Ciliopathic micrognathia is caused by aberrant skeletal differentiation and remodeling.

Ciliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties, including impaired feeding and breathing, and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we used the talpid2 (ta2 ), a bona fide avian model for the human ciliopathy oral-facial-digital syndrome subtype 14. Histological analyses revealed that the onset of ciliopathic micrognathia in ta2 embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion. Additional molecular analyses revealed that an imbalance in the ratio of bone deposition and resorption also contributed to ciliopathic micrognathia in ta2 embryos. Thus, our results suggest that ciliopathic micrognathia is a consequence of multiple aberrant cellular processes necessary for skeletal development, and provide potential avenues for future therapeutic treatments.

Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.

BACKGROUND: ARID2 belongs to the Switch/sucrose non-fermenting complex, in which the genetic defects have been found in patients with dysmorphism, short stature and intellectual disability (ID). As the phenotypes of patients with ARID2 mutations partially overlap with those of RASopathy, this study evaluated the biochemical association between ARID2 and RAS-MAPK pathway. METHODS: The phenotypes of 22 patients with either an ARID2 heterozygous mutation or haploinsufficiency were reviewed. Comprehensive molecular analyses were performed using somatic and induced pluripotent stem cells (iPSCs) of a patient with ARID2 haploinsufficiency as well as using the mouse model of Arid2 haploinsufficiency by CRISPR/Cas9 gene editing. RESULTS: The phenotypic characteristics of ARID2 deficiency include RASopathy, Coffin-Lowy syndrome or Coffin-Siris syndrome or undefined syndromic ID. Transient ARID2 knockout HeLa cells using an shRNA increased ERK1 and ERK2 phosphorylation. Impaired neuronal differentiation with enhanced RAS-MAPK activity was observed in patient-iPSCs. In addition, Arid2 haploinsufficient mice exhibited reduced body size and learning/memory deficit. ARID2 haploinsufficiency was associated with reduced IFITM1 expression, which interacts with caveolin-1 (CAV-1) and inhibits ERK activation. DISCUSSION: ARID2 haploinsufficiency is associated with enhanced RAS-MAPK activity, leading to reduced IFITM1 and CAV-1 expression, thereby increasing ERK activity. This altered interaction might lead to abnormal neuronal development and a short stature.

Tissue-specific analysis of Fgf18 gene function in palate development.

BACKGROUND: Previous studies showed that mice lacking Fgf18 function had cleft palate defects and that the FGF18 locus was associated with cleft lip and palate in humans, but what specific roles Fgf18 plays during palatogenesis are unclear. RESULTS: We show that Fgf18 exhibits regionally restricted expression in developing palatal shelves, mandible, and tongue, during palatal outgrowth and fusion in mouse embryos. Tissue-specific inactivation of Fgf18 throughout neural crest-derived craniofacial mesenchyme caused shortened mandible and reduction in ossification of the frontal, nasal, and anterior cranial base skeletal elements in Fgf18c/c ;Wnt1-Cre mutant mice. About 64% of Fgf18c/c ;Wnt1-Cre mice exhibited cleft palate. Whereas palatal shelf elevation was impaired in many Fgf18c/c ;Wnt1-Cre embryos, no significant difference in palatal cell proliferation was detected between Fgf18c/c ;Wnt1-Cre embryos and their control littermates. Embryonic maxillary explants from Fgf18c/c ;Wnt1-Cre embryos showed successful palatal shelf elevation and fusion in organ culture similar to the maxillary explants from control embryos. Furthermore, tissue-specific inactivation of Fgf18 in the early palatal mesenchyme did not cause cleft palate. CONCLUSION: These results demonstrate a critical role for Fgf18 expression in the neural crest-derived mesenchyme for the development of the mandible and multiple craniofacial bones but Fgf18 expression in the palatal mesenchyme is dispensable for palatogenesis.

Virtual Surgical Planning Assisted Management for Cleft-Related Maxillary Hypoplasia.

Maxillary hypoplasia is a common developmental deformity affecting patients with cleft lip and palate. Various surgical techniques including conventional orthognathic surgery, total maxillary distraction osteogenesis, and anterior maxillary segmental distraction have been applied to address the deformity. With the evolution of 3D computed tomography imaging, the visualization of skeletal complexities in different perspectives is greatly enhanced and comprehensive surgical planning is achieved. Intraoperative efficiency is also improved with the fabrication of 3D-printed templates. The study aims to present different surgical techniques with virtual surgical planning (VSP) and 3D-printed surgical templates and the solution of representative cases. From January 2014 to January 2019, VSP was transferred to actual surgery or distraction precisely in 80 adult patients with cleft-related maxillary hypoplasia. The accuracy was analyzed and the relapse was also estimated and observed in 18 patients after 1-year follow-up. Based on our experience, VSP provides a more reliable and effective option to conventional model surgery. It facilitates the preoperative planning and accurately transfers the virtual plan to correct the cleft-related maxillary hypoplasia.

Application of Bidirectional Distraction Osteogenesis for the Treatment of Mandibular Micriognathia Caused by Temporomandibular Joint Ankylosis.

BACKGROUND: Temporomandibular joint (TMJ) ankylosis is a joint disorder that refers to bone or fibrous adhesion of the anatomic joint components and the ensuing loss of function. When it happens on children, it is always accompanied by dentofacial deformities. The objective of this study was to describe the authors' experience of bidirectional distraction osteogenesis for the treatment of mandibular deformities caused by TMJ ankylosis. METHODS: Sixteen patients with TMJ ankylosis and severe secondary mandibular deformities were treated with bidirectional distraction osteogenesis and release of joint from January 2013 to December 2015. Clinical outcomes were assessed based on the oral function, radiography, and medical photography. RESULTS: No reankylosis was found during the follow-up period. Sufficient volume and density new bone had been formed after the consolidation period. All patients have maintained stable improvement in oral function during the follow-up period. Most of the patients achieved satisfactory outcomes. CONCLUSIONS: Bidirectional transport distraction osteogenesis technique is a good and effective therapeutic option in treatment of bilateral or unilateral TMJ ankylosis patients associated with mandibular micrognathia.

The Pierre Robin Mandible is Hypoplastic and Morphologically Abnormal.

BACKGROUND: For Pierre Robin sequence (PRS) patients, there is incomplete characterization of 3D differences and effects of mandibular distraction osteogenesis (MDO) on the mandible compared to normal controls. METHODS: PRS infants who underwent MDO at 2 craniofacial referral centerals with pre- and postoperative computed tomography (CT) scans were identified. A group of age-matched control patients with CTs were identified in the PACS database. Demographic and perioperative data were recorded. Mandibular lengths, angles, and volumes were measured. Morphologic and outcomes data were analyzed in a case-control comparison. RESULTS: Sixty-three CT scans were analyzed. Fifteen pre-op PRS patient and 15 control CTs were well matched in terms of age and sex. Mandibular volume (78%), ramus length (87%), and body length (95%) were all decreased in the PRS patients. Anterior symphyseal angle (84%) was significantly reduced in PRS patients while mandibular angle (102%) was maintained. Eighteen post-op PRS patient and 15 control CTs were well matched in terms of age and gender. Mandibular volumes (106%) were normalized following distraction with shorter mandibular rami (88%) and longer mandibular bodies (109%). Postoperatively, mandibular angle (100%) and anterior symphyseal angle (99%) were ultimately indistinguishable from controls. CONCLUSIONS: The mandible in PRS is dysmorphic compared to age-matched controls. Overall, they have a smaller volume, shorter ramus, and an obtuse symphyseal angle. MDO improves mandibular volume and normalizes the symphyseal angle, but results in a longer mandibular body and shorter mandibular ramus.

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome.

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency.

Etiology and pathogenesis of robin sequence in a large Dutch cohort.

Robin sequence (RS) can be defined as the combination of micrognathia and upper airway obstruction/glossoptosis causing neonatal respiratory problems, with or without a cleft palate and either isolated or non-isolated. Pathogenesis varies widely. We hypothesize that optimal treatment depends on pathogenesis and therefore patients should be stratified according to diagnosis. Here, we evaluate diagnoses and (presumed) pathogeneses in an RS cohort. Medical records of all RS patients presenting between 1995-2013 in three academic hospitals were evaluated. Four clinical geneticists re-evaluated all information, including initial diagnosis. Diagnoses were either confirmed, considered uncertain, or rejected. If uncertain or rejected, patients were re-evaluated. Subsequent results were re-discussed and a final conclusion was drawn. We included 191 RS patients. After re-evaluation and changing initial diagnoses in 48 of the 191 patients (25.1%), 37.7% of the cohort had isolated RS, 8.9% a chromosome anomaly, 29.3% a Mendelian disorder, and 24.1% no detectable cause. Twenty-two different Mendelian disorders were diagnosed, of which Stickler syndrome was most frequent. Stratification of diagnoses according to (presumed) pathogenic mechanism in 73 non-isolated patients with reliable diagnoses showed 43.9% to have a connective tissue dysplasia, 5.5% a neuromuscular disorder, 47.9% a multisystem disorder, and 2.7% an unknown mechanism. We diagnosed more non-isolated RS patients compared to other studies. Re-evaluation changed initial diagnosis in a quarter of patients. We suggest standardized re-evaluation of all RS patients. Despite the relatively high diagnostic yield pathogenesis could be determined in only 59.7% (71/119), due to limited insight in pathogenesis in diagnosed entities. Further studies into pathogenesis of entities causing RS are indicated.

Clinical features, diagnostic criteria, and management of Coffin-Siris syndrome.

Coffin-Siris syndrome (OMIM#135900) is a multiple congenital anomaly syndrome classically characterized by hypo- or aplasia of the fifth digit nails or phalanges, as well as coarse facial features, sparse scalp hair, and moderate to severe cognitive and/or developmental delay. The recent identification of molecular etiologies has served to effectively characterize a large set of patients who have been described with Coffin-Siris between the time of its initial description and the present. However, despite recent advances, a number of patients who traditionally fit the diagnosis have yet to have identified causes. This could be due to patients who lie outside the defined phenotype, or alternatively, to additional as yet unidentified genes which may play roles. Here we outline the range of clinical features described in the broader diagnostic category, review the continuing phenotypic challenges and note those subsets of patients for whom molecular causes have yet to be clarified. Finally, we discuss recommendations for clinical management of these individuals.

The ARID1B phenotype: what we have learned so far.

Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome.

Recently, de novo aberrations in PHF6 were identified in females with intellectual disability and with a distinct phenotype including a characteristic facial gestalt with bitemporal narrowing, prominent supraorbital ridges, synophrys, a short nose and dental anomalies, tapering fingers with brachytelephalangy, clinodactyly and hypoplastic nails, short toes with hypoplastic nails, and linear skin hyperpigmentation. In adolescent or older patients, this phenotype overlaps but is not identical with Borjeson-Forssman-Lehmann syndrome in males, caused by X-linked recessive mutations in PHF6. In younger girls there seems to be a striking phenotypic overlap with Coffin-Siris syndrome, which is characterized by intellectual disability, sparse hair and hypoplastic nails. This review will summarize and characterize the female phenotype caused by de novo aberrations in PHF6 and will discuss the overlapping and distinguishing features with Coffin-Siris syndrome.

Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.

This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future.

DOORS syndrome: phenotype, genotype and comparison with Coffin-Siris syndrome.

DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, mental Retardation, Seizures) is characterized mainly by sensorineural deafness, shortened terminal phalanges with small nails of hands and feet, intellectual deficiency, and seizures. Half of the patients with all clinical features have mutations in TBC1D24. We review here the manifestations of patients clinically diagnosed with DOORS syndrome. In this cohort of 32 families (36 patients) we detected 13 individuals from 10 families with TBC1D24 mutations. Subsequent whole exome sequencing in the cohort showed the same de novoSMARCB1 mutation (c.1130G>A), known to cause Coffin-Siris syndrome, in two patients. Distinguishing features include retinal anomalies, Dandy-Walker malformation, scoliosis, rocker bottom feet, respiratory difficulties and absence of seizures, and 2-oxoglutaric aciduria in the patients with the SMARCB1 mutation. We briefly discuss the heterogeneity of the DOORS syndrome phenotype and the differential diagnosis of this condition.

Molecular confirmation of nine cases of Cornelia de Lange syndrome diagnosed prenatally.

OBJECTIVES: Cornelia de Lange syndrome (CdLS) is characterized by distinct facial features, growth retardation, upper limb reduction defects, hirsutism, and intellectual disability. NIPBL mutations have been identified in approximately 60% of patients with CdLS diagnosed postnatally. Prenatal ultrasound findings include upper limb reduction defects, intrauterine growth restriction, and micrognathia. CdLS has also been associated with decreased PAPP-A and increased nuchal translucency (NT). We reviewed NIPBL sequence analysis results for 12 prenatal samples in our laboratory to determine the frequency of mutations in our cohort. METHODS: This retrospective study analyzed data from all 12 prenatal cases with suspected CdLS, which were received by The University of Chicago Genetic Services Laboratories. Diagnostic NIPBL sequencing was performed for all samples. Clinical information was collected from referring physicians. RESULTS: NIPBL mutations were identified in 9 out of the 12 cases prenatally (75%). Amongst the NIPBL mutation-positive cases with clinical information available, the most common findings were upper limb malformations and micrognathia. Five patients had NT measurements in the first trimester, of which four were noted to be increased. CONCLUSION: We demonstrate that prenatally-detected phenotypes of CdLS, particularly severe micrognathia and bilateral upper limb defects, are associated with an increased frequency of NIPBL mutations.

Visual diagnosis: 8-day-old hypotonic newborn with sparse hair.

A hypotonic newborn or infant with pale skin and sparse, friable, hypopigmented, or depigmented hair should have his copper and ceruloplasmin plasma levels evaluated because this is the usual clinical presentation of Menkes disease. Menkes disease is an X-linked recessive disease caused by a defect in the ATP7A gene, identified in 95% to 98% of the cases. Identifying the mutation confirms the diagnosis and allows for prenatal counseling and diagnosis in a future pregnancy. When administered within the first few months of life, copper histidinate, given subcutaneously in a dose of 50 to 150 mg/kg per day, appears to be effective not only by increasing life expectancy from 3 to 13 years but also by improving neurologic symptoms and neurodevelopmental outcomes in approximately 30% of the patients.

Surgical correction of neonatal obstructive sleep apnea due to a temporomandibular joint ankylosis.

In growing children, temporomandibular joint (TMJ) ankylosis and septic arthritis are uncommon. Retrognathia and micrognathia affect airway patency and can cause obstructive sleep apnea (OSA). No unified diagnostic criteria have been established for the management of this pathology. We describe the first case of treatment for pediatric TMJ ankylosis and severe OSA due to neonatal group B streptococcal septic TMJ arthritis. Untreated pathological changes in the TMJ will eventually lead to ankylosis. Among children, this will include facial growth disturbances leading to mandibular retrognathia, reduction in the oropharyngeal spaces, and OSA. Our patient had severe OSA with an apnea-hypopnea index of 24.9 events/h and oxygen saturation nadir of 73% as measured by polysomnography. She was treated successfully according to Andrade protocol. This is the first report of pediatric OSA due to TMJ ankylosis following neonatal group B streptococcal septic arthritis. CITATION: Pesis M, Goldbart A, Givol N. Surgical correction of neonatal obstructive sleep apnea due to a temporomandibular joint ankylosis. J Clin Sleep Med. 2024;20(1):173-179.

Severe rhizomelic chondrodysplasia punctata in a fetus due to maternal mixed connective tissue disorder.

Maternal systemic lupus erythematosus and autoimmune diseases have been extremely rarely reported to cause rhizomelic chondrodysplasia punctata. We report on a fetus aborted spontaneously at 21 weeks of gestation due to complications of maternal mixed connective tissue disorder. The fetus had micrognathia, a depressed nasal bridge, flat nose, long philtrum, short columella and rhizomelia. Radiographic study showed stippling of carpal and tarsal bones, short humeri and coronal clefts in the vertebrae. Ossification centers were present at the lower end of the femora and upper end of the tibiae.

Simultaneous costochondral graft and distraction osteogenesis in unilateral TMJ ankylosis associated with mandibular retrognathia and asymmetry.

The purpose of this study was to review the long-term effect of simultaneous costochondral graft (CCG) and distraction osteogenesis (DO) in the management of unilateral temporomandibular joint ankylosis associated with severe dentofacial deformities in our clinic. In addition, we sought to analyze the advantages and disadvantages of CCG and DO. Four patients were included in this clinical study during 2005 to 2007. The mean length of ankylosis history was 14.5 years. All patients had significant mandibular retrognathia and asymmetry histories and have been diagnosed with obstructive sleep apnea syndrome by a polysomnogram before surgery. A 1-stage surgery, with gap arthroplasty, CCG, and mandibular DO, was performed. The surgical plan and technique were reviewed. No severe complications were observed after surgery. Distraction was started on day 7 after surgery. The distance of distraction ranged from 20 to 25 mm (mean, 22.5 mm). Mouth opening was increased from 25 to 37 mm (mean, 33.5 mm) during the follow-up period (range of 3.5-5 y). No recurrence of joint ankylosis occurred based on the clinical and radiographic evaluations. All of the patients had significant improvement in obstructive sleep apnea syndrome after surgery. Mandibular asymmetry and retrognathia were well corrected in all of the patietns. In conclusion, a 1-stage surgical treatment with DO and CCG demonstrated its feasibility and effectiveness in management of temporomandibular joint ankylosis combined with severe dentofacial deformity. It is a safe and reliable method of treatment.

Orocraniofacial findings and dental management of a pediatric patient with Dubowitz syndrome.

Dubowitz syndrome is a rare genetic condition characterized by microcephaly, dysmorphic facial features and delayed general growth. It is transmitted through autosomal recessive inheritance. The purpose of this report is to describe the oral, craniofacial and systemic characteristics of a 7-year 11-month-old boy with Dubowitz syndrome and the dental management provided. The pediatric dentist should possess the ability to recognize this rare alteration, to provide dental treatment and to refer for the necessary medical and multidisciplinary treatment.