Craniofacial phenotypes associated with Robinow syndrome Conlon, Christopher J.; Abu‐Ghname, Amjed; Raghuram, Anjali C. ...
American journal of medical genetics. Part A,
December 2021, 2021-12-00, 20211201, Letnik:
185, Številka:
12
Journal Article
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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.
Dandy-Walker Malformation Monteagudo, Ana
American journal of obstetrics and gynecology,
December 2020, 2020-12-00, 20201201, Letnik:
223, Številka:
6
Journal Article
Healthcare recommendations for Joubert syndrome Bachmann‐Gagescu, Ruxandra; Dempsey, Jennifer C.; Bulgheroni, Sara ...
American journal of medical genetics. Part A,
January 2020, Letnik:
182, Številka:
1
Journal Article
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Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the “Molar ...Tooth Sign”. Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.
The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with ...intellectual disability (ID). First, 10 experienced clinicians (five from Africa and five from Europe) rated gestalt in 127 African non‐Down Syndrome (non‐DS) patients using either the score 2 for ‘clearly dysmorphic’, 0 for ‘clearly non dysmorphic’ or 1 for ‘uncertain’. The inter‐rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters (kappa‐coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome (DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80%) compared to African (36.8%). We trained the Face2Gene with a set of African DS and non‐DS photographs. Interestingly, the recognition in African increased to 94.7%. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic.
Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies.
We ...performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia.
A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort.
Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power—but also the challenges—of WES in prenatal diagnosis.
VACTERL/VATER Association Solomon, Benjamin D
Orphanet journal of rare diseases,
08/2011, Letnik:
6, Številka:
1
Journal Article
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VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal ...fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.
Development of the forebrain critically depends on the Sonic Hedgehog (Shh) signaling pathway, as illustrated in humans by the frequent perturbation of this pathway in holoprosencephaly, a condition ...defined as a defect in the formation of midline structures of the forebrain and face. The Shh pathway requires functional primary cilia, microtubule-based organelles present on virtually every cell and acting as cellular antennae to receive and transduce diverse chemical, mechanical or light signals. The dysfunction of cilia in humans leads to inherited diseases called ciliopathies, which often affect many organs and show diverse manifestations including forebrain malformations for the most severe forms.
The purpose of this review is to provide the reader with a framework to understand the developmental origin of the forebrain defects observed in severe ciliopathies with respect to perturbations of the Shh pathway. We propose that many of these defects can be interpreted as an imbalance in the ratio of activator to repressor forms of the Gli transcription factors, which are effectors of the Shh pathway.
We also discuss the complexity of ciliopathies and their relationships with forebrain disorders such as holoprosencephaly or malformations of cortical development, and emphasize the need for a closer examination of forebrain defects in ciliopathies, not only through the lens of animal models but also taking advantage of the increasing potential of the research on human tissues and organoids.
•Primary cilia are sensory and signaling organelles with central role in brain development.•Severe human ciliopathies encompass forebrain developmental malformations.•Forebrain malformations in ciliopathies overlap with microcephaly and holoprosencephaly.•Several forebrain developmental defects in ciliopathies can be attributed to Hedgehog/Gli perturbations.
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