Dysmorphic Facies Research Articles

Clinico-radiological correlation in a case of Schuurs–Hoeijmakers syndrome

Schuurs–Hoeijmakers syndrome is a very rare disease entity presenting as a neuro-developmental disorder with dysmorphic facies and a host of non-specific phenotypes. The diagnosis of this autosomal dominant disorder is made by genetic testing based on high clinical suspicion. Little is known about the radiological findings in such children. Here, we show a case of a 7-year-old boy diagnosed by whole exome sequencing and portray the various radiological and clinical findings that he presented with.

A novel variant BCL11B mutation in a pediatric patient with difficult‐to‐treat eosinophilic esophagitis

AbstractEosinophilic esophagitis (EoE) is an immunoinflammatory disease of the esophagus attributable to a complex interaction between genetic and environmental factors. While several genetic risk variants have been linked with EoE, we report a novel association between B‐cell lymphoma/leukemia 11B genetic mutation in a child with dysmorphic facies, developmental delays, atopic comorbidities, and difficult‐to‐treat EoE. After a prolonged course of EoE and multiple esophagogastroduodenoscopies with biopsies, this patient achieved clinical and histologic remission on a combination of swallowed topical steroids and high‐dose proton pump inhibitor (PPI) therapy. However, her EoE relapsed when we attempted to wean her off PPI, and it was finally controlled after adding PPI back to her regimen. This report underscores the importance of genetic testing in patients with unusual clinical features and difficult‐to‐treat EoE. Relevant to real‐world clinical practice, this case also raises the question of the treatment goals in children with EoE and underlying genetic mutation(s).

Complete Pentalogy Of Cantrell: Case Report And Review Of Literature

Introduction: Pentalogy of Cantrell (POC) is a rare congenital anomaly with two sub-categories: complete or partial. Complete has all five defects (anterior diaphragmatic defect, ventral abdominal wall defect, pericardial defect, intracardiac anomalies, and lower sternal defect). The first documented case was described by Cantrell et al. in 1958. Both sporadic and genetic causes have been proposed for POC, with a reported incidence of 5 - 10 cases per one million live births and various clinical presentations. The prognosis of POC depends on the severity of the defects and the associated cardiac anomalies. This case report seeks to increase awareness of this condition, emphasize the need for appropriate counselling in our environment, and review the literature on previous reported cases’ outcomes. Case Presentation: A 5-hour-old term female neonate was referred to our Children Emergency Center with multiple defects (ectopia cordis, sternal cleft, omphalocele, and limb abnormalities) with dysmorphic facies. A diagnosis of POC was made, and multidisciplinary management was instituted. The eviscerated heart and epigastric omphalocele were dressed and evaluated for palliative surgical care. However, she developed complications with sepsis and electrolyte derangements and died from multi-organ failure before any surgical intervention could be carried out. Conclusion: Though rare, the Pentalogy of Cantrell in its classical form does occur in our environment. The presence of extracardiac and limb deformities worsens the outcome. Based on poor outcomes, there is a need to emphasize appropriate antenatal and postnatal assessments to provide effective counselling on termination, neonatal palliative care, and surgical repairs as appropriate.

Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review.

Noonan syndro me is a rare autosomal dominant congenital abnormality associated with a gene defect located on the short arm of chromosome 12. It is characterized by dysmorphic facies, webbed neck, short stature, lymphatic obstruction, cardiac anomalies, and intellectual disability. Prenatal diagnosis of Noonan syndrome is rare because there are no pathognomonic sonographic signs. Studies on the prenatal sonographic features of Noonan syndrome have been reported in very limited numbers. This case series of severe fetal Noonan syndrome, together with a literature review, was conducted to establish prenatal sonographic features highly suggestive of Noonan syndrome to facilitate early detection by clinicians. This study reveals that Noonan syndrome has a relatively specific pattern, which facilitates prenatal molecular genetic diagnosis. Increased nuchal translucency (NT) in the late first trimester and fluid collection in the early second trimester could be warning signs for follow-up, prompting further investigation to detect late-onset features and leading to molecular genetic confirmation. Most structural abnormalities appear in the second trimester, with progressive changes noted throughout gestation. This review better characterizes the sonographic features of fetal Noonan syndrome based on a larger sample size, illustrating a wider spectrum of prenatal phenotypes, including lymphatic drainage disorders, cardiac abnormalities, polyhydramnios, and absent ductus venosus.

Intermediate phenotype between CMT2Z and DIGFAN associated with a novel MORC2 variant: a case report

Charcot-Marie-Tooth disease type 2Z is caused by MORC2 mutations and presents with axonal neuropathy. MORC2 mutations can also manifest as developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). We report a patient exhibiting an intermediate phenotype between these diseases associated with a novel MORC2 variant. A literature review revealed that the genotype‒phenotype correlation in MORC2-related disorders is complex and that the same mutation can cause a variety of phenotypes.

Novel mutation identified in CONT3 causes IDDSADF: a case report and literature review.

The carbon catabolite repression 4-negative on TATA-less transcription complex subunit 3 gene (CONT3) plays a key role in regulating the mRNA transcription and protein translation of other genes. Mutations in CONT3 have also recently been implicated as a causative factor of intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF). However, to date, only a few CONT3 mutations have been reported to be associated with IDDSADF-related diseases. In the present case, we report a Chinese patient with developmental delay, verbal regression, and facial dysmorphism, in whom cerebral magnetic resonance imaging showed an expansion of the lateral ventricle. The patient was diagnosed with an IDDSADF-related disease caused by a de novo c.1616_1623del mutation in exon 14 of CONT3, which was confirmed by whole-exome sequencing and direct Sanger sequencing. This case report is the first known documentation of a pathogenic mutation at the c.1616_1623del locus of CONT3 in the worldwide population. It provides a critical theoretical basis for the specific gene-based diagnosis of IDDSADF-related diseases and expands the mutation profile of CONT3.

COEXISTENCE OF GOLDENHAR SYNDROME WITH JUVENILE IDIOPATHIC ARTHRITIS: A CAUSAL LINK OR MERE COINCIDENCE?

Goldenhar syndrome, a rare congenital anomaly primarily affecting the face, external ear and vertebrae, and juvenile idiopathic arthritis (JIA), a chronic inflammatory disease in children under 16, represent distinct and uncommon clinical entities. We report the case of a five-and-a-half-year-old girl, with a history of treated congenital hip dislocation, admitted for persistent joint pain for over 6 months, affecting both knees, wrists and ankles with inflammatory signs without associated visceral manifestations. Clinical examination revealed a dysmorphic facies characteristic of Goldenhar syndrome, including facial asymmetry with mandibular hypoplasia, auricular anomalies such as a bilateral pre-tracheal appendix, an acrochordon on the right cheek, a pre-auricular sinus, microtia, and a closed right external auditory canal. A lumbar scoliosis was also identified on dorsolumbar spine imaging, with a CT scan of the rock that objectified an imperforation of the right external auditory canal and lack of visualization of the tympanic membrane, consolidating the diagnosis of Goldenhar syndrome.Biologically, the patient presented with inflammatory anemia with a moderate inflammatory syndrome, as well as hypergammaglobulinemia detected by protein electrophoresis. Tests for antinuclear antibodies and rheumatoid factor were negative (15 IU/mL). X-rays of the affected joints were taken, and the diagnosis of Idiopathic Juvenile Arthritis was retained after eliminating all differential diagnoses. This unusual coexistence raises complex diagnostic and therapeutic challenges, requiring a multidisciplinary approach and ongoing surveillance for comprehensive management.

The lethal homozygous variant in the ATP1A2 gene is associated with FARIMPD syndrome phenotypes in newborns.

FARIMPD (Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies) syndrome is a severe condition caused by ATP1A2 gene variants. The syndrome's novelty and rarity have limited its clinical and molecular knowledge. This research tries to provide new insight by investigating the cause of the early deaths due to FARIMPD syndrome in a particular family and reviewing previous studies. DNA and RNA were extracted from the blood samples of newborns and their parents, followed by whole exome sequencing and segregation analysis. A pathogenic homozygous nonsense variant (c.1234C > T: p.Arg412*) in the ATP1A2 gene was found in newborns. This variant is reported as homozygous for the first time. The migraine symptoms were the result of the heterozygous state of this particular variant, which supported the dominant inheritance pattern of this disease. Real-time PCR was used to analyze ATP1A2 gene expression in the newborns compared to parents and control subjects. The expression analysis also showed significant mRNA degradation in the newborns compared to heterozygous and healthy individuals, due to Nonsense-mediated mRNA Decay phenomena. Our study describes an ATP1A2 nonsense variant (c.1234C > T) that appears compatible with infant survival in the heterozygous and compound heterozygous states but is lethal in the homozygous state.

Deciphering the etiology of undiagnosed ocular anomalies along with systemic alterations in pediatric patients through whole exome sequencing

Inherited and developmental eye diseases are quite diverse and numerous, and determining their genetic cause is challenging due to their high allelic and locus heterogeneity. New molecular approaches, such as whole exome sequencing (WES), have proven to be powerful molecular tools for addressing these cases. The present study used WES to identify the genetic etiology in ten unrelated Mexican pediatric patients with complex ocular anomalies and other systemic alterations of unknown etiology. The WES approach allowed us to identify five clinically relevant variants in the GZF1, NFIX, TRRAP, FGFR2 and PAX2 genes associated with Larsen, Malan, developmental delay with or without dysmorphic facies and autism, LADD1 and papillorenal syndromes. Mutations located in GZF1 and NFIX were classified as pathogenic, those in TRRAP and FGFR2 were classified as likely pathogenic variants, and those in PAX2 were classified as variants of unknown significance. Protein modeling of the two missense FGFR2 p.(Arg210Gln) and PAX2 p.(Met3Thr) variants showed that these changes could induce potential structural alterations in important functional regions of the proteins. Notably, four out of the five variants were not previously reported, except for the TRRAP gene. Consequently, WES enabled the identification of the genetic cause in 40% of the cases reported. All the syndromes reported herein are very rare, with phenotypes that may overlap with other genetic entities.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders

BackgroundNeurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. MethodsWe enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. ResultsWe studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. ConclusionsOur study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

Unraveling DREAM-PL: A Case Report on Challenges and Management

An uncommon autosomal recessive condition called DREAM-PL syndrome is typified by dysmorphic facial features, renal agenesis, male ambiguous genitalia, microcephaly, polydactyly, and lissencephaly. The CTU2 gene, which is in charge of tRNA post-transcriptional modification, is mutated in the syndrome. This alteration is necessary for the correct translation of genes, and its disruption can result in several aberrant embryonic processes. The severity of DREAM-PL syndrome can vary from moderate to severe, and the clinical characteristics can be diverse. While some patients may exhibit only some of the distinguishing features, others may have all of them. The most common characteristics include ambiguous genitalia, dysmorphic facies, and microcephaly. Diagnosis of DREAM-PL syndrome is typically based on clinical signs and confirmed through genetic testing, which can identify mutations in the CTU2 gene. Material and methodology: In the case being referred to as a study, a 37-week-old male neonate was delivered by lower segment cesarean section. The baby's birth weight was 2.760 Kg, and a heterozygous CMP mutation of the CTU2 gene was confirmed through whole-exome sequencing (WES). Unfortunately, there is currently no known cure for DREAM-PL syndrome. Result: Treatment focuses on managing the symptoms and providing supportive care. In some cases, surgical correction of birth defects may be beneficial.

FBXO11 variants are associated with intellectual disability and variable clinical manifestation in Chinese affected individuals.

F-box protein 11 (FBXO11) is a member of F-Box protein family, which has recently been proved to be associated with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA, OMIM: 618089). In this study, 12 intellectual disability individuals from 5 Chinese ID families were collected, and whole exome sequencing (WES), sanger sequencing, and RNA sequencing (RNA-seq) were conducted. Almost all the affected individuals presented with mild to severe intellectual disability (12/12), global developmental delay (10/12), speech and language development delay (8/12) associated with a range of alternate features including increased body weight (7/12), short stature (6/12), seizures (3/12), reduced visual acuity (4/12), hypotonia (1/12), and auditory hallucinations and hallucinations (1/12). Distinguishingly, malformation was not observed in all the affected individuals. WES analysis showed 5 novel FBXO11 variants, which include an inframe deletion variant, a missense variant, two frameshift variants, and a partial deletion of FBXO11 (exon 22-23). RNA-seq indicated that exon 22-23 deletion of FBXO11 results in a new mRNA structure. Conservation and protein structure prediction demonstrated deleterious effect of these variants. The DEGs analysis revealed 148 differentially expressed genes shared among 6 affected individuals, which were mainly associated with genes of muscle and immune system. Our research is the first report of FBXO11-associated IDDFBA in Chinese individuals, which expands the genetic and clinical spectrum of this newly identified NDD/ID syndrome.

New Discovery of a Rare Robertsonian Translocation (15;22) - A Case Report from India

The rob(15;22) is one of the rarest translocations which accounts for only 0.6% of the entire Robertsonian translocations reported in humans. A case of rob(15;22) in association with trisomy 21 still has not been reported. In the present study, a case of a 3-year 6-month-old male child with rob(15;22) with trisomy 21 is focused. The phenotype comprises generalized hypotonia, delayed developmental milestones, simian crease, dysmorphic facies, etc. Chromosome analysis with peripheral blood was executed and the karyotype was interpreted as 46,XY,der(15;22)(q10;q10)+21. To analyse whether the chromosomal translocation was de-novo or inherited, the chromosome analysis with the peripheral blood of his parents was performed. The karyotype of the father was interpreted as 46,XY, and of the mother was 45,XX,der(15;22). It was concluded that the rob(15;22) was inherited from his mother, although trisomy 21 was a de novo incidence. Hence, this case study can be proven useful in the understanding of rob(15;22) in solo and rob(15;22) in association with trisomy 21.

A novel variant in NSUN2 causes intellectual disability in a Chinese family

NSUN2-intellectual disability syndrome, also known as intellectual disability type 5 (MRT5), is an autosomal recessive disorder that is characterized by intellectual disability (ID), postnatal growth retardation, dysmorphic facies, microcephaly, short stature, developmental delay, language impairment and other congenital abnormalities. The disease is caused by mutations in the NSUN2 gene, which encodes a tRNA cytosine methyltransferase that has an important role in spindle assembly during mitosis and chromosome segregation. In this study, we recruited a family that had two individuals with ID. Whole exome sequencing was performed to identify a homozygous frameshift variant (c.1171_1175delACCAT(p.Thr391fs*18*)) in NSUN2 (NM_017755.5) in the proband. The varint was confirmed as segregating in his affected brother and his parents by Sanger sequencing. The individuals that we described showed a similar dysmorphology profile to that associated with MRT5. To analyze the correlations between genotypes of NSUN2 and phenotypes of individuals with ID, we examined 17 variants and the associated phenotypes from 32 ID individuals in current and previous studies. We concluded that mutations in NSUN2 cause a wide range of phenotypic defects. Although some clinical manifestations were highly variable, the core phenotypes associated with NSUN2 mutations were dysmorphic facies, microcephaly, short stature, ID, growth restriction, language impairment, hypotonia and delayed puberty. Our study expands the genetic spectrum of NSUN2 mutations and helps to further define the genotype-phenotype correlations in MRT5.

Ethmocephaly: a rare but lethal congenital anomaly

Ethmocephaly is a rare but lethal congenital anomaly. Its incidence rate is 1 in 15,000 live births and 1 in 250 in abortuses. Babies have typical dysmorphic facies in form of orbital hypotelorism, proboscis and low set malformed ears. 32 years old, daily wage labourer delivered a baby with ethmocephaly. Baby had typical facies, and no extracranial abnormality present. Baby was stillborn. She had no antenatal checkup or ultrasonogram done. However, she had history of ingestion of certain plants during early months of pregnancy. Ethmocephaly is a lethal anomaly and mostly eliminated prenatally. Although there is no diagnostic test for ethmocephaly, and confirmation of it is done only by appearance of baby after birth, important clues like recognition of risk factors like maternal diabetes, alcohol intake, ingestion of certain plants, antenatal hydrocephalus, should not be missed. Importance of routine antenatal checkup and ultrasonogram is emphasized. Recognition of risk factors and a possible co-relation with ingestion of certain other plants is also emphasized.

Biallelic OTUD6B variants associated with a Kabuki syndrome-like disorder in three siblings: A clinical report and literature review.

Biallelic variants in the OTUD6B gene have been reported in the literature in association with an intellectual developmental disorder featuring dysmorphic facies, seizures, and distal limb abnormalities. Physical differences described for affected individuals suggest that the disorder may be clinically recognizable, but previous publications have reported an initial clinical suspicion for Kabuki syndrome (KS) in some affected individuals. Here, we report on three siblings with biallelic variants in OTUD6B co-segregating with neurodevelopmental delay, shared physical differences, and other clinical findings similar to those of previously reported individuals. However, clinical manifestations such as long palpebral fissures, prominent and cupped ears, developmental delay, growth deficiency, persistent fetal fingertip pads, vertebral anomaly, and seizures in the proband were initially suggestive of KS. In addition, previously unreported clinical manifestations such as delayed eruption of primary dentition, soft doughy skin with reduced sweating, and mirror movements present in our patients suggest an expansion of the phenotype, and we perform a literature review to update on current information related to OTUD6B and human gene-disease association.

Novel In-Frame Deletion CNOT3 Variant in a Family With Intellectual Developmental Disorder With Speech Delay and Dysmorphic Facies

Novel In-Frame Deletion <i>CNOT3</i> Variant in a Family With Intellectual Developmental Disorder With Speech Delay and Dysmorphic Facies

Exploring Genetic Testing for Rare Disorders of Obesity: Experience and Perspectives of Pediatric Weight Management Providers.

Background: This study describes experiences and perspectives of pediatric weight management (PWM) providers on the implementation of genetic testing for rare causes of obesity. Methods: Purposive and snowball sampling recruited PWM providers via email to complete a 23-question survey with multiple choice and open-ended questions. Analyses include descriptive statistics, Fisher's exact test, one-way ANOVA with Tukey's post hoc test, and qualitative analysis. Results: Of the 55 respondents, 80% reported ordering genetic testing. Respondents were primarily physicians (82.8%) in practice for 11-20 years (42%), identified as female (80%), White (76.4%), and non-Hispanic (92.7%) and provided PWM care 1-4 half day sessions per week. Frequently reported patient characteristics that prompted testing did not vary by provider years of experience (YOE). These included obesity onset before age 6, hyperphagia, dysmorphic facies, and developmental delays. The number of patient characteristics that prompted testing varied by YOE (p = 0.03); respondents with 6-10 YOE indicated more patient characteristics than respondents with >20 YOE (mean 10.3 vs. mean 6.2). The reported primary benefit of testing was health information for patients/families; the primary drawback was the high number of indeterminate tests. Ethical concerns expressed were fear of increasing weight stigma, discrimination, and impact on insurance coverage. Respondents (42%) desired training and guidance on interpreting results and counseling patients and families. Conclusions: Most PWM providers reported genetic testing as an option for patient management. Provider training in genetics/genomics and research into provider and family attitudes on the genetics of obesity and the value of genetic testing are next steps to consider.

Arthrogryposis Renal Dysfunction Cholestasis Syndrome: An Uncommon Presentation in a Newborn

A preterm baby born at 35 weeks of gestation was noted to have severe limb deformities suggestive of arthrogryposis along with dysmorphic facies and developed seizures, renal dysfunction in addition to cholestasis. MRI brain showed corpus callosum agenesis. Although there are several isolated cases of arthrogryposis, the association with other congenital anomalies are rarely seen. The constellation of anomalies noted in this case along with renal tubular dysfunction and direct hyperbilirubinemia with normal GGT is suggestive of Arthrogryposis renal dysfunction Cholestasis (ARC) syndrome. It is a very rare autosomal recessive multisystem disorder resulting from mutations in the vacuolar protein sorting 33B (VPS33B) or VPS33B-interacting protein, and apical-basolateral polarity regulator (VIPAR) genes. This disorder is associated with a very poor prognosis with children seldom surviving beyond 1 year of age necessitating a detailed genetic evaluation to identify the various mutations and appropriate genetic counselling.

Mermaid baby: Fairy tale in practical

Sirenomelia, also called Mermaid syndrome is a rare and fatal anomaly which is characterized by a single lower extremity featuring a Mermaid like appearance where head and trunk is like humans and lower extremity is like tail of a fish. It is associated with other gastro-intestinal, genito-urinary and other organ abnormalities. Most patients die shortly after birth. The exact cause of Sirenomelia is unknown. Here we present a newborn baby with Sirenomelia. Mother had bad obstetric history, antenatal ultrasonography revealed severe oligohydramnios and renal agenesis. On examination there was dysmorphic facies, fusion of lower limbs, single leg with two foot and ten toes. There was no identical external genitalia and anus.