Thick Eyebrows Research Articles

EGFR Mutation in Neonatal Nephrocutaneous Syndrome: Unveiling a Genetic Challenge

AbstractEpidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that exhibits tyrosine kinase signaling activity, playing a pivotal role in various cellular processes. Overexpression or overactivity of EGFR is significantly associated with inflammatory and malignant diseases, particularly lung cancer. Conversely, germline loss-of-function mutations in EGFR have been distinctly linked to a rare condition known as neonatal nephrocutaneous syndrome. We report a case of a preterm female neonate, born to consanguineous parents and from a pregnancy that was complicated by polyhydramnios. From birth, she displayed distinctive clinical features, including fragile skin and widespread erythema, sparse scalp hair, bilateral ankyloblepharon, thick eyebrows, and arachnodactyly. Subsequently, she developed progeroid features marked by skin desquamation, along with failure to thrive, diarrhea, and severe electrolyte and acid–base imbalances. Additional complications comprised anemia, generalized mucocutaneous candidiasis, external otitis, and recurrent septic episodes. Genetic analysis confirmed a homozygous EGFR mutation c.1283G > A p.(Gly428Asp). The infant's neurological status remained stable, albeit requiring pain management through oral morphine and gabapentin. Palliative care became imperative, given the dismal prognosis. The identified mutation is exceedingly rare, with only 24 reported cases known thus far. Each of these instances resulted in a complex multisystemic condition marked by a wide range of challenging symptoms and signs. This clinical journey highlights the intricate interplay among genetic mutations and complex medical conditions, and underscores the critical significance of multidisciplinary care.

Clinical characteristics and genetic analysis of mental retardation disorder with TRIO gene variant

Objective: To summarize the clinical and genetic characteristics of mental retardation disorder (MRD) with TRIO gene variant in children. Methods: Case series study. The data of 9 children with TRIO gene variants were collected retrospectively from August 2019 to March 2024 in Department of Neurology, Beijing Children's Hospital, Capital Medical University and Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University. The data included gender, age, intellectual and motor development, appearance, seizures, neuroimaging and genetic results. The clinical features and genotype-phenotype correlations were summarized. Results: Of the 9 children, 6 boys and 3 girls, 4 MRD63 children presented with moderate to severe developmental delays accompanied by macrocephaly; 5 MRD44 children had mild to moderate developmental delays with microcephaly. A total of 5 children had dysmorphic facial features (flat occiput, thick eyebrows, unibrow, large ears, short fingers, pale skin, yellow hair, and strabismus), 2 children experienced seizures (1 child with myoclonic seizure and 1 with absence seizure), 4 children had feeding difficulties, 1 child had congenital cataracts, 1 child had congenital heart disease, 1 child had recurrent infections, and 1 child had tiger-striped changes in the fundus examination. TRIO gene variants carried by the 9 children were all de novo, involving 8 variant sites, including 7 missense variants and 1 frameshift variant, c.3232C>T/p.R1078W (2 cases), c.3920A>G/p.Y1307C, c.4112A>T/p.H1371L, c.4283G>T/p.R1428L, c.4394A>G/p.N1465S, c.6041T>C/p.I2014T, c.6821G>A/p.R2274H, c.7027delC/p.Q2343Sfs*70. Among them, 2 sites are located in the Spectrin domain, 4 sites are in the GEFD1 domain, 2 sites are in the GEFD2 domain, and 1 site (frameshift variant) is in the PH2-SH3 domain. The individual with frameshift variant exhibit absence seizures, mild developmental delay, and the mildest phenotype. The child with myoclonic seizures was treated with valproic acid and levetiracetam for seizure control, while the child with absence epilepsy was treated with valproic acid and lamotrigine for seizure control. All 9 children underwent regular rehabilitation exercises, making slow progress. Conclusions: TRIO gene related MRD is characterized by varying degrees of developmental delay, and often accompanied by macrocephaly or microcephaly, dysmorphic facial features, and with or without seizures. The main variant types are missense variants, which are mostly concentrated in the Spectran domain and GEFD domain. p. R1078W may be a relative hotspot variant. The phenotype caused by the frameshift variant is relatively milder.

Chromosome Xp22.3 deletion syndrome with X-linked ichthyosis, Kallmann syndrome, short stature, generalized epilepsy, hearing loss, attention deficit hyperactivity disorder, and intellectual disability – A rare report with review of literature

Chromosome Xp22.3 deletion syndrome is a very rare contiguous gene deletion syndrome with variable phenotype due to the deletion of genes from the distal short arm of the X chromosome (Xp), including the short-stature homeobox (SHOX), anosmin-1 (ANOS1), arylsulfatase (ARSL), neuroligin-4 (NLGN4), and steroid sulfatase (STS) genes. We have reviewed the available literature on the chromosome Xp22.3 deletion syndrome. A 10-year-old boy presented with global developmental delay, generalized epilepsy, decreased hearing, and hyperactivity. He had no significant family history. Examination revealed microcephaly, short stature, and dry and scaly skin lesions on the trunk. He had thick arched eyebrows, a depressed nasal bridge, a long philtrum, high arched palate, retrognathia, brachytelephalangy, brachymetatarsia, and mild scoliosis. Brainstem-evoked response audiometry testing revealed moderate hearing loss. Magnetic resonance imaging showed cerebellar tonsillar ectopia. Clinical exome sequencing revealed a likely pathogenic contiguous deletion (~8.10 Mb) spanning genomic location chrX:g.(_630898)_(8732037_)del encompassing ANOS1, ARSL, NLGN4X, SHOX, and STS genes. We have reviewed the available literature for reported associations of Chromosome Xp22.3 deletion syndrome and report a novel association of X-linked ichthyosis, Kallmann syndrome, global developmental delay, short stature, bilateral hearing loss, generalized epilepsy, attention deficit hyperactivity disorder, and intellectual disability.

Association between the three-dimensional facial shape and its color in a boundary group of young to middle-aged Asian women

Visual cues strongly influence an individual's self-esteem and have fundamental sociopsychological functions. The color and shape of the face are important information for visual cues and are hypothesized to be correlated with each other. However, few studies have examined these relationships. Thus, this study determined the association between color and shape of the face. For this purpose, we evaluated Chinese women in their 30s and 40s (n = 166). Three-dimensional (3D) image-capture devices that provide shape morphology along with standardized photographs (color information) were used to obtain 3D images of women. The coordinates and red‒green–blue color data on the 3D images were utilized to perform principal component (PC) analysis, and shape and color PCs were generated. A canonical variate analysis was then conducted to check for significant correlations between the shape and color PCs. As a result, 6 significant correlations were found (p < 0.05). In detail, in addition to the physical correlations (i.e., steric faces or faces with protrusion of the cheek showed greater shadows, retrognathism was related to a shadow under the lower lip and vice versa), biological correlations (fatty faces showed greater redness and remarkable marionette lines; faces with age-related sagging showed greater darkness, possibly related to cumulative ultraviolet radiation exposure of the skin; and robust mandibles and supraorbital ridges were related to thick eyebrows) were found. This insight can aid both medical and cosmetic practitioners in comprehending the intricate details conveyed by facial features, thereby facilitating more comprehensive diagnosis and treatment planning, including makeup.

Variants in KMT2A in Three Individuals with Previous Suspicion of 22q11.2 Deletion Syndrome.

The condition known as 22q11.2 deletion syndrome (MIM #188400) is a rare disease with a highly variable clinical presentation including more than 180 features; specific guidelines for screening individuals have been used to support clinical suspicion before confirmatory tests by Brazil's Craniofacial Project. Of the 2568 patients listed in the Brazilian Database on Craniofacial Anomalies, 43 individuals negative for the 22q11.2 deletion syndrome were further investigated through whole-exome sequencing. Three patients (6.7%) presented with heterozygous pathogenic variants in the KMT2A gene, including a novel variant (c.6158+1del) and two that had been previously reported (c.173dup and c.3241C>T); reverse phenotyping concluded that all three patients presented features of Wiedemann-Steiner syndrome, such as neurodevelopmental disorders and dysmorphic facial features (n = 3), hyperactivity and anxiety (n = 2), thick eyebrows and lower-limb hypertrichosis (n = 2), congenital heart disease (n = 1), short stature (n = 1), and velopharyngeal insufficiency (n = 2). Overlapping features between 22q11.2 deletion syndrome and Wiedemann-Steiner syndrome comprised neuropsychiatric disorders and dysmorphic characteristics involving the eyes and nose region; velopharyngeal insufficiency was seen in two patients and is an unreported finding in WDSTS. Therefore, we suggest that both conditions should be included in each other's differential diagnoses.

Portrayal or Betrayal? A Few Thoughts on Milton’s Curls

In one of his most frequently reproduced portraits, John Milton appears as a young man, depicted in a three-quarter view, looking sideways, not directly at but rather beyond the beholder. His small mouth and undereye lids hint at a faint smile. He has rather thick eyebrows, a straight nose, and the full cheeks and round chin of a youth. His long hair parted in curtains falls in graceful curls far below his shoulders, over his white collar and black robe. This familiar image that the general public associates with the name of John Milton differs however from authenticated portraits of the poet, and results from a series of alterations that started in the 19th century. The purpose of this essay is twofold: firstly, to trace the modifications made on portraits of the author of Paradise Lost, and to study them in the context of changing aesthetic preferences and psychological debates; secondly, to initiate a theoretical reflection on historical portraits. Drawing on recent scholarship on biofiction, this article will suggest that distorted images affect the portraits of “great men” by fictionalizing historical figures and presenting “iconofictions” that pass as portraits. Located at the intersection of art, history, and biography, this paper intends to discover how a modified portrait of John Milton became iconic even while it lost its status as a documentary piece.

Dental Treatment Approach in an Adolescent Patient With Coffin-Siris Syndrome

Coffin-Siris Syndrome (CSS) is a rare genetic disease with delayed growth, congenital anomalies, abnormal facial features, and mental retardation. Hypoplasia of the 5th fingers or nail agenesis, hirsutism, coarse facial appearance, thick eyebrows, wide lips and nose, dentofacial anomalies, and delayed eruption of teeth are clinically distinctive features. Specific findings and multidisciplinary approac-hes are important for dental treatments. This case report includes the clinical, oral findings, and dental treatments of the patient with CSS. A 15.5-year-old female patient consulted our clinic with the complaint of tooth sensitivity and missing teeth. The patient's family was informed that the patient has CSS. In clinical examination, coarse face, mental retardation, hypoplastic 5th fingers, wide mouth, and lips, sparse hair, and hirsutism, in the oral examination, poor oral hygiene, dental caries, delayed dentition, lack of upper perma-nent first incisor, gingival hyperplasia, gingivitis, and hypoplasia were seen. Panoramic radiography and tomography revealed that the upper permanent incisor and supernumerary canine teeth were impacted. Under general anesthesia, dental scaling, fillings were made, impacted permanent incisors, canine, and lower left third molars were extracted. After general anesthesia, fluoride application and a fiber-supported Maryland bridge designed from the patient's teeth were applied to the anterior region. Regular controls of the patient continue. After the growth and development, the oral surgery department will be consulted for implant application. In den-tistry, preventive applications, oral hygiene motivation, pharmacological and non-pharmacological treatments are important for CSS patients. After consultation with relevant departments, multidisciplinary approaches and appropriate treatments increase the quality of life.

Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias.

We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.

Cornelia De Lange Syndrome in the International Classification of Functioning, Disability and Health Perspetive: A Case Report

Background: Cornelia de Lange syndrome (CdLS) is a genetic disorder featured by multi-systemic malformations, such as microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. Multidisciplinary and holistic care is needed in the management and rehabilitation of individuals with CdLS. One of the tools that can be used as a clinical measurement in holistic care is the International Classification of Functioning, Disability, and Health (ICF). Objective: To provide a holistic approach and intervention by using the ICF assessment in CdLS individuals. Case: A 53-month-old boy was admitted to Physical Medicine and Rehabilitation outpatient clinic of Primasatya Husada Citra (PHC) hospital of Surabaya in February 2021, due to global developmental and growth delay. The patient had low body weight and short stature. The patient had thick eyebrows, a short nose, a concave nasal ridge, thin upper lip vermillion, smooth philtrum, and small hands with small fifth fingers. Was only able to say several words, and it was not clearly pronounced. During the daily activity, he had difficulty going downstairs and wearing his socks, long pants, and shirt. Attended pre-school, had difficulties with speaking, reading, and focusing attention. Conclusion: ICF can help physicians to assess a patient’s condition thoroughly, to set goals, and to provide condition-appropriate treatment and rehabilitation programs for CdLS patients.

A Study on the Aesthetic Characteristics of Hetaira Beauty Style Expressed in Greek Pottery

This study studied the aesthetic characteristics of Hetaira's costume and beauty style expressed in pottery paintings of the Greek era as the contents of Greek mythology were recently re-examined as the subject of humanities interest. In ancient Greece, the common name for prostitutes was Hetaira, and she was a religious prostitute who was at the top of the list of prostitutes in Greek society, enjoying the wealth of freedom and status more than any other woman. The aesthetic characteristics of the Hetaira beauty style of the Greek era were largely shown as An ornament beauty, An ostentatious sensuality and symbolic beauty of power. First, An ornament beauty was the makeup of a Greek Hetaira woman, who emphasized her eyes with thick and dark black eyebrows and black eyeliner. The Hetaira woman's face was white with white lead, her eyes were emphasized with eyeshadow using black cowl, and she applied orange short yarn to her cheeks and mouth to put on intense color makeup. Hetara dyed her hair in all sorts of colors, decorated her hair with hairpieces, wore thin cloth ribbons and chest bands, and sprayed perfume made with special prescriptions. Second, ostentatious sensual beauty was applied to various sexual zones of the feminine body and the whole body, such as the nipple and buttocks, which can stimulate men's sexual pleasure, and Hetair's outfit was in the form of a full-body keyton or revealing the upper body. The hair was as voluminous as possible, and the method of dispersing the tarae on the forehead was used to make it look as sensual as possible. Curled hair with thick waves was naturally curled up and expressed sensibly using a signon shape and long hair. Third, the symbolic beauty of power is that ancient Greece's ‘privilege fashion’ was ‘nature’, a power that only men could have, but Hetaira had equal power with men in the symposium with nakedness. The hairstyle seems to have been able to wear a veil or a laurel crown, which is exclusively for men. In the form of a wig, he preferred a curling style with no forehead exposed, and it was found that he produced blade hair. Hetaira's style, represented in Greek pottery paintings, had hair, makeup, and fashion styles that represented the Greek era, possessed greater power and wealth than ordinary women in the Greek era, and was found to have the privilege of wearing heavy makeup, light hair colors and hair decorations that were not allowed by ordinary women. Therefore, it was found that it was very meaningful to study Hetaira's beauty style in studying the beauty culture of the Greek era.

PARK2 microdeletion in a multiplex family with Autism Spectrum Disorder.

PARK2 (PRKN; MIM*602544) encodes Parkin protein, an ubiquitin-protein ligase required for proteasomal degradation and operating in the synaptic compartments. Copy Number Variations (CNV) involving PARK2 have been associated with autism spectrum disorder (ASD). We report on a family with ASD (multiplex family) harbouring a microdeletion at chr. 6q26 causing PARK2 disruption. CNV analyses was performed using CGH/SNP-array platforms and the detected microdeletion was confirmed by real-time quantitative PCR. Standardized psychometric evaluation was used for neurobehavioral characterization. We found an intragenic ~ 157 kb microdeletion of the chromosomal region 6q26 causing PARK2 disruption in two male sibs with ASD and syndromic phenotype. They both had dysmorphic facial features with coarse faces, deeply set eyes with long horizontal palpebral fissures, long eyelashes and thick eyebrows, fleshy lips, and mild skeletal problems. We found an intra-familial clinical heterogeneity owing to different severity of the autism symptoms between the affected sibs: the younger one had minimally verbal autism and severe intellectual disability while his older brother presented high-functioning autism and preserved speech. Parental analysis and real-time PCR using a PRKN fragment mapping within the deletion demonstrated that the deletion was inherited from their father having subthreshold features of ASD consisting with broad autism phenotype. The study corroborates the hypothesis that PARK2 aberrations may be associated with ASD and highlights correlations between CNV affecting PARK2 and ASD in a multiplex family. We show remarkable intrafamilial variability in the severity of inherited ASD associated with PARK2 microdeletion.

On the Body

On the Body

A Study on Eyebrow Design to Enhance the Image of Square and Long Face

Eyebrows makeup is an important part of makeup, which is essential for personalized face expression and image change. Therefore, the best eyebrow makeup requires an understanding of eyebrow type suitable for one’s own face and technical skills of expressing it. Thus, in this study, we aimed to measure the thickness and height of the eyebrows and the width of the glabella, so effectively applied for personalized face expression and image enhancement that the woman can easily and correctly express their personalized eyebrows to enhance their facial images. For this reason, at first, a thorough literature review of eyebrow makeup was made, and then a related survey, a set of experiments and expert evaluation were carried out in order. An exploration into eyebrows design for complementing face shape and enhancing face image showed that long face shape most often evoked ‘calm’ or ‘composed’ feelings, thereby allowing penciling thick eyebrows to be most effective for improving face image when applying ‘straight’ eyebrow design good for complementing face shape. When eyebrows design was applied to express a ‘composed’ image, delineating the distance from the midpupil to the upper edge of the eyebrow, the glabella seems to be less wide than in the case of ‘composed’ image producing the intended results. It may be because a ‘composed’ image gives a relatively more calm and motionless feeling, causing eyebrows low in height with narrow glabella to have the effect of deepening the sincerity of face. An ‘angled’ face image usually evoked ‘trustworthy’ or ‘superb’ feelings. Therefore, when making ‘arched’ eyebrow makeup to supplement the shape of the face, drawing thick eyebrows with a pencil and delineating the narrow distance from the mid pupil to the upper edge of the eyebrows, which makes the eyebrows look very wide and produce an ideal effect. This may be because ‘trustworthy’ or ‘superb’ images creates a dynamic and upright impression, allowing thick eyebrows with narrow glabella to enhance face images more effectively. Overall, it may be said, the results of this study show what type of eyebrows helps complement the face shape and enhance face images and provide exact quantification of the thickness and height of the eyebrows and the width of the glabella, effectively applied for personalized face expression and image enhancement. And a further important implication is that the results might serve as the inspiration for marketing and sales promotion of eyebrow-related products and tools to weather the storm of sales drop in the cosmetics industry due to COVID-19.

KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients

Genetic variants in Ankyrin Repeat Domain 11 (ANKRD11) and deletions in 16q24.3 are known to cause KBG syndrome, a rare syndrome associated with craniofacial, intellectual, and neurobehavioral anomalies. We report 25 unpublished individuals from 22 families with molecularly confirmed diagnoses. Twelve individuals have de novo variants, three have inherited variants, and one is inherited from a parent with low-level mosaicism. The mode of inheritance was unknown for nine individuals. Twenty are truncating variants, and the remaining five are missense (three of which are found in one family). We present a protocol emphasizing the use of videoconference and artificial intelligence (AI) in collecting and analyzing data for this rare syndrome. A single clinician interviewed 25 individuals throughout eight countries. Participants’ medical records were reviewed, and data was uploaded to the Human Disease Gene website using Human Phenotype Ontology (HPO) terms. Photos of the participants were analyzed by the GestaltMatcher and DeepGestalt, Face2Gene platform (FDNA Inc, USA) algorithms. Within our cohort, common traits included short stature, macrodontia, anteverted nares, wide nasal bridge, wide nasal base, thick eyebrows, synophrys and hypertelorism. Behavioral issues and global developmental delays were widely present. Neurologic abnormalities including seizures and/or EEG abnormalities were common (44%), suggesting that early detection and seizure prophylaxis could be an important point of intervention. Almost a quarter (24%) were diagnosed with attention deficit hyperactivity disorder and 28% were diagnosed with autism spectrum disorder. Based on the data, we provide a set of recommendations regarding diagnostic and treatment approaches for KBG syndrome.

Treatment of Cornelia de Lange syndrome: Evidence-based medicine and expert opinion

Background: Cornelia de Lange syndrome is a rare genetic condition of highly variable phenotype making ranging from classic syndrome with many cardinal features to mild syndrome with less characteristic features. Materials and methods: The mother of a three and half years old boy brought her son to our clinic because of significant developmental delay and over-activity. The mother denied the presence of relevant family history. Results: The boy was mentally retarded and had facial dysmorphic features including thick eyebrows with synophrys, long or smooth philtrum, thin upper lip vermilion, and low set ears. The boy poor adaptive skills and has not achieved urine and bowel control and was unable to hold spoon appropriately to feed himself. He had no speech development and was not saying any word. At the clinic, he was very active, but he was responding to name and had acceptable eye contact and therefore, he was not considered to have autistic features. It was not possible to convince him to take a pen to scribble. Based on our extensive published experiences with treatment of mental retardation syndrome, we recommended an initial therapeutic course which included a course of intramuscular piracetam 600 mg given daily in the morning every third day (Ten doses over one month). Conclusion: An expert therapeutic recommendation for the condition is described.

A 15-Year-Old Girl with Trichorhinophalangeal Syndrome Type 1 with Non-ossifying Fibroma in Femur: A Case Report

Introduction: Trichorhinophalangeal syndrome (TRPS) is a sporadic autosomal dominant disorder with approximately 200 reported cases worldwide. We aimed to report a 15-year-old girl with TRPS type 1 (TRPS1) and the second reported case with a rare non-ossifying fibroma (NOF) in the distal part of her left femur. Case Presentation: We introduce a 15-year-old girl who presented to the outpatient rheumatology clinic at 17 Shahrivar Children's Hospital, Rasht, Iran, with the chief complaint of osteoarticular pain and bone deformities. She had sparse hair, a recession of the fronto-temporal hairline, and unusually thick eyebrows at the medial and abnormal sparseness of the lateral margins. Physical examination of the limbs revealed short fingers and toes with proximal interphalangeal (PIP) ulnar deviation of the second and third fingers in both hands. Shortness of the fourth fingers, especially in the right hand, and the swelling of the PIP joints of both hands were prominent. Genetic analysis showed deletion mutation in the TRPS1 gene in chromosome 8q24 compatible with TRPS1. Conclusions: Several symptoms and signs, including distinctive craniofacial features and ectodermal and skeletal abnormalities, are used for proper TRPS diagnosis. A correct and on-time diagnosis is essential to perform supportive care for the patient to prevent morbidities. Bone lesions, such as NOF1, can also be presented in TRPS1 patients and may be correlated with TRPS1 mutation. Further investigations are required on the association of the TRPS gene with NOF bone lesions.

Treatment of Cornelia de Lange syndrome: Evidence-based medicine and expert opinion

Background: Cornelia de Lange syndrome is a rare genetic condition of highly variable phenotype making ranging from classic syndrome with many cardinal features to mild syndrome with less characteristic features. Materials and methods: The mother of a three and half years old boy brought her son to our clinic because of significant developmental delay and over-activity. The mother denied the presence of relevant family history. Results: The boy was mentally retarded and had facial dysmorphic features including thick eyebrows with synophrys, long or smooth philtrum, thin upper lip vermilion, and low set ears. The boy poor adaptive skills and has not achieved urine and bowel control and was unable to hold spoon appropriately to feed himself. He had no speech development and was not saying any word. At the clinic, he was very active, but he was responding to name and had acceptable eye contact and therefore, he was not considered to have autistic features. It was not possible to convince him to take a pen to scribble. Based on our extensive published experiences with treatment of mental retardation syndrome, we recommended an initial therapeutic course which included a course of intramuscular piracetam 600 mg given daily in the morning every third day (Ten doses over one month). Conclusion: An expert therapeutic recommendation for the condition is described.

A novel nonsense variant in ARID1B causing simultaneous RNA decay and exon skipping is associated with Coffin-Siris syndrome

Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband’s clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype.

Lobster Claw Hand Deformity - Cornelia de Lange Syndrome

Background: Cornelia de Lange syndrome is a genetic syndrome characterized by intellectual disability, facial features with synorphrys or fused eyebrows, upper limb anomalies and atypical growth. It is caused by spontaneous mutations in genes responsible for structural or regulatory function of cohesin complex.&#x0D; Report: We present two newborns cases admitted to our NICU with characteristic dysmorphic features of microcephaly, ectrodactyly and thick eyebrows. One baby also had associated congenital heart defect and sensorineural hearing loss. Both babies are under followup with developmental early intervention programs. Parents were offered genetic counselling for future pregnancies.&#x0D; Conclusion: Cornelia de Lange is predominantly a clinical diagnosis by identifying typical dysmorphic features. Labelling a syndromic diagnosis helps to provide genetic counselling to the parents, identify associated co-morbidities at earlier stages and improve the quality of living of such children.

A Novel de Novo Variant in 5' UTR of the NIPBL Associated with Cornelia de Lange Syndrome.

Background: Cornelia de Lange syndrome (CdLS) is a genetic syndrome characterized by intellectual disability, special facial features, growth retardation, feeding difficulties, and multiple organ system abnormalities. NIPBL variants occur in approximately 80% of CdLS cases. Aims: We report a novel de novo heterozygous pathogenic variant in the NIPBL and its association with CdLS. We also examined the key regulatory sequences of the 5′ untranslated region in NIPBL mRNA. Few studies have reported mutation sites in the 5′ untranslated region (UTR) of the NIPBL that result in CdLS. Methods: The patient’s medical history, clinical manifestations, physical examination, laboratory examination, Griffiths development assessment scale—Chinese version, and cardiac B-ultrasound were examined. Mutation screening was conducted using trio whole exome sequencing (trio-WES) and Sanger sequencing. Quantitative PCR was performed to measure the NIPBL expression in peripheral blood mononuclear cells. A Dual-Luciferase reporter assay was conducted to evaluate the transcription of truncated mutants. Results: The proband showed characteristics of CdLS including thick eyebrows, a concave nasal ridge, long and smooth philtrum, downturned corners of the mouth, intellectual disability, postnatal growth retardation, and a short fifth toe. A novel de novo heterozygous pathogenic variant in the NIPBL (c.-467C > T) was identified. A Dual-Luciferase reporter gene assay showed that SPO1 (-490 bp to -360 bp) and SPO3 (-490 bp to -401 bp) induced the highest activity. Conclusions: We found a novel de novo heterozygous pathogenic variant (c.-467C > T) in the NIPBL resulting in CdLS. Our findings expand the spectrum of pathogenic mutations for CdLS. Our in vitro experiments elucidated important regulatory sequences in the 5′ UTR of the NIPBL.