Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

Craniofacial phenotypes associated with Robinow syndrome.

Robinow syndrome is characterized by mesomelic limb shortening, hemivertebrae, and genital hypoplasia. Due to low prevalence and considerable phenotypic variability, it has been challenging to definitively characterize features of Robinow syndrome. While craniofacial abnormalities associated with Robinow syndrome have been broadly described, there is a lack of detailed descriptions of genotype-specific phenotypic craniofacial features. Patients with Robinow syndrome were invited for a multidisciplinary evaluation conducted by specialist physicians at our institution. A focused assessment of the craniofacial manifestations was performed by a single expert examiner using clinical examination and standard photographic images. A total of 13 patients with clinical and molecular diagnoses consistent with either dominant Robinow syndrome (DRS) or recessive Robinow syndrome (RRS) were evaluated. On craniofacial examination, gingival hyperplasia was nearly ubiquitous in all patients. Orbital hypertelorism, a short nose with anteverted and flared nares, a triangular mouth with a long philtrum, cleft palate, macrocephaly, and frontal bossing were not observed in all individuals but affected individuals with both DRS and RRS. Other anomalies were more selective in their distribution in this patient cohort. We present a comprehensive analysis of the craniofacial findings in patients with Robinow Syndrome, describing associated morphological features and correlating phenotypic manifestations to underlying genotype in a manner relevant for early recognition and focused evaluation of these patients.

Cerebellofaciodental syndrome in an adult patient: Expanding the phenotypic and natural history characteristics.

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.

Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS.

Al-Raqad syndrome (ARS) is a rare autosomal recessive congenital disorder, associated mainly with developmental delay, and intellectual disability. This syndrome is caused by mutations in DCPS, encoding scavenger mRNA decapping enzyme, which plays a role in the 3-prime-end mRNA decay pathway. Whole-exome sequencing was performed on an offspring of a consanguineous family presenting with developmental delay, intellectual disability, growth retardation, mild craniofacial abnormalities, cerebral and cerebellar atrophy, and white matter diffuse hypomyelination pattern. A novel biallelic missense variant, c.918G>C p. (Glu306Asp), in the DCPS gene was identified which was confirmed by sanger sequencing and segregation analysis subsequently. Few cases of ARS have been described up to now, and this study represents a 7-years-old boy presenting with central and peripheral nervous system impaired myelination in addition to ocular and dental manifestation, therefore outstretch both neuroimaging and clinical findings of this ultra-rare syndrome.

Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5.

Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15-year-old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.

Parsing the craniofacial phenotype: effect of weight change in an obstructive sleep apnoea population.

PURPOSE: Craniofacial structure is an important risk factor in the development of obstructive sleep apnoea. Most craniofacial imaging methods are not feasible for large-scale studies or the clinic. Craniofacial photography is a high-throughput technique for facial phenotyping; however, derived measurements are a composite of skeletal and soft tissue craniofacial information. Weight change is a paradigm to help determine which facial measurements most relate to regional soft tissue (i.e. change with weight) versus skeletal structure (i.e. stable with weight changes). We aimed to assess the association between weight change and changes in key facial measurements from facial photography. METHODS: Calibrated frontal and profile photographs were taken of participants in weight loss studies (N = 106). Univariate linear regression was used to assess whether weight change explained changes in facial dimensions. RESULTS: Patients lost 11.7 ± 10.8 kg body weight and 2.0 ± 2.0 cm of neck circumference. Weight changes influenced face width (r = 0.3, p < 0.001), mandibular width (r = 0.4, p < 0.001) and cervicomental angle (r = 0.3, p = 0.001). Facial angles, facial heights and mandibular length were not influenced by weight change. CONCLUSIONS: A weight loss paradigm suggests that face and mandibular width and cervicomental angle most strongly reflect regional adiposity. Facial angles and heights are insensitive to weight change and could be more representative of craniofacial skeletal structure. This study informs the interpretation of facial phenotype assessed by this craniofacial photographic method which can be applied to future studies of craniofacial phenotype in OSA.

Facial Expressiveness in Infants With and Without Craniofacial Microsomia: Preliminary Findings.

OBJECTIVE: To compare facial expressiveness (FE) of infants with and without craniofacial macrosomia (cases and controls, respectively) and to compare phenotypic variation among cases in relation to FE. DESIGN: Positive and negative affect was elicited in response to standardized emotion inductions, video recorded, and manually coded from video using the Facial Action Coding System for Infants and Young Children. SETTING: Five craniofacial centers: Children's Hospital of Los Angeles, Children's Hospital of Philadelphia, Seattle Children's Hospital, University of Illinois-Chicago, and University of North Carolina-Chapel Hill. PARTICIPANTS: Eighty ethnically diverse 12- to 14-month-old infants. MAIN OUTCOME MEASURES: FE was measured on a frame-by-frame basis as the sum of 9 observed facial action units (AUs) representative of positive and negative affect. RESULTS: FE differed between conditions intended to elicit positive and negative affect (95% confidence interval = 0.09-0.66, P = .01). FE failed to differ between cases and controls (ES = -0.16 to -0.02, P = .47 to .92). Among cases, those with and without mandibular hypoplasia showed similar levels of FE (ES = -0.38 to 0.54, P = .10 to .66). CONCLUSIONS: FE varied between positive and negative affect, and cases and controls responded similarly. Null findings for case/control differences may be attributable to a lower than anticipated prevalence of nerve palsy among cases, the selection of AUs, or the use of manual coding. In future research, we will reexamine group differences using an automated, computer vision approach that can cover a broader range of facial movements and their dynamics.

A novel mutation in the proteolytic domain of LONP1 causes atypical CODAS syndrome.

Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images. We detected compound heterozygous mutation in LONP1. One allele contained a paternally inherited frameshift mutation (p.Ser100Glnfs*46). The other allele contained a maternally inherited missense mutation (p.Arg786Trp), which was predicted to be pathogenic by web-based prediction tools. The two mutations were not found in Exome Variant Server or our 575 in-house control exomes. Some features were not consistent with CODAS syndrome but overlapped with Marinesco-Sjögren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation.

Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.

CHARGE syndrome gastrointestinal involvement: from mouth to anus.

CHARGE syndrome is an autosomal dominant disorder that occurs as a result of a heterozygous loss-of-function mutation in the chromodomain helicase DNA-binding (CHD7) gene, which is important for neural crest cell formation. Gastrointestinal (GI) symptoms and feeding difficulties are highly prevalent but are often a neglected area of diagnosis, treatment, and research. Cranial nerve dysfunction, craniofacial abnormalities, and other physical manifestations of this syndrome lead to gut dysmotility, sensory impairment, and oral-motor function abnormalities. Over 90% of children need tube feeding early in their life and many experience weak sucking/chewing, gastroesophageal reflux disease (GERD), and aspiration. The mainstay of treatment thus far has consisted of feeding therapy, GERD medications, Nissen fundoplication, gastrostomy/jejunostomy, and food texture limitation. Owing to the multitude of severe medical issues associated with this genetic disorder, GI involvement is often overlooked. Here, we report on five patients with CHARGE syndrome who manifested a range of severe GI and feeding difficulties.

Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder.

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.

A Rare Case of Hanhart Syndrome with Mild Developmental Delay.

Hanhart Syndrome (OMIM 103300) is an extremely rare syndrome with some congenital malformations. It is characterized by hypoglossia, adactylia/hypodactylia, peromelia of arms and/or legs and micrognathia. The severity of the symptoms can differ from patient to patient. Some affected individuals may have only a part of these clinical features. In this case report, we want to present a Turkish girl with hypoglossia, micrognathia and peromelia who was diagnosed according to the clinical and radiographic findings.

Further supporting evidence for the SATB2-associated syndrome found through whole exome sequencing.

The SATB2-associated syndrome (SAS) was recently proposed as a clinically recognizable syndrome that results from deleterious alterations of the SATB2 gene in humans. Although interstitial deletions at 2q33 encompassing SATB2, either alone or contiguously with other genes, have been reported before, there is limited literature regarding intragenic mutations of this gene and the resulting phenotype. We describe five patients in whom whole exome sequencing identified five unique de novo mutations in the SATB2 gene (one splice site, one frameshift, and three nonsense mutations). The five patients had overlapping features that support the characteristic features of the SAS: intellectual disability with limited speech development and craniofacial abnormalities including cleft palate, dysmorphic features, and dental abnormalities. Furthermore, Patient 1 also had features not previously described that represent an expansion of the phenotype. Osteopenia was seen in two of the patients, suggesting that this finding could be added to the list of distinctive findings. We provide supporting evidence that analysis for deletions or point mutations in SATB2 should be considered in children with intellectual disability and severely impaired speech, cleft or high palate, teeth abnormalities, and osteopenia.

Myogenic bladder defects in mouse models of human oculodentodigital dysplasia.

To date, over 65 mutations in the gene encoding Cx43 (connexin43) have been linked to the autosomal-dominant disease ODDD (oculodentodigital dysplasia). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. BSMCs (bladder smooth muscle cells) from wild-type and two Cx43 mutant lines (Cx43(G60S) and Cx43(I130T)) that mimic ODDD exhibit a significant reduction in total Cx43. Dye transfer studies revealed that the G60S mutant was a potent dominant-negative inhibitor of co-expressed Cx43, a property not equally shared by the I130T mutant. BSMCs from both mutant mouse strains were defective in their ability to contract, which is indicative of phenotype changes due to harbouring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in controls and mutants containing BSMCs, but the non-muscle myosin heavy chain A levels were only reduced in cells from control mice. Although the Cx43(G60S) mutant mice showed no difference in voided urine volume or frequency, the Cx43(I130T) mice voided less frequently. Thus, similar to the diversity of morbidities seen in ODDD patients, genetically modified mice also display mutation-specific changes in bladder function. Furthermore, although mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43(I130T) mice are likely to be complemented by neurogenic changes.

The craniofacial morphology and maximum bite force in sleep bruxism patients with signs and symptoms of temporomandibular disorders.

OBJECTIVES: The purpose of the present study was to compare craniofacial morphology and bite force of bruxist patients with signs and symptoms of temporomandibular disorders. METHOD: Fourteen subjects with sleep bruxism and 14 healthy subjects participated. The signs and symptoms of the temporomandibular disorders were identified according to the Craniomandibular Index (CMI). Maximum bite force was measured using strain-gage transducers. Lateral cephalometric films were taken, and linear and angular measurements were performed. RESULTS: Bite force between bruxist and non-bruxist females was not significant, whereas males with bruxism revealed higher bite forces. None of the linear and angular measurements differed significantly between bruxist and non-bruxist males. However, higher mandibular corpus length and anterior cranial base length, and lower gonial angle were observed in bruxist females compared to non-bruxist females. Negative correlation between bite force and CMI values was found in both genders. DISCUSSION: Bruxist females had higher CMI values than bruxist males, which could lead to relatively lower bite forces.

Facial abnormalities in Nablus mask-like facial syndrome: multidetector computed tomography findings.

Nablus mask-like facial syndrome (NMLFS) is a rare microdeletion syndrome characterized by a mask-like facial appearance. NMLFS has been reported in only 6 patients and has a recognizable facial appearance, along with other clinical features. The first case of NMLFS has been described by Teebi in 2000, in a 4-year-old Palestinian boy. Three years later, Salpietro et al reported a second example of NMLFS in a 21-month-old girl. The same patient recently came to our hospital to undergo a computed tomography (CT) study to evaluate the degree of development of the zygomatic-maxillary region for orthodontic treatment and orthognathic surgery. To the best of our knowledge, no reports have previously illustrated the maxillofacial CT findings of NMLFS in the radiologic data. We report the multidetector CT (MDCT) facial characteristics/abnormalities of this syndrome, emphasizing the usefulness of multiplanar reformations (MPRs) in preoperative planning.

The bite force and craniofacial morphology in patients with acromegaly: a pilot study.

OBJECTIVES: Acromegaly is a metabolic disorder caused by increased growth hormone secretion. As a consequence of acromegaly some typical craniofacial morphology changes appear. This pilot study was conducted to compare the bite force and the characteristic size and shape of the craniofacial components of acromegalic patients with the healthy Turkish individuals. In addition, the correlations between bite force and craniofacial morphology of patients with acromegaly and control individuals were evaluated. STUDY DESIGN: The maximum bite force of the participants was recorded with strain-gage transducer. Lateral x-ray scans were made under standard conditions, in centric occlusion. On cephalograms, the linear and angular measurements was performed. RESULTS: Patients with acromegaly showed increased anterior and posterior total face height, ramus length, width of frontal sinuses, gonial angle and a negative difference between maxillary and mandibular protrusions. In addition, females with acromegaly showed larger lower anterior face height and sella turcica, decreased facial angle, increased mandibular plane angle. The cephalometric measurements, except one did not showed correlation with the bite force in acromegalic patients. In control group, significant correlations were observed between anterior total face height and anterior lower face height, mandibular plane angle and gonial angle. CONCLUSIONS: The greater changes were observed in the mandible. The maximum bite force of patients with acromegaly showed no difference from healthy individuals. The non-significant difference of bite force between healthy participants and acromegalic patients provide important information for dental treatment and prosthetic rehabilitation of acromegalic patients.

Perspectives and challenges in advancing research into craniofacial anomalies.

Development of the craniofacial region is a remarkably complex and tightly orchestrated process. It is therefore not surprising that genetic and environmental insults frequently result in craniofacial anomalies. Nonetheless, our knowledge of their etiology and pathogenesis is still scarce, limiting our efforts at prevention. Furthermore, few standardized protocols have been developed to guide clinical and surgical interventions. In this Issue of the Seminars, reviews on the most recent research advances on craniofacial conditions, from genomics and epigenetics to ontology and medical care are discussed with emphasis on the most common anomalies of the craniofacial region: orofacial clefts, craniosynostosis, craniofacial microsomia, facial dysostosis, Robin sequence, jaw and dentition anomalies, and anterior neural tube defects. Phenotypic variability and the importance of detailed characterization using standardized terminology to better distinguish between phenotypes, new technologies (and their limitations) for genetic diagnosis, and the use of mouse models to study these conditions in both their complex phenotypic and genetic aspects are highlighted.

Congenital heart defects in oculodentodigital dysplasia: Report of two cases.

Oculodentodigital dysplasia is caused by mutations in the GJA1 gene. Oculodentodigital dysplasia presents with a spectrum of clinical features including craniofacial, ocular, dental, and limb anomalies. Although recent findings implicate the major role of GJA1 during cardiac organogenesis, congenital heart defects are infrequently reported in oculodentodigital dysplasia. Here we report on two patients with GJA1 mutations presenting with cardiac malformations and type III syndactyly. Patient 1 presented with pulmonary atresia, an intact septum, right ventricular hypoplasia and tricuspid stenosis. The infant had a small nose, thin columella and bilateral 4-5 syndactyly of the fingers. A de novo c.226C>T (p.Arg76Cys) mutation was identified. Patient 2 presented at 6 months with a ventricular septal defect. The child had hypoplastic alae nasi with a thin columella and bilateral 4-5 syndactyly of the digits. A de novo missense mutation, c.145C>G (p.Gln49Glu) was found. Our two patients underscore the importance of cardiac evaluations as part of the initial workup for patients with findings of oculodentodigital dysplasia. Conversely, those patients with type III syndactyly and congenital heart defect should be screened for GJA1 mutations.