of recurrence, consanguinity, chromosomal, and genetic abnormalities reinforces the hypothesis of a nontraditional inheritance model. The phenotypic refinement provided by this series contributes to an investigation regarding the etiology of OAFNS.
Topics: Humans; Ear, External; Eye Abnormalities; Spine; Goldenhar Syndrome; Phenotype
PubMed: 37282829
DOI: 10.1002/ajmg.a.63319 -
Plastic and Reconstructive Surgery Jan 2024
Topics: Humans; Infant; Craniosynostoses; Computer Simulation
PubMed: 37344937
DOI: 10.1097/PRS.0000000000010879 -
The Cleft Palate-craniofacial Journal :... Sep 2023This paper describes 20 years of microtia and craniofacial microsomia (CFM) psychosocial and healthcare studies and suggests directions for clinical care and research. A... (Review)
Review
This paper describes 20 years of microtia and craniofacial microsomia (CFM) psychosocial and healthcare studies and suggests directions for clinical care and research. A narrative review of papers January 2000 to July 2021 related to psychosocial and healthcare experiences of individuals with microtia and CFM and their families. Studies (N = 64) were mainly cross-sectional (69%), included a range of standardized measures (64%), and were with European (31%), American (27%), or multinational (23%) samples. Data were generally collected from both patients and caregivers (38%) or patient self-report (35%). Sample sizes were 11 to 25 (21%), 26 to 50 (19%), 51 to 100 (22%), or over 100 (38%). Studies addressed 5 primary topics: (1) Healthcare Experiences, including Medical Care, Hearing Loss/Amplification, Diagnostic Experiences, and Information Preferences; (2) Psychosocial Experiences, including Teasing, Behavioral Adjustment, Psychosocial Support, and Public Perception; (3) Neurocognitive Functioning and Academic Assistance; (4) Pre- and Post-Operative Psychosocial Outcomes of Ear Reconstruction/Canaloplasty; and (5) Quality of Life and Patient Satisfaction. Care involved multiple specialties and was often experienced as stressful starting at diagnosis. Psychosocial and neurocognitive functioning were generally in the average range, with possible risk for social and language concerns. Coping and resiliency were described into adulthood. Satisfaction and positive benefit of ear reconstruction/canaloplasty were high. Care recommendations include increasing: hearing amplification use, microtia and CFM knowledge among providers, efficient treatment coordination, psychosocial support, academic assistance, and advances to minimize surgical scarring. This broad literature overview informs clinical practice and research to improve psychosocial outcomes.
Topics: Humans; United States; Goldenhar Syndrome; Congenital Microtia; Quality of Life; Cross-Sectional Studies; Adaptation, Psychological
PubMed: 35382590
DOI: 10.1177/10556656221091699