Abnormal Facies Research Articles

A Growth-Restricted Neonate with Abnormal Facies and Lax Skin.

A Growth-Restricted Neonate with Abnormal Facies and Lax Skin.

Multiple congenital anomalies in a late-preterm neonate: A case of possible carbimazole embryopathy

ABSTRACT The use of carbimazole in the treatment of hyperthyroidism in pregnant women is associated with several congenital anomalies, especially when used during early pregnancy. Some of the reported congenital anomalies include aplasia cutis congenita, choana/esophageal atresia, facial dysmorphism, and cardiovascular/gastrointestinal anomalies. We report the case of a 17-day-old late-preterm neonate who presented with complaints of difficulty in breathing, darkening of the lips/extremities, and abnormal facies observed since birth. The mother had been on tablet carbimazole 20 mg daily for the treatment of hyperthyroidism until the fifth week of gestation from the time she was confirmed to be pregnant. Physical examination and further evaluations revealed multiple congenital anomalies, including facial dysmorphism, bilateral arthrogryposis of the lower limbs, micropenis, complex congenital heart disease, and intestinal obstruction. This case report, therefore, highlights the need to avoid the use of imidazole derivatives such as carbimazole during the pre-conception period as well as in the first trimester of pregnancy.

Cases of Digeorge Syndrome

Abstract DiGeorge syndrome is a primary immunodeficiency caused by the abnormal growth of the third and fourth pharyngeal pouches throughout prenatal development. It is typified by a triad: hypocalcemia due to hypoparathyroidism, some heart defects, and thymic hypoplasia or aplasia. This syndrome is associated with a microdeletion in the chromosomal region 22q11.2. DiGeorge syndrome together with other dysfunctions like velo-cardio-facial syndrome and Takao syndrome have overlapping traits. The symptoms are hidden under the name CATCH22. It describes signs like a cardiac defect, abnormal facies, thyme hypoplasia, cleft palate, hypocalcemia, and chromosome 22q11.2 deletions. Its incidence is estimated to be approximately 1:3000 live births. The disorder is inherited in an autosomal dominant pattern or arises from de novo mutation. 22q11.2 microdeletion is associated with an increased risk of developing mental diseases, including schizophrenia. In the general population, 1-2% of people suffer from schizophrenia. In DiGeorge syndrome this ratio is much higher, around 25-30%. Nowadays, the fluorescence in situ hybridization (FISH) is a gold standard method for the diagnosis of microdeletion syndrome. Currently, there is no effective therapy to prevent the development of the disease.

THROMBOCYTOPENIA, HYPOGAMMAGLOBULINEMIA, AND POOR VACCINE RESPONSE IN A PATIENT WITH TAKENOUCHI-KOSAKI SYNDROME

<h3>Introduction</h3> Takenouchi-Kosaki Syndrome (TKS) is a rare congenital developmental disorder characterized by thrombocytopenia, facial abnormalities, and varied multisystemic anomalies including immunodeficiency. Heterozygous deficiency of CDC42, an intracellular signaling GTPase, has been found in all TKS patients described to date. The immunological phenotypes of TKS patients are heterogeneous: recurrent infections have been noted in some patient series but with variable penetrance. Herein we describe a case of TKS causing hypogammaglobulinemia, B-cell lymphopenia, and poor vaccine response. <h3>Case Description</h3> A fifteen-year-old girl with history of developmental delay, multiple congenital defects, and lymphedema was referred to the immunology clinic for evaluation of recurrent ear infections that began at 3 months of age requiring tympanostomy tube placement at 18 months. Her physical exam was notable for abnormal facies, scoliosis, strabismus, abnormal thumbs, and unilateral lymphedema. Her laboratory evaluation revealed macrothrombocytopenia, mild leukopenia with low T-cells and markedly low B-cells by flow cytometry, and notably low IgA (11.7, RR 69 – 309) and IgG (423, RR 613 – 1295). She had a poor response to a full course of PCV7 with PPSV23 booster (9 of 23 > 1.3). Whole exome sequencing identified a heterozygous p.Y64C mutation in CDC42 consistent with TKS. <h3>Discussion</h3> The Y64C mutation in CDC42 is a TKS Group I lesion causing ineffective intracellular signaling, resulting in <i>in vitro</i> defects including abnormal cellular proliferation and disruption of cell polarity. Actin remodeling disorders such as Wiskott-Aldrich Syndrome and TKS should be considered in patients with immunodeficiency and congenital thrombocytopenia.

Rubinstein–Taybi syndrome: a case report

Rubinstein Taybi syndrome (RTS) is a rare genetic condition caused by a mutation or deletion in the CREBBP and/or EP300 gene located on chromosome 16. It is characterized by short stature, moderate to severe learning difficulties, distinctive facial features and broad thumbs and toes. It occurs in estimated 1 in 1,25000 to 3,00000 births. Diagnosis mainly depends upon the presence of distinctive features, abnormal facies, abnormalities of limbs. These patients are also at increased risk of developing meningioma, other brain tumours and leukaemia, thus early diagnosis and recognition of malignancy can aid in successful life-saving interventions.

OA25 Constitutional trisomy 8 mosaicism is associated with a paediatric incomplete Bechet’s-like phenotype

Introduction/BackgroundBehcet’s disease is a rare paediatric diagnosis and to date there is no single confirmatory gold-standard test or approach. Instead, decisions are clinician-led based on experience, pattern recognition and categorisation according to international criteria. Diagnostic dilemmas arise when patients present at early ages with an incomplete or atypical phenotype. Such cases should prompt clinicians to consider Bechet-like mimics with emphasis of monogenetic and chromosomal causes in younger children.Description/MethodA 5-year-old boy with constitutional Trisomy 8 mosaicism was referred to a Bechet’s disease National Centre of Excellence paediatric clinic with cyclical episodes of fever, mouth ulcers, pseudofolliculitis and headaches.During the initial outpatient assessment period (6-12 months) symptoms were reported every 2-3 months and would last for around 1-2 weeks at a time. Physical examination and a photo diary reveal oral ulcers and rashes. He had pre-existing skeletal dysmorphism with severe pectus carinatum, scoliosis and widespread limb contractures secondary to Trisomy 8. Serial blood testing around episodes showed an associated inflammatory response.Although his phenotype was incomplete; with evidence of recurrent autoinflammation a trial of immunosuppression with colchicine was commenced. He displayed a dose-dependent improvement as evidenced by reduction in the frequency and severity of episodes.His Behcet’s-like disease remains well controlled and to date there has been no amyloidosis, ocular, gastrointestinal or cardiovascular complications.Discussion/ResultsBehcet’s disease is a multisystem chronic vasculitis presenting with widespread mucosal involvement occurring in a relapsing-remitting fashion. Classic manifestations are recurrent sterile aphthous ulcers, genital ulcers, mucosal eye involvement and a positive Pethargy test.It usually presents with all of these classic features by the 3rd or 4th decade of life; children can be affected but usually present with paucity of symptoms not reaching diagnostic criteria. As such, the accumulation of symptoms during a follow-up period may lead to a diagnostic lag of around 3-5 years. The young age of this patient therefore raised clinical suspicion for an alternative diagnosis.The aetiology of Bechet’s disease has elucidated rheumatologists since the first description in 1937. An association with HLA-B51 antigen is well documented but not fully understood. The advent of widely available next-generation genetics provides important clues to its aetiology and helps delineate monogenic and chromosomal mimics. To date 21 genetic loci have been identified through genome-wide association studies and least 11 monogenic and chromosomal mimics been described in the literature.Constitutional Trisomy 8 mosaicism has been shown to be a chromosomal-driven mimic of Behcet disease. It is rare (1-25.000 to 1-50.000 live births) with a 5:1 male predilection; those affected present with a spectrum of abnormal facies, vertebral and limb anomalies including contractures.Interestingly a similar Bechet-like disease is also seen in patients who acquire Trisomy 8 mosaicism in cells affected by myeloid malignancies. Such cases are more numerous and predate those associated with the constitutional form.The final common pathogenesis is thought to be activation of the NF-κB pathway. Reports postulate overexpression of several cytokine genes, production of proinflammatory cytokines and reactive oxygen species. The exact pathogenesis is not fully understood, further research may reveal clues to understanding both Constitutional Trisomy 8 mosaicism and Behcet Disease.Key learning points/ConclusionLearning points:1. Consider monogenic and chromosomal Behcet Disease mimics in those patients who present at young ages or at any time with atypical or incomplete features.2. Our patient with Constitutional Trisomy 8 Mosaicism with Behcet-like disease showed a dose-dependent improvement with colchicine.

Intracranial Vascular Tortuosity in an Infant With Dysmorphic Facies

A 17-month-old female with a history of pulmonary artery stenosis, diminutive descending aorta, abnormal facies, but no extracranial tortuosity was evaluated in a child neurology clinic for mild motor developmental delay. She was born at term, weighing 2.8 kg (22nd percentile), with a head circumference of 33 cm (10th percentile). The patient sat upright at 9 months, crawled at 12 months, and had not begun walking. She was cruising at the time of evaluation. Language and social development were normal.

De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.

Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.

The RASopathies: Biology, genetics and therapeutic options.

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies.

Rhizomelic limb shortness and abnormal facies: short stature syndrome sharing some manifestations with robinow syndrome

In children, short stature and disproportionate skeletal growth are associated with many syndromes and these syndromes have characteristic radiological changes which help in their diagnosis. However, many of them have no well-defined diagnostic criteria, and thus overlap between apparently distinct syndromes is common. Here, we report a child with characteristic features seen distinct from any other dwarfing syndrome known to us with some of the features similar to Robinow syndrome. Newborn had a broad and prominent forehead, mid-face hypoplasia, hypertelorism, flat nasal bridge, upturned nose, elongated philtrum, protruding tongue, single crease in the left hand, widely spaced nipple, brachydactyly in lower limbs, and disproportionately short rhizomelic upper and lower limbs. Based on these features, a diagnosis of Robinow syndrome was made. The case was the first of his kind admitted to our institute. The diagnosis was made clinically after follow-up.

The Neuropathology of 1p36 Deletion Syndrome: An Autopsy Case Series

1p36 deletion syndrome is the most common terminal deletion syndrome, manifesting clinically as abnormal facies and developmental delay with frequent cardiac, skeletal, urogenital, and renal abnormalities. Limited autopsy case reports describe the neuropathology of 1p36 deletion syndrome. The most extensive single case report described a spectrum of abnormalities, mostly related to abnormal neuronal migration. We report the largest published series of 1p36 autopsy cases, with an emphasis on neuropathologic findings. Our series consists of 3 patients: 2 infants (5-hours old and 23-days old) and 1 older child (11 years). Our patients showed abnormal cortical gyration together with a spectrum of neuronal migration abnormalities, including heterotopias and hippocampal abnormalities, as well as cerebellar hypoplasia. Our findings thus support the role of neuronal migration defects in the pathogenesis of cognitive defects in 1p36 deletion syndrome and broaden the reported neuropathologic spectrum of this common syndrome.

Utility of Immunohistochemistry and Western Blot in Profiling Clinically Suspected Cases of Congenital Muscular Dystrophy.

Objective:Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort.Materials and Methods:This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,β1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed.Results:The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-β1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker–Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation.Conclusion:The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

Inherited Cholestatic Diseases in the Era of Personalized Medicine.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-mack a video presentation of this article.

Day 0–28 of Human Embryonic Development: Importance of Studying Cell and Tissue Interactions in Head and Heart Development

All vertebrates start their development from a zygote and the processes from this cell to a complex organism are often complicated and include many gene regulatory networks, cell migrations, cell differentiations, communication between cells and between tissues, etc. Earliest mis‐regulations in those processes lead almost always to the demise of the developing embryo – often before the women even realizes she is pregnant. This is because the most exciting and complex processes related to body plan formation happen during the first 8 weeks of embryonic development. Even more fascinating is that at the end of the first months (28 days after fertilization) the head and heart region are clearly distinguishable: the heart is beating, u‐shaped and atria and ventricles are aligned, the pharyngeal arches are present, as are eye and ear anlagen (placodes), in the brain several regions are distinct, including forebrain, midbrain, and hindbrain. There are many remarkable research groups all over the world studying one or the other system (brain, cardiovascular, craniofacial), but only few groups study the interactions between all tissues (ectoderm, mesoderm, endoderm – neural crest as special tissue derived from ectoderm). However, understanding precisely those interactions during earliest and later development will help us to understand human syndromes with the same underlying genetic defect but that present with a huge variety of phenotypes.For example, the DiGeorge Syndrome is caused by a deletion of a region at 22q11.2 that contains 30–40 genes. Due to its involvement of several system it is also called CATCH22 – Cardiac anomalies, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia. Each of those abnormalities could be caused by the involvement of cranial neural crest cells during embryonic development, even the heart anomalies as cardiac neural crest cells are part of the posterior population of cranial neural crest cells. Also, in the region of the 22q11.2 is the Tbx1 gene that was shown to be essential during earliest cardiopharyngeal mesoderm development and differentiation. The cardiopharyngeal field is a progenitor field that gives rise to the first heart field and the pharyngeal mesoderm. The latter will differentiate into the second heart field derived cardiac musculature and the branchiomeric (head) muscles. Yet, neither our knowledge of neural crest cell involvement nor our understanding of cardiopharyngeal mesoderm development, fully explains the variety of symptoms seen in DiGeorge Syndrome patients.Therefore, a detailed summary of what is currently known about the first 28 days of head and heart development and the tissue interactions will help us to understand complex syndromes. Furthermore, it will be possible to identify regions that need more research focus. Last, but not least, a better understanding of our own developmental processes also provides insights into evolutionary processes and studying animal developmental processes further contributes to a deepened knowledge of the evolutionary development of our own body. Here, I will present a summary of the first 28 days of head and heart embryonic development in humans and highlight regions of research that next generation scientists might be interested in.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Novel Unbalanced Translocations Affecting the Long Arms of Chromosomes 10 and 22 Cause Complex Syndromes with Very Severe Neurodevelopmental Delay, Speech Impairment, Autistic Behavior, and Epilepsy

Isolated abnormalities in terminal regions of chromosomes 10q and 22q were formerly described in patients affected by neuropsychological impairment, abnormal facies, and heterogeneous structural abnormalities of the body. Chromosomes 10q and 22q harbor important genes that play a major role in CNS development, like DOCK1 and SHANK3, and in overall body growth, like FGFR2 and HTRA1. By using clinical, neuroradiological, neurophysiological, and genetic assessment, we studied 3 siblings affected by 2 different forms of very severe neuropsychological impairment with structural physical abnormalities, epilepsy, and body overgrowth. The genetic analysis revealed 2 different unbalanced translocations t(10;22)(q26.13;q13.32) of genetic material between the long arms of chromosomes 10 and 22, deriving from a maternal balanced translocation. Consequences of the unbalanced translocation were the simultaneous partial monosomy of 10q26.13 to 10qter and partial trisomy of 22q13.32 to 22qter in 2 patients and the simultaneous trisomy distal q10 and monosomy distal q22 in 1 patient, respectively. To the best of our knowledge, we here describe for the first time a causal association between an unbalanced translocation t(10;22) affecting the long arms of both chromosomes 10 and 22 and a very severe neurodevelopmental delay in 3 siblings.

Myhre-LAPs syndrome and intubation related airway stenosis: keys to diagnosis and critical therapeutic interventions

ObjectivesMyhre-LAPS syndrome is a recently recognized disease caused by a mutation in the SMAD4 gene. This results in a range of pathology including laryngotracheal stenosis, arthropathy, prognathism and short stature, or LAPS syndrome. We aim to delineate the role of intubation in development of airway stenosis in these patients as well as provide insight into diagnosis and management of this syndrome. Herein we present four patients with Myhre-LAPS syndrome complicated by airway stenosis and perform a systematic review of all cases of Myhre-LAPS syndrome with reported airway pathology. Study designRetrospective review MethodsAll patients diagnosed with Myhre-LAPS syndrome and airway stenosis at a single institution from 1981 to 2014 were reviewed. ResultsFour patients (4F, median age 42) were identified that met inclusion criteria. Initial presenting signs included progressive shortness of breath, dyspnea on exertion and respiratory distress. All four (100%) patients had multi-level airway stenosis most commonly in the subglottic and glottic regions and all patients had undergone at least one endotracheal intubation prior to presentation. One patient with a history of nasal tracheal intubation presented with nasal obstruction and was found to have choanal as well as subglottic stenosis. Two of the four (50%) patients are tracheostomy tube dependent, 1/4 (25%) died of a fatal cardiac arrhythmia and 1/4 (25%) has had 6 endoscopic treatments for subglottic stenosis in 4 years with rapid symptom recurrence. ConclusionsMyhre-LAPS syndrome is characterized by progressive systemic fibrosis and patients are diagnosed by characteristic findings of prognathism, short stature, abnormal facies, and thick skin among other abnormalities. Airway management is complicated by recurrent, refractory subglottic stenosis often preceded by elective intubation as well as maxillary hypoplasia, trismus, and limited neck extension. Endotracheal intubation and surgical intervention should be approached with caution in these patients and multidisciplinary care teams are necessary to address all manifestations of this syndrome.

Filippi Syndrome: Report of a Rare Case

Filippi syndrome is an autosomal recessive condition characterized by syndactyly of fingers and toes, microcephaly, growth retardation and abnormal facies. We are describing a boy who presented with syndactyly, mental retardation, microcephaly, depressed nasal bridge and growth retardation. In addition he had some dental abnormalities like missing bilateral lateral incisors and delayed eruption of teeth. We concluded it to be Filippi syndrome by studying pathognomic clinical features and reviewed the literature. This is the second case report from India.

Squared nasal root, nasal voice -indicators of 22 q11.2 deletion in patients with psychiatric illness

Background 22q11.2 Deletion Syndrome DGS (22q11) is a micro deletion syndrome caused by the deletion on chromosome 22. It is a multi system disorder which affects Cardiovascular system, immune system, facial features covered by acronym CATCH22 (Cardiac defects aortic arch anomalies, conotruncal anomalies, ventricular septal defect, patent ductus arteriosis and tetra logy of fallot; Abnormal facies ; Thymic hypoplasia; Hypocalcemia). Few children will not present with all of the above clinical features but only delayed motor mile stones, learning disability and mild behavioral issues which may progress onto psychiatric illness in adulthood. In this study, we aim to study the prevalence of DGS in patients with psychiatric illness.

A case of congenital myopathy masquerading as paroxysmal dyskinesia

Gastroesophageal reflux (GER) disease is a significant comorbidity of neuromuscular disorders. It may present as paroxysmal dyskinesia, an entity known as Sandifer syndrome. A 6-week-old neonate presented with very frequent paroxysms of generalized stiffening and opisthotonic posture since day 22 of life. These were initially diagnosed as seizures and he was started on multiple antiepileptics which did not show any response. After a normal video electroencephalogram (VEEG) was documented, possibility of dyskinesia was kept. However, when he did not respond to symptomatic therapy, Sandifer syndrome was thought of and GER scan was done, which revealed severe GER. After his symptoms got reduced to some extent, a detailed clinical examination revealed abnormal facies with flaccid quadriparesis. Muscle biopsy confirmed the diagnosis of a specific congenital myopathy. On antireflux measures, those episodic paroxysms reduced to some extent. Partial response to therapy in GER should prompt search for an underlying secondary etiology.

Prepenile scrotum- an extreme form of penoscrotal transposition.

A full-term newborn male baby was brought with abnormal genitalia. The baby was a product of non-consanguinous marriage and the antenatal checkups and sonography were unremarkable. The boy had passed urine and meconium before arrival. Baby was warm, pink and active. There was no abnormal facies. Limbs and spine were normal. Local examination (Fig. 1) revealed a normal phallus with meatus at the tip of glans but it was positioned in the perineum between the scrotum and anus. The hemiscrotums were well developed and contained testis on either side. The anus was patent and its site was normal. Sonography of spine,cranium and urinary tracts showed no pathology. Echocardiogram was also normal.