Distinctive Facial Features Research Articles

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Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome.

Nance-Horan syndrome (NHS) is a rare X-linked developmental disorder caused mainly by loss of function variants in the NHS gene. NHS is characterized by congenital cataracts, dental anomalies, and distinctive facial features, and a proportion of the affected individuals also present intellectual disability and congenital cardiopathies. Despite identification of at least 40 distinct hemizygous variants leading to NHS, genotype-phenotype correlations remain largely elusive. In this study, we describe a Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing (WES). The affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies. Furthermore, brain imaging showed corpus callosum anomalies and periventricular leukoencephalopathy. We expand the phenotypic and mutational NHS spectrum and review potential disease mechanisms underlying the central neurological anomalies and the potential neurodevelopmental features associated with NHS.

Anaesthetic Management in a Child with Cutis Laxa for Bilateral Ureteric Reimplantation

Cutis laxa is a rare congenital multisystem connective tissue disorder. Patients with cutis laxa can present with distinctive facial features, pulmonary emphysema and right-sided heart failure. Anaesthetic management is important because of difficult airway and respiratory/cardiac abnormalities. We have reported the preoperative evaluation and anaesthetic management of a child with Cutis laxa with right cleft lip and palate.

The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children

Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age); the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS.

Bilateral open-angle glaucoma in a young female with Desbuquois syndrome

Desbuquois dysplasia is characterized by the presence of short stature, short extremities, joint laxity with frequent dislocation, osteopenia, vertebral abnormalities, distinctive facial characteristics, and other abnormalities including myopia and glaucoma. A variant form of Desbuquois type skeletal dysplasia (DBQD), the Kim variant, has also been described and is characterized by short stature, joint, and minor facial anomalies. Here, we report a case of bilateral open-angle glaucoma and high myopia occurring in a young female who presented with Desbuquois syndrome, a rare type of osteochondrodysplasia. The patient presented to the ophthalmology clinic with persistent eye pain and unstable refractive error. Her preliminary examination revealed raised intraocular pressure, high myopia, and skeletal deformities. A complete systemic examination and genetic workup suggested DBQD, Kim variant. With no detailed ophthalmic reports of such patients existing in the literature, it is important that such patients undergo a complete ophthalmic survey to rule out glaucoma, high myopia, and strabismus.

Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature

BackgroundLarge-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES).MethodsThirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES.ResultsFor 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%).ConclusionsA high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.

Expanding the neurological and behavioral phenotype of White-Sutton syndrome: a case report

BackgroundWhite-Sutton (WHSUS) is a recently recognized syndrome caused by mutations of the POGZ gene. Approximately 70 patients have been reported to date. Intellectual disability, hypotonia, behavioral abnormalities, autism, and typical facial dysmorphisms are recognized as WHSUS features; however, still few patients receive a comprehensive psychometric, behavioral and neurological examination. In this report, we describe the pediatric, dysmorphological, neurological, psychometric and behavioral phenotype in a new WHSUS patient due to a novel heterozygous POGZ mutation, highlighting the distinctive epileptic phenotype and the cognitive pattern.Case presentationThe patient, an 8 years-old girl, presented history of hypotonia, motor and speech delay, and distinctive facial features. The diagnosis of WHSUS followed the identification of the de novo variant p.Asp828GlyfsTer36 (c.2482dupG) in the POGZ gene. The patient showed a distinctive neurological phenotype with the occurrence of both paroxysmal not-epileptic events in the first 6 months of age and EEG abnormalities without evidence of clinical seizures after the first year of age. Psychological and behavioral testing highlighted moderate intellectual and communication deficit, mild autism spectrum and visual-motor integration deficit.ConclusionsThis is the first described case of WHSUS with a co-existence of paroxysmal not-epileptic events and abnormal EEG without seizures in the same patient. Together with the available literature data, this observation suggests that paroxysmal not-epileptic events could be more frequent than expected and that this feature belongs to the WHSUS phenotypic spectrum. Autism is a known comorbidity of WHSUS but is still poorly investigated. Specific clinical testing could help detect also mild autistic phenotypes and better define autism prevalence in POGZ-related syndrome. Special attention should be given to symptoms such as stereotypies, social withdrawal, and hyperactivity that, when present, should be considered as possible signs of autism symptoms. The dissection of the neurological and behavioral phenotype is crucial for individualized therapies tailored to patient’s needs.

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome.

Down syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (β-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

Wolf-Hirschhorn Syndrome with Hyperparathyroidism: A Case Report and a Narrative Review of the Literature.

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.

Expanding the clinical phenotype and genetic spectrum of PURA-related neurodevelopmental disorders

BackgroundPURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 deletion syndrome and PURA syndrome. PURA-NDDs are characterized by neonatal hypotonia, moderate to severe global developmental delay/intellectual disability (GDD/ID), facial dysmorphism, epileptic seizures, nonepileptic movement disorders, and ophthalmological problems. PURA-NDDs have recently been identified and underestimated in neurodevelopmental cohorts, but their diagnosis is still challenging. MethodsWe retrospectively reviewed the clinical characteristics, genetic spectrum, and diagnostic journey of patients with PURA-NDDs. ResultsWe report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding difficulties (4/5, 80%), and respiratory problems (4/7, 57%) in the neonatal period. All of them had severe GDD/ID and could not achieve independent walking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual fixation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no significant differences in clinical phenotypes between 5q31.3 microdeletion syndrome and PURA syndrome. PURA-NDDs need to be considered as a differential diagnosis in individuals who show severe hypotonia, including feeding difficulties since birth and severe developmental retardation with distinctive facial and ophthalmological features. ConclusionsOur data expands the phenotypic and genetic spectrum of PURA-NDD. Next-generation sequencing methods based on the detailed phenotypic evaluation would shorten the diagnostic delay and would help this rare disorder become a recognizable cause of neurodevelopmental delay.

Weighted statistical binary patterns for facial feature representation

We present a novel framework for efficient and robust facial feature representation based upon Local Binary Pattern (LBP), called Weighted Statistical Binary Pattern, wherein the descriptors utilize the straight-line topology along with different directions. The input image is initially divided into mean and variance moments. A new variance moment, which contains distinctive facial features, is prepared by extracting root k-th. Then, when Sign and Magnitude components along four different directions using the mean moment are constructed, a weighting approach according to the new variance is applied to each component. Finally, the weighted histograms of Sign and Magnitude components are concatenated to build a novel histogram of Complementary LBP along with different directions. A comprehensive evaluation using six public face datasets suggests that the present framework outperforms the state-of-the-art methods and achieves 98.51% for ORL, 98.72% for YALE, 98.83% for Caltech, 99.52% for AR, 94.78% for FERET, and 99.07% for KDEF in terms of accuracy, respectively. The influence of color spaces and the issue of degraded images are also analyzed with our descriptors. Such a result with theoretical underpinning confirms that our descriptors are robust against noise, illumination variation, diverse facial expressions, and head poses.

Behavioral and cognitive functioning in individuals with Cantú syndrome

Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (KATP ) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults.

Anaesthesia and orphan disease: management of a case of Nicolaides-Baraitser syndrome undergoing cleft palate surgery

BackgroundNicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by mutations in the SMRCA2 gene, which affects chromatin remodelling and leads to a wide range of symptoms including microcephaly, distinct facial features, recurrent seizures, and severe mental retardation. Until now, less than 100 cases have been reported.Case presentationA 22-month old male infant with NCBRS underwent elective cleft palate surgery. The anaesthetists were challenged by the physiological condition of the patient: narrow face, very small mouth, mild tachypnea, slight sternal retractions, physical signs of partial monosomy 9p, and plagiocephalus, midface hypoplasia, V-shaped cleft palate, enhanced muscular hypotension, dysplastic kidneys (bilateral, estimated GFR: approx. 40 ml/m2), nocturnal oxygen demand, and combined apnea. In addition, little information was available about interaction of the NCBRS displayed by the patient and anaesthesia medications.ConclusionsThe cleft palate was successfully closed using the bridge flap technique. Overall, we recommend to perform a trial video assisted laryngoscopy in the setting of spontaneous breathing with deep inhalative anaesthesia before administration of muscle relaxation to detect any airway difficulties while remaining spontaneoues breathing and protective reflexes.

Whole exome sequencing identified a pathogenic mutation of COL2A1 causing Stickler syndrome in a Vietnamese family

Stickler syndrome is a group of rare inherited diseases associated with abnormalities in connective tissues, specifically collagen of the eyes, ears, craniofacies, skeleton and joints. The inheritance pattern of this disease is either an autosomal dominant or an autosomal recessive based on the causative gene. Stickler syndrome is characterized by severe nearsightedness, vitreous abnormalities, distinctive facial features, hearing problems and joint anomalies. Herein, we report a case of a 37-year-old man from Vietnam suspected of Stickler syndrome, presenting a phenotype of retinal detachment and complete loss of vision, and his 3-year-old son with congenital high myopia and vitreous abnormalities. Genetic analysis using whole exome sequencing (WES) revealed a nucleotide substitution (c.C2818T/p.R940X) in exon 42 of the COL2A1 gene that was previously reported as a pathogenic variant causing Stickler syndrome. Validation of COL2A1 c.C2818T in all members of this family by using Sanger sequencing detected the presence of this pathogenic variant in the heterozygous form in the affected father and son but not in the mother and another son without any signs of a vision problem. Thus, our study contributes to not only the knowledge base of clinical and genetic aspects of Stickler syndrome in Vietnam but also the awareness of the importance of genetic counseling in patients with COL2A1 c.C2818T mutation, as well as early diagnosis and appropriate treatment to prevent serious complications, especially blindness.

The effect of distinctive facial features on destination memory.

Destination memory involves remembering to whom we told information. Low accuracy of this memory is linked to higher self-focus and lower attentional resources allocated to the recipient of the information. The present paper aimed to investigate whether the existence of distinctive features (e.g., tattoos) of destination face would improve destination memory, in a within- (Experiment 1 and 2) and between-participants (Experiment 3) design. In a destination memory task, participants had to tell proverbs to faces that presented a distinctive feature and to other faces that did not. Results showed that a destination memory advantage only occurs when faces with different distinctive features are compared to faces without distinctive features (Experiment 1). These results are in accordance with the existing theoretical framework on destination memory and distinctiveness; highlighting the importance of personal attributes, namely, the distinctiveness of the destination face and the relativity of distinctiveness in destination memory.

A recurrent de novo ZSWIM6 variant in a Japanese patient with severe neurodevelopmental delay and frequent vomiting

A recurrent ZSWIM6 variant, NM_020928.2:c.2737C>T [p.Arg913*], was identified in a Japanese male patient with severe neurodevelopmental delay, epilepsy, distinctive facial features, microcephaly, growth deficiency, abnormal behavior, and frequent vomiting but without frontonasal or limb malformations. In this patient, distinctive facial features gradually became apparent with age, and severe vomiting caused by gastroesophageal reflux continued even after percutaneous endoscopic gastrostomy.

First episode of psychosis in Kleefstra syndrome: a case report

ABSTRACT Kleefstra syndrome (KS) is a genetic syndrome caused by a haploinsufficiency of the EHMT1 gene and characterized by intellectual disability, language disorders, childhood hypotonia and distinct facial features. Only a few cases of first episode of psychosis in KS have already been reported. We describe a young female patient with KS who presented a first episode of psychosis. In a context of an initial diagnosis wavering and a lack of recommendations, this clinical observation illustrates the importance of psychiatric comorbidities and their diagnostic and therapeutic complexity in KS; with a need for multidisciplinary management considering its specific aspects and vulnerabilities.

Carrier frequency and incidence estimation of Smith\u2013Lemli\u2013Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis

BackgroundSmith–Lemli–Opitz syndrome (SLOS) is an autosomal, recessively inherited congenital malformation syndrome characterized by multiple congenital anomalies such as microcephaly with mental defects, distinctive facial features, genital abnormalities, and 2–3 syndactyly of the toes. SLOS is caused by defective 7-dehydrocholesterol reductase, which is encoded by the DHCR7 gene. This study aimed to analyze the carrier frequency and expected incidence of SLOS in East Asians and Koreans using exome data from the Genome Aggregation Database (gnomAD) through the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline (2015 ACMG-AMP guideline).MethodsWe analyzed 9197 exomes for East Asian populations from gnomAD, comprising 1909 Korean, 76 Japanese, and 7212 other East Asian populations. All identified variants were classified according to the 2015 ACMG-AMP guideline.ResultsAccording to the 2015 ACMG-AMP guideline, 15 pathogenic variant/likely pathogenic variant (PV/LPV) cases were identified in 33 East Asian individuals (33/9191 = 0.4%). Among them, four PVs/LPVs were identified in 19 Korean individuals (19/1909 = 1.0%). The predicted incidence, based upon the carrier rates of PV/LPV of DHCR7 alleles, is 1 in 310,688 in East Asians and l in 40,380 in Koreans.ConclusionsThis study is the first to identify carrier frequencies in East Asians and Koreans using gnomAD. It was confirmed that East Asians (0.4%) had a lower carrier frequency than did other ethnicities (1–3%) and Koreans (1.0%) had similar or lower carrier frequencies than other ethnicities. The variant spectrums of DHCR7 in East Asian and Korean populations differed greatly from those of other ethnic groups.

Comprehensive analysis of clinical spectrum and genotype associations in Chinese and literature reported KBG syndrome.

BackgroundPatients with KBG Syndrome due to ANKRD11 mutations and 16q24.3 microdeletions including ANKRD11 were identified. Classical and most frequent phenotypes include various degrees of intelligence disability (ID), short stature (SS), delayed bone age, macrodontia, distinctive facial features and skeletal anomalies. The variable expressivity of KBG syndrome makes it challenging to establish genotype-phenotype correlations, which also affects further studies for this novel syndrome. We aim to report three unrelated patients with KBG syndrome caused by ANKRD11 gene pathological variants and to evaluate potential associations among ANKRD11 gene variant types, the 16q24.3 microdeletion, and the clinical spectrum of KBG syndrome.MethodsThe genetic etiology of three unreported KBG patients was identified by whole exome sequencing and confirmed via Sanger sequencing. Literature review was conducted to summarize the phenotype-genotype relationship based on three unreported Chinese cases and 186 reported cases.ResultsTwo pathological variants (c.7407dupC, p.P2530Rfs*61; c.G3046A, p.D1016N) and one reported variant (c.6792dupC, p. P2271Pfs*8) were detected in our patients. Compared with the 16q24.3 microdeletion, patients harboring ANKRD11 gene mutations showed significantly higher frequency of malformations including macrodontia, long philtrum, abnormal eyebrows, widely spaced eyes, anteverted nares, eyelid ptosis, brachydactyly, brachycephaly (P<0.05), and significantly lower risk of congenital heart diseases and frontal bossing (P<0.05). The intellectual disability (ID) was significantly milder among patients carrying truncating variants located between repression domain 1 (RD1) and activation domain (AD) than those carrying mutations disrupting repression domain 2 (RD2) alone and disrupting all functional domain (RD1, AD or RD2) (P<0.05).ConclusionsNovel pathological variants harbored in the ANKRD11 gene contribute to the KBG syndrome variant spectrum. ANKRD11 gene variants disrupting RD1 and RD2 or RD2 alone are more likely to have more severe ID, which warrants different intervention strategies for KBG syndrome.

Further delineation of van den Ende‐Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42%) of whom had known pathogenic variants in SCARF2, 6 (16%) with negative SCARF2 testing, and 15 (42%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.